Nelson 2007 Parte 9 y 10 Gen Metab

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Geneticsatl)(.|uman

With the completion of the human genome sequenceand the hap-

lotype map, investrgaciveand diagnostic tools are available to

determine the qenetic contributions to both uncommon and

common disordirs. Information about the genetic aspects of all

pedi ric diseaseshas grown rremendously and is readily avail

able n mufti ple websitesand in other locations Table78-1).

TH E BURDET{ F GENETIC ISOBOEBSN CHI[0H000. Although

mr-rltifacrorialgenetic condition was a major contributor to pedi-

atric hospital admissions (in 1978) in approximately 257o of

patients. The majority of chronic diseases n children has an

obvious genetic component or is influenced by genetic suscepti-

bility. Thirty-four percent of deaths of hospitalized childten are

associatedwith an underlying genetic disorder. Major categories

of genetic disorders rn chrldren include singlegene,chrornosomal,

an d multifactorial condit ions.

lndividualll', single-genedisorders are rare, but collectively they

representatr rmportanccontribution to childhood disease. he y

includedisorders uchas sicklecell anemiaan d cystic6brosis,as

rvell as a myriad of extremely rare conditrons thar have been seen

rn only a few families. Srngle-genedisorders tend to occur when

mutations have a pro{ound effect on function of the gene product.

Sucheffects include product (structural protein, enzyme, rnetabo-

lite) denciency as wellas oss or gain of fLrnction,The phenotypes

associaredwith single-genedisorders can be variable and modi-

6e d by the action of other genesor the envrronment.Th e hall-

cases this is due to rhe founder effect, in which a mutalion

achreves elarively high frequency in population derived from

a small number of Founders hat rem ns closed to rnterbreeding

lvith those outside the populatron- Thrs is the casefor Tay-Sachs

disease n Ashkenazi Jews and French Canadians. Other muta-

resistanceo malaria,Chromosomal disorders such as Down syndrome are assocl_

ated with rhe presenceof an extra copy (trisomy) of chromosome

21 . Only a fe w trisomies ar e compatible with live birth (chro-

mosomes 13. 18. and 21, as well rhe X and Y chromosomes)j

most lead to early miscarriage as a result of severegenetic imbal

ance. Subtle changes of individual chromosome srructure

(rnicrodeletions) hate also been rdentified. Many of these are

associated with disrinctive phenotypes thar can be recognized

clinically; some produce nondescrrpt phenotypes of developmen

ral impairment wirh variable effects on intellect as well as growth

an d physrcalappearance.

Multifactorial inheritance occurs when multiple genesor gene-

environmental effecrs cause a disorder Multifactorial inheritance

in pediatrics is seen with certain congerriral anomalies, such as

spina bifida or cleft lip/palate. These trairs may clusrer rn fa

lies but usually do not segregate n accordance w'ith mende

domrnant or recessive inheritance. The responsrble genesunknown, and genetic counseling is based on empirical data. T

conceot of mulcifactorial rnheritance extends to common dis

ders, iuch as asthma and diabetes mellitus.

THE CHANGINGPARADIGMOFGENETICSN IIiIEDICINE, CIAIi

few genecic disorders were amenable to treatment in the p

management was focused largely on prevention and managem

of chronic illnesses . nborn errors of metabol ism &'ere the f

genetic disorders to be recognrzed; many are amenable to tre

ment by dietary manipulation (seeChapter 84), These condirr

result from genetically determined deficrencyof specific enzym

leading ro the burldr.rp of coxic substrates and/or defciency

crirical end products. The expansion of newborn genetic

metabolic screening includes a much larger array of sc ree

disorders, made possrble by the use of tandem mass spectro

try, permirting detection of a wide vanety of metabolites

a single, inexpensive assay. Expanded newborn scree

will dramatically increase he number of metabolic disor

in children that are amenable to rrearmeflt (see Chapcer

and 94i.ln addit ion co available creening rograms,more therapie

in development for the treatment of many lysosomal storage

orders that were lerhal or associated wrth intracrable chro

illness. The basis or rreatment in this case s enzyme replacem

usrng specially modified enzymes that are administered

intravenous nfusion and are then taken up by cells and inc

purared nto ly'osome:. Condit ions such a, Gau.her drsea.e

Fabry diseaseare rouonely treated; rreatments for others suc

Pompe disease nd mucopolysaccharidosis re in developm

This places an added responsibiliry on the pediatrician to esl ish an early diagnosis,which is a challengegiven rhe ra

of these disorders and relatively nonspec ific naturc of esvmDtoms.

Tlrerapeutic advances are extending to other nonmetabgenetic drsorders as we)1. mprovemenrs in surgical treament

congenitalanomalies uchas hearrdefectsar e excending he vival of children with birth defects or conditions such as Do

syndrome. The life expecrancy of those rvirh cystic fibrosis

steadily ncreased, argely owrng to improvements n antibi

therapy as well as the managementof boch chronic pulmon

drseaseand malabsorpcion. A malor consequenceof th

advances s that affecced ndividuals survive inco adulthood,

aring a need o transirioncare rom pediatric o adult provrd

Gene replacement therapies have long been anticipared, tho

there have been major challenges rn developmenr of safe

effective approaches for the insertion of genes inro disea

rrssuesand achievement of physrologically meamngful level

geneexpression. The advent of therapeutics based on use of s

cells also offers the possibilrtv of rrearmenc for previo

rntractabledisorders.

Longsrandrng and highly successfulcarrier screeningprogra

have existed for disorders such as Tay Sachs disease and m

orher rare, single-genedisorders rhat are prevalent in specifrcp

ulations. Couples are commonly offered screening for a var

of conditions, in parr based on ancestry (Tay-Sachs dise

hemoglobinopathies, ysdc 6brosrs).Couples ound to be at

can be offered prepregnancy or prenatal testing, rvhich is ba

on gen€tic tests aimed at detecrion of specific mutarions.



486x PARTX F HumanGenetics

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ro lc i f l all aspectsof pediatric pracfice. Genctic variationenzyrnes involved iLr drr.rg mctabolisrn underhe differcnccthcrapeunceffecran d roxiciry,arrdshould bc taken lto acci l rhe determinationof clrugdosage.Basecl n their gerlotrl

ferent ndividuirls vil l respond diifcrcnrly to specif icdrugsLoring trearment ro individual variations in clrug rnetaboresponsiveness,nd susceptibil ity o coxiciq rvil l leacl o pe

aiizatronof rnedrcal rcatment. Genetic ests vil l c()nre () nn

lic a high proporcion of all medical decisions an d rvi l

scamlessll ncorporatcd rDto rourine medical care. (ieneric

r- i lLalso be used n predicnve esting br predisposit ion o chro the exteri! lhirt such tesrine can lcad to strafe.qies o llredisease r improve outcome (secChapter 8j).

6EMrlCS ANDPEOIAIRICRACTICE enetics rofcssiooalsT78 2) includcph,vsicians'h o complcre csidenciesn genericarc cerrified by rhc American tsoard of l\.'ledical icrLcrics, enized bv rhc American Board of N' lcdjcalSpecial, ies.GecoLrnselofsccelve l1raste]-'scgrcc n generic ou[s,: l ingardccrtif iedhy rhe \merican Board of (ieneticCouuselitrg. hcr

:1lsonursc-gcneticists ho rccoiveadr.arced rairin.g n gcn

lblLou,ilg complerrono{ nursing educarron.Fo r rare singlc-genedisorders, rhe pcdratriciarru' i l l r

closell rvith specialisrsn many disciplines Tablc 711-3).

agerneur ' i l l focus on achievinga correct diargnosiri,ounsthe family regardingnatural hisroryan d managernelrof theorder as wclL as recurrencc isk, anrl implemenradcn oi a maq r tnc r r t r r r . i l ea t rncn r l rn . A . t he s .o f ' c , ' i t e r r r t r i t eincreases.he pediacrician vill be ncreasingly chelk:ngcd oognize elativcl,vare clisordershat arc amcnable o tr earnreto identifv chiLdren ,! 'ho re ar risk on rhe basisoi f:rrnil) 'hisrvho ma,v of !e t dispLay ymptorns f disease. csrin panelsbe developed or conmoLr, conplex problems.sucl as devmental delav. Somedisorders or lvhich eallv rreafrnenr s ccal nray bc added to novborn or earl,v childhood scrccpatels; ochcrs ,r.rl l e the subjccf oi clinical practice guidc

Fanrily historl n'rll be an incrcastnglv r.aluablc rool to recogchilclren r risk. rvho can be esredend thcn oFiered ersonaapproachesro preventx)r of managemenr.Cicnetic resrs

Lrcreasingly Lndcrlielar

fo ddv treatmcnldccisions or comdisordcrsnor rradit iorrall,v icrvcd as genefrc.

ETHICAI-SSUESGcnctic tescing, iagnosis, rrrd rearmcnt nbe performcd rvirh a hr._ehegree of confidcntialitl. rvojdirg srig,ma or fhe paficnr. (lenetic clscriminafion shorrld bc ilbecause ubdc or nor so subtle elfectsof havine,a persorlfrmil,v gcncrrcdiagnosisma y occasionall_1ffect employrneth c ebilir), ro obtarn healrh or life insuralce. Norhing is sosoual as one'r genetic natcrial.The decision o Lln(ler[ lo ctcsl lng s complicarcd. he tlecisron bout whethcr !() pcfiof

naral tesrirg ls aLsooffered for chromosorral clisordcrssuch

as Do$'n syn(lrome. wich !rn increasing numl)cr of affecredpregnanclcs erng ecognizcd y nonirlvasive clccnl l ls esfs uc h

as matcfl)aiserllnlmarkcr screening Dd cra]ulrrasound.Prenara l diagnosis al be conlirmcd by anuiocenccsis r l6-18 rveeks

er chorionic vil lus sampling at l0-12 weeks. Prcimplantation

gcneticdiagnosis PCD) of earll ' cmbfTos Lr,v nalvsisof srngle

blastorneres an selcctonlv ullaffectcdcmbrvos or implantarron.

Approaches o notrlvasile prcnaral cliagnosis ry samplng ofletal cclls or fefal I)\A in maternal blood are also being devcl-oped irr spccialized aLroratorics.

(;enefic tcstinS s increasingl,v vailable br:r u' ide variety of

borh rerc and rclati! 'clJ cornmon gcnctjc Jlsorders Testingcan

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seletic test on a child is evenmore drfficult, becausehe child

-annot al*ays participate n d iscussions bout the testtng.The

uftimatedecisionhingeson how the resultsoi the test will help

or harm the child. The interestof rhe chrld s always oremost;

thus, open discussionof rhe pros and cons of testingshould

alwayscenreron the chrld's nterests.Molecular diagnosticcests

are often used to diagnosemalformation syndromes,mentalretardation,or orher disabilirieswherein here s a clear benefitto the child. In other cases, he decisronwhether o test a child

is more difficult.Policies egardinggeneric estingof children have been ssuedjointly by the American Societyof Human Genetics nd Ameri-can Collegeof Medical GenetrcsAmerI Htm Genet 1995;57:.1,233-1,241,)nd by the AmericanAcademyof PediatricsPediatr

2001,;107:1,451-1455).he AAP recommendationsnclude the

following:

l. Btablirhedewborneenin{etttthouldeeviewedandevaluatedPedodi(allyto€mit

nodifGtionf heprogramraliminationf neffectiveompon€ntt.henlroductionf

ne* newbom(eeninger$should€ ondudedhrc0gharcfullyonitotedctcarh

ptoto(olr,

2. Ceneti(ertt ikemost iagnostkorarapenk ndeavo6fordildren,requitepn(est I

infomedarentalonrentnd heolder ild3astent.e{,bom(e€ning rogransre

enouragedoevalu.teroto(oknwhkhnfomedntent rom aPnttsobtained.hefirquenq f nfomedefugahhouldemonitored.egeardo mprovefieeffdenq nd

effectiveneltf nfoflnedonrentornatbont(recningt warnnted,

3. The APoer otupportfiebroadi4of adet etting r5(eeningndildrefl radoles-(entr. dditional€readl eedtobe ondwtedn ar d iteening[ dildrcn nd doles'(entr,he rk andbenefittf (adet meningn hepediatti(opulationhoulde

evallatedn(ar€fullymonitoredini(al alsb€t0ret ir offered na hoad ale (arier

irceninqorpregnaltdoles(entrt ot oneadolesrenEntid€nggrcgnanq ay e

appropriate.

L Geneti(eatingoradult-onsetonditiofi enerallyhouldedefertedntil duhhoodr

untilan dolescentnterertedn erting at evelopeduturc edtion'malingap.dtiet.

The APelievesh.tgeneti(testingofdildtenanddoleg(enttoptedictate-ontetitor'

der r nappop tewhenh€geneti(nfomationas ot e€nhowno cduce otbidity

andmortalitythrroughnterventionrnitialedn t ldhood.

5, Becaureeneti((rcelingnd eslinq ay otbewell nde6tood,ediatftianteed0

prcvidearentghe eaessarynformitionnd@unrelingbouth€ imittofgenetknowl'€dge nd reatmentapabilitiei,hepotenthlarmhatmiybedone ygailng ertnin

geneti(ntonnatioDndudingheportibilitietotPty(hologicalanh,tigmatitation,nd

dircrimination,andedi(alonditiongnd itabilitynd otentialrcatmeiBnd eryi(e!

fordildrciwith eneti(onditiont-ediatftiantnnbe 5sittednninaging any f h€(omplex!ru6 nvolvedngenetk€tting , (ollaboBtionith enetkittg,amtkoun_

reloE,nd renatalcarercvideE.

5. The APupporbhe lp.nsion[educationalpportunitietnhumanenaticotmedi(il

rtudents,esidentr,nd radi(ingiytidantnd heexpantioif rainingrogtamtor

g€neti( rcfegtionab.

Borighr AP, Kere J, SchererSw: The generics f childhood disease nd deveL-

opment, A serres f review ardcles.?eddtr Res2003;53:4-9.

Braude P: Preimplanration diasnosrs br seneticsusceptibjliry.N Ersl / Med

2006;355:541-541.

Burton PR, Tobin MD, Hopper JL: Key concepts n genericepidemjology.

Lancet 2005;366:941-9 50.

creety HT: Bannrnsseneticdiscrimjnarion-N Ezgl l Med 2005;353:865-867.

Gu$macher AE, Collins FS: Genomic medicine--A ptilller N Ensl ! Med

2002;347.1572-1520.

Hall lC, PowersEK, Mcllvaine Rl et al: The frequencl.and inancial br.rrden

of senericdisease n a pedialric hospital. Az / Med Geftet 1978;11417.

McCandlessSE, Brunser Jw' Cassidy SB: The burden of genetic diseaseon

inpatienr care n a children's hosplral.Au.,f H!l,n Cenet 2004;7+121 127

StevensonDA, Care-v C: Contribudon of malformations and senecicdisor-

ders to mortatity in a children's hospital. Az l Med Cerct A

2004r126:393-337

Chapler 9 r TheHumanGenomo

Knorvledge f the structureand funcrion of DNA ushered n era of molecularbiologn with arr ncreasingly ich undersraing of the processes f DNA replication, ranscription, ran

tion, and protein processing.Many genetic disordersunderstood t the molecular evel, esulting n specifrc iagnotestsand appropriace reatments. he Human GenomeProjculminating n che equencing f the humangenomejmade t psible o studyvirtually any humangeneand to explore he roof senesn both rare and common disorders. t has also becapparent hat the genome ncludes ar more than a coded stof informatron o produceproteins.

The human genomehas approximately25,000 genes,whare the individual units of heredityof all traits.Reproductivgermlinecellscontain one copy (N) of this generic omplemand are haploid, whereassomatic(non-germline) ells contrwo completecopies 2N) and are diploid, The genesare ornrzed nto long segments f DNA, which, during cell division,compacted nto inrricarestructureswith proteins o form ch

mosomes.Each somatrccell has 45 chromosomes 22 oairsaurosomes,r non-sexchromosomes.nd I pair of se i chmosomes XY in a male, XX in a female]).Germ cells (esperm) ontain 22 autosomes nd 1 sexchromosome,or a !oof 23. At fertilization, he full d iploid cbromosome omplemof 46 is again ealized n the embryo.

Mosc of the geneticmaterial s contained n rhecell'snucleThe mitochondria thecell'senergy-producingrganelles) onttheir own uniquegenome,The mitochondrialchromosome sistsof a double-strandedircular pieceof DNA, which conta16,568 ase airs bp )of DNA and s completelyequencedproteins hat comprise he mitochondriamay eicherbeproduin the mitochondria (from information contained n the mchondrial genome)or produced rom information containethe nucleargenome nd transporred nto the organelle.All michondria are maternallyderived(becar.rseperm do not usucarry mitochondria nto fertilized eggs);different mitochonwithin a singlecell with a variety of genomeseflect he manal ines rom which heydescended.

FUNDAMENTATSF M0LECUIAB ENETICS-he cenrral enemoleculargenericss that rnformationencodedn DNA predoinantly locaced n the cell nucleus s transcrjbed nto messeRNA (mRNA),which s then ransportedo the cytoplasm, ,'ir is rranslatednto proteil. A gene s a unir that rncludes rulatory regionand a coding region hat stores nformation cresponding o the sequence f amino acids n a specrfic rore

DNA consistsof a pair of chainsof a sugar-phosphateabone inked by pynmidineand purine bases o form a douhelix (Fig.79-1). The

sugar n DNA is deoxyribose. he pynidinesare cvtosine C) and thymine (T); the purinesare guan(G ) and adenine A) . The bases re inkedby hvdrogen osuch hat A alwayspairswith T and G with C. Each strandthe double helix has polariry,wirh a free phosphate t one e(5')an dan unbonded ydroxylon thesugar t theorher ndThe cwo srrandsare oriented n oppositepolaritv in the douneltx.

The replicarion of DNA follows the paring of bases n parenrDNA strand.The original two strandsunwind by breing rhehydrogen ondsbetween ase airs.Freenucleotides,sisting of a base attached ro a sugar-phosphate,orm nhydrogenbondswith their complemenrary aseson rhe parsuand; ne&' phosphodiester onds are created by the enzyDNA polymerase.Replicarionof chromosomes eginssimu



488 r PABI X I HumanGenetics

- Adenine

Thymine

'fl=, GuanineCytosine

Fisure 79 1. DNA double helix, nrrh sugarphosphatebackbone and nitroge

nous bases. From lorde LB. Carey JC, Bamshad v!, et al leditorsl: Medical

Cenetics, nd ed. St. Louis, lv{osby,1999, p 8.)

neously ar multiple sites, orming replication bubbles that expandbrdirectionallyunril the entire DNA molecule (chromosome) s

repllcated. Errors in DNA replication, or mutations induced by

environmenral mutagens such as irradiation or chemicals, are

detected and potentially corrected by DNA repair systems,

A procotl'pical gene consrsts of a regulatory region, segments

called exons thar encode the amino acid sequenceof a protein,

and intervemng segmentscalled introns (Fig. 79-2). Transcription

srarts at the promorer region and contmues through the enrire

length of the gene to form mRNA. The introns are then removed

and the exons spliced together to form a marure message,which

is then exported to the cyroplasm. There the mRNA is bound to

ribosomesand ffanslated nl o protein.

Transcnptron is iniriared by attachment of RNA polymerase to

rhe promoter site upstream of the beginning of the coding

sequence.Specificproteins bind to the reglon to either reprederepress ranscription by opening up the chromatin, whichcomplex of DNA and histone proteins. It is the productio

these regulatory proteins (transcription factors) that determwhen a gene is turned on or off. Some genes on specific cmosomes rn defined areas are turned off more or lessoermanby epigeneticmerhylarionol cyrosinebaser hat are adjaceguanines (CpG bases).Gene regulation is flexible and responwith genes being turned.on or.off during developmento

responseo envlronmenralsllmulr,Transcriprion proceeds rhrough the full length of the gene

thesizingmRNA in a 5'to 3'direccion. RNA, hke DNA,

sugar-phosphate chain with pyrimidines and purines. The sin this case s ribose; uracil replacesthymrne rn RNA. The Rreads off one strand of DNA to copy a complementary R

sequence. A "cap" consisrrng of 7-methylguanosine is adde

the 5' end of the RNA rn a 5'-5' bood and. for most lranscseveral hundred adenine basesare enzymaticall y added to cend after transcriprion, mRNA processing occurs in rhe nuand consists of excrsron of the inrrons and splicing togerhlhe exons. Soeci6cseouencesat the start and end of introns mrhe sires where the splicing machinery wil l act on the transcIn some cases, here mav be tissue-specificpatterns to splicinthat the same primary transcript can produce multiple dis

protelns.The processed transcript is next exported to the cyropl

where it binds to ribosomes, which are protein-RNA compleThe genetic code is then read in triplets of bases,each tnplet

responding wrth a speciGcamrno acrd or provrdng a signal

terminates translation. The triplet codons are recognize

transfer RNAs (tRNAs) rhat include complemencary "codons" and bind the corresponding amino acid, delivering

the growing pepride. A new amino acid is enzymatically atta

to the peptide; each time an amino acid is added, the ribos

moves one rflplet codon "step" along che nRNA. Event

a stop codon is reached, at which point translation endsthe peptide is released, In some proceins, there may be p

translational modifications such as attachment of sugars (g

sylatron); the protein is then delivered to its destination withi

outside the cell by trafficking mechanisms hat recognize portof the peptide.

GENETIC ARIATI0N.The processof production of protein

a gene s subject o disruption at mult iple Jevels wing ro a

ations in rhe coding sequence .Ftg.79-3).Changes n rhe

moter region can lead to altered gene regulatron, inclu

increased or decreased ares of rfanscrlptron, failure of gene

va t ron , r ac r i va t ion f rhegene r napp rop r ia reim es r i n i

propriate cells. Changes in the coding sequence can lea

substitution of one amino acid for anorher (missensemutat

or creation of a stop codon in the place of an amrno acrd co

Some srngle-base hangesdo not affect the amino acid, since

may be several codons thar correspond with a single amino (silentmutarion). Amino acid subscitutionsmay havea profo

effecr on protein function if the chemical properries of the slituted amino acid are markedly differenc from the usual

substitutions may have a subtle or no effect on protein func

if the substituted amino acid rs chemically similar to the orig

one.

Genetic changesmay also include insertions or deletions. I

rions or deletions of a non-integral multiple of three bases

rhe coding sequenceeads o a frameshift,altering chegrou

of bases into triplets- This leads to translation of an rnco

amino acid sequence nd usuall y the eventualproduction

srop codon. Ioserrionor deletronof an inregralmuhiple of t

bases into the coding sequence will insert or delele a c

sponding number of amino acids rom the protein. Larger

insertions or deletions can disrupc a coding sequenceor resu

compleLe elerionof an entire Henc )r group ol genes.

"'1-

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III



Fi l i tsrc 9.: . Summarv f thc steps eading ron DNA b pr o

teins Rephcaoon nd transcr ipt ion .cur in thc cel l nucleus

The nRN-A is rhen transportedk) thc crroplasm, rvhete rans-

lar ion ol ' the mRNA rnto amino rcid sequencesomposrng

protein oc.urs. (l.rom Jorde l.B. alarey (i, Bamsh.td 'U. er al

led;tots):Medrcdl Ce etirs,2nd ed Sr louis, Mosbl. 1999, p

1 2 1

Mutations usuallycan be classif ied s causinggain of function

or loss of fulrcnon. A gain-of-functionmuration can resulr n an

increase n the abilicv of a proteiD molecule o perform one or

more normal functions!or , more comm()nl)' , r can result u ovet-

expression r inappropriareexpression i a geneproduct. Gain-

ofliuncti{)n mutations most frequentl,v produce aurosomal

dominant disorders (see Chapcer 80). Charcot-Marie-Tooth

disease, ype lA, or peroneal muscular atroph)' . the most

common form of chronrc peripheral neuropath-y f childhood,

resulcs rom dup[cation of rhe gene for penpheral m,velin protein

22 , rcsult ing n ovetexpression f rhe geneproduct. The gain-of-iunccion murarion in achondroplasia, he rnost comrnon of rhe

shorc inTbed keletaldysplasias, xernplif ies he enhanced unc-

rion of a normal ororein. Achondroplasia resuLtsrom a muta-

rion in f ibroblast growth recepror 3 (FCFR3). w'hich eads to

acti\.arion f the recepror, ven n the absence f 6bnrblasrgrou rh

iacror (FGF).Loss-of-functionmutations are frequendvobserved

in autosomal recessive isorders n rv hich loss of 507" enzyme

activity n th e heterozygote ontinues o allow fbr normal func

tion. A lternativell. , oss of funccionmutations can result n con-

dirions in which 50% of the gere product is insuff icienc or

normal function (haploinsuff iciencv). oss of-function rnutations

can have a dominant negarive ffect ,r,henhe abnormal protein

product actively rnterferes v irh rhe function of rhe normal protein

produo.

Cha[ter79 r TheHomanGenome

Anochercategorvof mLltationsma]' ' onfer a novel propertfhe protein sy'nrhesized,,vichouraltering the proteins norfernctions. n sickle cell disease,an amino acrd is subsciinto the hemoglobin rnoLeculebat has no effect on the abof che protein to transport oxvgen. Howeve! unlike norheruogLobin. nder condicions f deoxygenation, icklehemoLrinchains aggregare! ormrng fibers that deform the red cA 6nal caregorl'o( mutations results n abnormaLexpressja gene over spaceand time. Many cancercausinggenes ogenes)are normal regularors of cellular proliferation du

devel<:pment;when expressed n adulc l i fe, and in cellrvhich they usually are not erpressed, thev may resulreoplasla.

l)elerionscan varl in rheir extent and, even rvhennot viat the cytogenetic er.el, an involve several enes; hese re otenned microdeletions. 81. a variety of rearrangemencs, corions eterred o as contiguous en esyndromesma y be generTh e clinician ma1,be alerted o this poss ibil itv bv an unusdiversearray of chnical earures n any indrvidualor thc presof addirional eatures o a known condit iol. For example,ouro the closeph,vsical roximicl' of a series f genes, ifferent drions nvolving he shorr arm of cheX chromosomecan prodinclividualswith various combinationsof the followine Fear ih th r , , . r . ,Ka l l rnann l r rd rom e , iu la r a lb rn i rm ,m cn ( ; l re larion, chondrodysplasia unc!ata,and short srature.The rnd



490 PAnTX I HunanGeneticg

Promoter

Filwe 79-3- Various types of inrragenic mucations. Promoter mutarions alrer rate of transcription or disrupt gene reguLarion.Base chang€swithin e

can havevarious effects!as shown. Mutations within Lntrons an lead ro inclusion of some nrronic sequencen the final processedmRN-A" or can lead to e

skipping.

ual eaturesn each ase epend n the nvolvement fthesegenes

and the ossof DNA sequencesn the underlyilg reaffangement.Many other chromosome deletion syndromes have beendescribed n humans, including Smith-Magenis,Rubinstein-Taybi, DiGeorge, 0illiam, and Prader-Willisyndromes.

Rearrangemenls uch as translocationsalso take place insomaticcells.The best understoodare the rearrangementshatoccur in lymphoid cells.Some earrangements re required orthe formation of funcrional immunoglobul in in B cells andantigen-recognizingeceptorson the T cell, Large segments fDNA, which code or the variableand the constant egionsofeither immunoglobulin or the T-cell receptor, are physically

joinedat a specilic tage n the development f an immunocom-petert lymphocyte.The rearrangemenrsake placeduring devel-opment of the ymphoid cell lineagen humansand result n theextensive iversiryof immunoglobulinand T-cell eceptormole-

cules. t is as a result of rhis post-germlineDNA rearrangementrhat no t'vl'o ndividuals,not even dentical wins, are really den-tical,because ature ymphocltes rom eachwill haveundergonerandom DNA rearrangemenls t theseoci.

Studiesof che humin genomesequenceeveal thar any twoindividualsdiffer in about one basen a thousand.Someof thesedifferences re silent;some esult n changeshat explainPheno-typic differenceshair or eye coloq physicalappearance); omehave medicaL ignif icance, ausingsinglegenedisorders uch as

sicklecell anemiaor explainingsusceptibility o commondisor-derssuchas asthma.Genetic ariantswithin the samegeneoccur

commonly in the population and are referred o as polymphisms.Thesemay be silenr or subtleor have signilicantphetypic effects.

GEI{OTYPE-PHENOTYPEORREI.ATIONSN GENETICDISEGenotype s the geneticconstirutionof an individual and reto whichparticularalternative ersion allele)of a genes preat a specfic ocation (locus)on a chromosome. henotJpesobserved tructural,biochemical, nd physiologic haracterof an individual, determinedby the genotype,and refers o obsepedstructuraland functionaleffectsof a mutant allelespecific ocus.Many mutations esult n predictable henoty

Therefore, dentificationof a specilicmutation in an individ

ofren can be used o predict clinicaloutcomesand plan appriate treatmentstfategles.

The ong QT syndrome xemplifies disorderwith predictgenotype-phenotypeorelations (seeChapter435.5). Longsyndrome (phenotype) an be causedby mutadons n sevgeaes(genotypes),whicb are designatedLQT1, LQT2, LQT3, all encodingcardiac on channels,The risk for carevents syncope, borted ardiacarrest,or sudden eath) s higwith mutations ̂ t the LQTL locus (53%) or the lQT2 lo(46y.) thar amongsubjectswith mutations at the l8T3 lo

{ 8o/o).n addition, hosewith LQfl mutarions xperienceof thei r episodes uring exercise nd rarely during rest or slthosewith LQT2 ar.d QT3 mutationsare more ikely to h

episodes uring sleepor rest,and rarely during exercise.



l \ ' lutations n the 6bnllin-1 geneassocialed ' ith Marfan syn-

diome reptesent another example of predictable genorype-

phenotypecorrelations seeChaprer 700). Marfan syndrome rs

charactenzed v the combination of skeletal,ocular,an d aorric

manifestarions, vith the mosc devastacing utcome being aortic

root djssectron nd suddendeath. Sixcy-five xons make uP th e

fibril l in 1 gene,an d mutations have been ound in almost all of

rhese exons. The locatron of the mutarion within the gene (geno-

lung diseasecaused by mutations in the CF transmembrane con

duccance regulator (C}-TR) gene. More than 1,000 different

mutations harrebeen dentif ied; he most common is the AI508

mutation, which accounts for 707" of all mutalions and is asso-

ciatedwith severe isease. everalmulations associatedvirhmrld

disease ave been denrif ied, ncl uding 3272-25A+G, 3849+10

kb C-+T, IVSS-5T,and 2789+5GrA. Patienrs 'rrh at leaston e

3272-26A-+G alleleand a second mutaced allele (compound het-

erozygote) associated rvirh severe disease are more likely to be

diagnosed ater and have berter ung function, a lower incidence

of Pseudomonas aeruginosa colon:tzatton,and normal pancreatic

funcrion. Homozl,gotes or rhis mutarion are no! obseruedan d

may nor have clinical disease. Conversel)', lhose with

2183AA-+G mutations, eicher homozygous or heterozygous ,rvrth

another CF muration, are more lik ely to have early-onset, evere

disease. hose wich this mutation tended o have severe ancre-

aric involvement, failure to thflve, varrable lung Involvemenc, and

relativelyearly death.

With any given mutation! modifrer genes for a different gene

producl may altenuate th e murared gene'sphenotvpe. W'hen

srcklecell anemia is co-inherired rl'irh the gene or hereditary per

srstence f fetal hemoglobin, he sicklecel l phenotypicexpression

is less severe. Modifrer genes in CF may rnfluence the develop-

ment of congenitalmeconiu ileus,or colonizationwith P aerlg-

fuosa. -Nlodifer genes ma also affect rhe manifesrations of

HUMANGEN0ME B0JEGT. en emapping s performed by genetic

linkage analysis, hich is basedon the principle that Leles t

t\r'o genetic loci thac are located near one another rvill gregate

together i a family unless they are separated bv genetic recom-

bination, he fre<luercyof recombinarionbetween he loci is a

measureof physical distance.A set of polvmorphic generic oc i

is dentif iedand is closely' paced long be entirehuman genome

and eou ld be used o map an r gc t t e t t era i t .

Phy mapping of the genome nvoLvessolation of segmenrs

of rhe an genomewith lengths rom hundredsor thousands

to a ferl million basepairs and placing them in micloorganisms

su!h a\ hacrerir or )ea\I. AuronratedseqLren(ingvstem\ pcrmit

the base sequenceof these segments o be decermined The seg-

ments could chen be pieced togerher by examining !he sequence

of overlap regions and by relacing rhe sequenced segments to

sequencing be fragments,an d rhen using a compllter to order

the fragmentsbasedon overlappingsegments.

Analysis of the human genome has producedsome surprising

resulcs s well. The number of genes s str l l not known preciselY

but appears o be around 25,000. This is fewer rhan had been

ChaDter9 a TheHumanGenome

of alternarive promoter regions in some genes, alternatite sp

ing, and post cranslationalmodrfications.

Ic is a lso apparent ha t moscof rhe genomedoes no t encprorein ( lesschan5% is rranscribed nd translared).Many tr

scribed sequences are not translated but represent genes t

encodeRNAs that servea r egulatory role. A high proporcio

th e genomeconsistsof repeatedsequenceshac are interspe

among chegenes.Someof theseare ransposable eneric lem

rhat have he ability ro move from placeco place n lh e geno

Others are stacicelements hat Eere exoanded arrddisoerse

rhepa r t du r rnghum anevo lu r ion . rhe i repea redequen (e \

play a struccural tole. There are also regions of duplicationgenomic regions.Such duplJcations re substrate br evolutallowing geneticmocifs o be copied an d modif ied to servenroles n the cell. Duplicarionsma v also form rhe basis or ch

mosomal rearrangement,permitring nonhomologous chrom

some segments o pair during merosrsand exchangemate

This is another sourceof evolutionarvchanse.an d also serve

a p ' t rn r ia l \ ou rceo l ch rom u \o rna lns tab i l i i yead ing o cong

ital anomaliesor cancer

Availability of the genome sequencepermits the stud,v of la

groups of genes, ooking for patterns of gene expres siogenomealteration.N,licroarra]s av e beendeveloped ha t per

tensor hundredsof thousandsof gencs o be anaLyzed n a smglasschrp. Pat terns of geneexpressionprQvidesigcatures for p

ticLllardisease tates, uch as cancer,or rn response o ther(F rg .79 -4 j .



492 PAnT I Humrn Gnotics

ChristensenK, Murray JC: whar genome-wideassocia.ionstudiescan do for

medicine. N Engl J Med 2007;356:1094-1097.

Cordefl HI, Clayton DG: Genetic association sfidies, Ldn et

2005i366:1121-1130,

Hatrersley AT, Mccarthy Ml Wlrat makes a good geneticassociarion rudyl

Lancet 2005 366 1315-L323.

JarvisJN, CentotaM: cene-expression rofiling: Time lorclinical apphcation?

Lancet 2005 3651199100.

Lander ES, Linton LM, Birren B, er al, Initial sequencing nd analysisoI rh€

human genome.Naturc 2001;4091.6822):860-921.Mcchee SA, Mccabe ERB: Genome-wide esrhg: genomicmedicine. PedrTtt

Res 200660243-244 .TeareMD, BarreftJH: Genetic inkage studies. -rncet 2005i36611036-r044.

VenrerJC, Adams MD, Myers EW, et al: The sequence { the humangenome.

Science 001 2911S5O7 l 3O4.

FAmltY HISTORY IUDPEDIGREEl0TAnOfl. The farnily historyremains he most important screening ool for pediatricians nidentifyinga patient's isk for developinga wide range of dis-eases,ncludingmultifactorialconditions, ike diabetes nd atten-tion defrcitdisorder, o s ingle-geneisorders uchas osteogenesisimperfectaand cystic ibrosis,Through a detailed amily historythe physician an ascertain he modeof genetic ransmission ndthe risks to family members.Because ot all familial clusteringof diseases due ro geretic actors,a family historycan also den-tify commonenvironmental nd behavioral actors hat influencethe occurlence f disease. he main goal of the family history sto identifygenetic usceptibili ty, nd he cornerstone f the familyhisrory s a systematicnd srandardizededigree.

A pedigree rovidesa gaphic depictionof a famrly'sstructureand medicalhisrory. The person providing the information is

termed the proband, and is typically designated by an artow- his important when raking a pedigree o be systematicand usestandardsymbolsand configurations Fig. 80-1) so that anyonecan read and understand he information. A three-eenerationpedigree houldbe obrained s an iniri alscreenor iue.y ne *patienr to identify possiblegeneticdisorderss€gregating ithinthe familn the inheritancepattern, and rhe risk to the patient.The closer he relationshipof rhe proband to the person n thefamily with the geneticdisorder, he greater s the sharedgeneticcomplement. irst-degreeelatives, uchas a parent, ull sibling,or child,shareY, heir genetic nformation on average; stcousinsshareY5. ometimes diseasen a more distant elativemay createa greater isk; for thar reason, more extendedpedigreemay beneededo identify risk for certaindisorders.A hisroryof a distantmaternally elaredcousinwith mental retardationdue to lragi le

X syndromemay have itde significanceor the male nfant youare examining,or it may mean har this child is ar elevated iskfor fragile X syndrome.

MEITIEtIAl{ NHEBITAI{CE

There are threeclassic orms of genetic nheritance: utosomaldominant.autosomal ecessive. ndXJinked. Theseare referredto asmendelian nheritance orms,after GregorMendel, he 19thcenturymonk whoseexperimentsed to the laws of segregationof characteristics,ominance, nd ndependent ssortment. heseremain he oundationof single-genenheritance.0ith mendelianinheritance,a singlegene'seflect rs necessaty nd sufficieflt ocausea particular phenotype.This is in conttast to oth€r forms

f tttare

I Femate

Sexunspecified

ra |,1$'.:1,',::i#""lO,qfiecteo

r. il:lH::[3$ffi'"XT;Obligala arder, il lnotmanifest isea$s

Proband

Deceasedndividual

sti bidh

Adoptednto amily

Adopted d ol family

Marriag€ r union

Divorced

Consanguinity

Monozygoticwinsff

EO

TFj/.

trl

Dizygoticwins

Twinsot unknownzygosity

Nootfspring

lvlultiplenions

Figur€ 8O-1. Peati4reenotation. Symbols commody used ir pediSree cAlrhough there s no uniform syst€mof pedi8ree otation, the symbolsshere are according o recent recommendationsmade by professionals

6eld of geneticcourselhg, (From BennettRL, SteinhausKA, LlhrrchSBRecommendations or standardizedpedigreenomenclatve. I Genet Co1995A:267-279.1

of geneticallydetermined raits, such as impriotirg condittriplet repeatdisorders, nd multifacto rial raits, in which ofactors nfluencewhether he disease ill bepresent n somwho carries he genetic hange.

AutosomalDominantnhoritance. utosomal dominant intance s determined y thepresence f one abnormalgeneon

of the autosomeschromosomes

-22), Thegenes

n thesemosomesexist in pairs, with eachpatent contnbufing one c!7ith an autosomaldominant trait, one of the pairedgenean effecton the phenotype hat dominateshe effectof rhe oof the pair.Phenotype efersnot only to physicalmanifestabut also o behavioral haracteristics r to differences eteconly through aboratory ests, uchas biochemical bnorma

The pedigree or an autosomaldominant disorder(Fig,8demonstrates ertain characteristics,1) The disorder s trmitted n a vertical (parent o child) pattern,appearingn mple generations. his s rllustratedby individual .1 (see ig 8passing n the changed ene o IL2 and II.5. (2) An affectedvidual has a 50% (1 in 2) chanceof passingon the deletegenesor eachpregnancn nd hereforeof havinga child affeby the disorder.This is referred o as the recurr€nc€isk fo

disorder.3)

Unaffected ndividualsfamily

memberswho domanilest he !:.aitldo not pass he disorder o their childreMales and females re equally affected.Although nor a chteristicper se, 5) the inding of male-to-maleransmissiontially confirms autosomal dominant inheritance. Vertransmission analsobe seenwith X-linked raits.However,a father passes n his Y chromosome o a son, male-totransmission anno t be seenwith an X-linked trair. Theremale-to-male ansmissioneliminat€sXlinked inheritanceoossible xolanation.While male-to-malelansmission an owith YJinkid genes swell, there arevery ew Y-linkeddisocomparedwith thousands aving he autosomal ominant nrtanceDattem,

Although parent to child transmiss ion s a characte risautosomal ominant nheritance,or manypatrefltswith an a



somaldominart disorder here s no history of an affected amily

member. hereare several ossibleeasons,irst, hepatienrmayrepresen!a new mutation; second,many autosomaldominantconditionsdemonsrratencompletepenetrance,neaning hat not

all individualswho carry the mutationhavephenotypicmanifes-

tations. n a pedigreehis may app€a!as a ek ipped eneration,n

which an unaffectedndividual links two affectedpersons Fig.

80-3). There are many potential reasons hat a disorder mayexhibit incompletepenetrance,ncluding the effect of modifier

Benes,nvironmental actors,gendeq nd age,Third, individuals

with the sameaurosomaldominant mutation will manifest hedisorder o different degrees. his is termedvariableexpression

and is a characteristic f many autosomaldominantdisorders.Founh, somespontaneous eneticmutationsoccurnot in the egg

or sperm hat forms a child but rather n a cell n the developingembryo. Such eventsare referred o as somaticmutations.The

resultingphenotype aused y a somaricmutation can bevaried,but it is usuallymilder than if all cellscontain the mutation. Ingermlinemosaicism,he mutation occurs n cells hat populate

the gernline that produceeggsor sperm.A germlinemosaicwillhaveno manifestations f the disorderbut will producemultipleeggsor sperm hat carry the mutation.

AutosonalRecessivenheritance. utosomal recessivenheri-tance nvolvesmutations n both copiesof a gene.Examplesofautosomal recessive iseases re cysdc fibrosis and sickle cell

disease.Characteristicsf autosomal ecessiveraits (Fig. 80-4)

include(1) horizontal transmission,he observation f multipleaffectedmembersof a kindred in the samegeneration,but noaffected amily members n othergenerations;2) recurrenceiskof 257o or parentswith a previousaffected hild; (3) malesandfemales eingequallyaffected, hough some raits exhibit differ-ent expr€ssionn males and females ovariancancer,hypospa-dias); (4) increased requencyof consaDguinity,articularlyfortate tratrs.

The chance hat any two parentscarry an identical mutantallele s increasedf the couple s consanguineous.onsanguinityis relationshiobv descentrom a common ancestor. onsanguin-ity between arinrs of a child with a suspected eneticdis;rderimplies (but does not prove) aurosomal ecessivenheritance.

Although consanguineous nions are uncommonin Western

society, n other parts of the world (southern ndia, Japan, he

ChaFor I P|ttor[!ol Gonoticrsnsmislio

l l t 1 2

Fture 80-3. Incomplete penetrance.This family segregates familial csyndrome, familial adenomatouspollposis, Individual II.3 is an ob

carrleq but there are no findings to suggest he disorder. She s rermedpenerranr.

Middle East) heyarecornmon.The risk of a genetic isordethe offspring of a first-cousinmarriage 6-8%o)s about dothe risk n thegeneral opulation (3-4"/.), Therearesomegersolates small populations separatedby geography, eliculture, or language)n which rare recessive isordersare mcommon than in the generalpopulation. Even though conguinity may not be increased n thesepopulations,becaulimited mate choice, he chanceof a couple from an isogenetic egion havinga child wirh an autosomal ecessiveotion may

be as high as that observed n first-cousinmarriScreening rogramshave beendevelopedn suchgroups o

Figure 80-2. Autosomal dominant pedigree.Pedigree howing ryprcal nheritanceof a form of sensorineural eafness DFNAS/ inhedted as an aurosomainant trait, Blue. affecredDati€nts.



Fisurc ti(}4. ,qurosomat ecessive edigreex.ith parental consanguinitr. Purple, carriers; Red, afl'ected

494 r PARTX ! HumanGonrtics

tect heterozygotes t rrsk for having affected hildren,A varietyof autosomal recessive onditions are more common among

Ashkenazi ews hann

thegeneral opulacion.Natronalpractice

guidelines ecommend creening symptomaticAshkenazr ewsfor rhe neurodegenerative rsorder Tay-Sachsdisease,andCanavandisease arrier screening or other disorders Fanconi

anemia,Gaucherdisease, ystic ibrosrs, amilial dysautonomia,nesidioblastosis)s under considerationor this population.

The prevaLencef carriersof certainaulosomal ecessiveenesin sorneargerpopr-:lationss unusuallyhigh. In suchcases, et-erozygoteadvantage s postulared.The carner frequencies fsicklecelldiseasen cheAfricanpopularionand of cystic rbrosrs

in thenorthernELrropeanopulationaremuchhigher han would

beexpected rom new mutations. t is possiblehat heterozygous

carriershave had an advanragen terms of surv ivaland repro

ducrion over noncarriers.n sickle cell disease,he carrier stale

may confer some resrstanceo malaria; in cystic fibrosis, rhe

carrier statehas beenpostulated

co confer resistanceo cholera

or enteropathogenicscherichia oh rnfections, opulation-based

carrierscreeningor cystic ibrosis s recommendedor individu-als of northern European and AshkenaziJewish background;population-basedcreeningor srckle ell diseases recommendedfor individualsof African background.

If the irequencyof an autosomal ecessive iseases known,che requencyof lhe heterozygote r ca rrier statecan be calcu-lated rom cheHardy-Weinberg ormula:

p:+2pq+q' 1

wherep is the frequencyof one of a pair of allelesand 4 rs chefrequencyof the other. For examp , if the frequencyof cysticlibrosis among white Americanss in 2,500 (p2), hen the fre-

quencyof cheheterozygote2pq an be calculated:f pr = Ythenp=|ro an dq = a'7t,,2pq= x Ysoxa%o,or pproximt/2.

lo r 3.921").Every human probably has several are, harrnful, recesgenes.Becausehesemutantgenes re frequendynot identifiaby laborarory ests, he heterozygous dult usually earnsabtheseharmful recessive enesafter the birth of a homozyg(and thereforeaffected)child. Relatedparentsare much mlikely to be heterozygousor the sameharmful recessive ebecausehey have a common ancestor

Ps€udodominantnheritance, seudodominantoheritarrceeto rhe observation f apparentdominaflt(parent o child) cramissionof a known autosomalecessiveisorder Fig.80-5).Toccurs 'hena homozygous ffected ndividualhasa parrnerwis a heterozygous arrierrand it is most likely to occurfor retively common trarts,such as sickle cell anemia or congendeaFnessue o connexin26 en emutation,

Xiinked lnheritance.Characteristics f X-linked inherita(Fig.80-5) nclude he following: (1) Males aremore commoand more severely ffected han females. 2) Female arriersgenerally naffected, r if affected, heyare affectedmore milthan males. 3) Affecredmaleswill have onLvcarrierdaughtThey have no chanceof havrng an affectedson (male-to-m

transmjssion xcludes -linkageand s seenwith aurosomal oinant and Y-linked nheritance). 4) Carrier women havea 25risk for havrngan affecred on, a 257. risk for a carrier dauter, and a 507o chance or a child rhat does not inherrt mutated X-linked sene.

A femalemay oicasionallyexhibit signsof an X-hnked t

similarly to a male. This may occur owing to nonrandominacrivarion,homozygosiryor an X l inked trait, or presenc

a sex chromosome bnormality 45,X or 46,XY female).



Fisurc 80'5. Pseudodominanrinherirance. Red, alfected(deaf ) .

GhoDter{l r Pon.msotceletic Tr6nsnission

Of specialnote s rhepseudoautosomalegiorton the Y chmosome, hesmall egionof bomologychat s sharedby bothand Yp- Very few genes eside n this region. One of the feSHOX. Hererozygous SHOX mutadofls cause Leri-Wdyschondrosteosis,rareskeletal ysplasia hat nvolvesbilatbou.ineof the forearmswith dislocarions f the ulna at the wand generalized hort stature.Homozygousmutationscausemuch more severe angermesomelic war6sm.

0lGENlCNHERITANCE.igenic inheritanceexplains he ocrence f retinitispigmentosa RP) n childrenof parentswho ecarry a different RP-associatedene.Both parentshave norvision,aswould be expected, uc he offspringwho were douhererozygotes eveloped RP Digenic pedigees (Fig. 80exhibit characceristics f both autosomal dominant (ver

transmission) nd autosomal ecessivenheritance 1 in 4 rerence isk). A couple n whrch the two partnersare carriersrwo different genesmay have affected children. Anv chhowever,might transmit both mutations o an offspring, adommant nherltance,

PSEUD0GENEC NHERITANCENDFAMlt lA[CIUSTERINGhare nongenetic easols or the occurrence f a diseasen muple family members; hesecan mrmic genetic fansmissron.sible explanations include environmental factors, teratoexposure,and as yet undetermined nd undefined actors.Mtiple srblingsmayhaveasthmadue o exposureo cigaretre mfrom rheir parents.A woman may have multiple children wsmall size,developmental elay,and unusual acial appearowing to her useof alcohol during pregnancl'. hernatively

diseasemay be very common n the generalpopulatiol- Brcancerwill allect 1|Yo of all womenr t is oossible hat sevwomen n a familywill develop realr ancer ecause|; erutermined faccors. t rs usually possible o differentiate amwith generrcally etermined igh-riskcancersyndromes, ucthat associated ith a BRCAI mutation, by their earlier agonsetof breastcancer n multiple family members.

NONTRAOITIONATNHERITAIiIGE

Sone eenetic disorders are inherired in a manner that doesfollou.classical mendelian oatrerns. This nontraditional inh

tance partern includes mitochondrial disorders, triplec repexpansion diseases,and rmpnnting defecrs.

X chromosomenactivationoccursearly n development ndinvolves andom and irreversible nactivationof most genes non eX chromosomeyeach el l Fig.80-7). n some ases, pre-ponderanceof cells may inactivate he sameX chromosome,resulting n phenotypicexpression f an Xlinked mutation if it

resideson the activechromosome.This may occur owng to

chance r to selection gainst ells hat have nactivated nolmal

X if the other X carriesa structural earrangemen!.Thereare someX-linked drsorders, alledX-linked dominant,

in which female a iers ypically manifesr bnormal indings An

affectedman rvill ave only affecteddaughtersand unaffeced

sons, and half of rhe offspring of an affectedwoman will be

affecred1Fig.80-8). Some X-linked dominant conditions arelethal in males. An example is incontinentia pigmentl (see

Chapter651). The pedigree howsonly affecred emales, nd an

overall ratio of 2 : 1 females o maleswich an increased umberof miscarriagesFig.80-9).

Y-I|NKED NHEBITANCE.here are few Y-linked craits, These

demonstrate zly male-tomale raDsmission , nd only malesareaffected Fig.80 10). r{ostYJinkedgenes rerelated o malesex

decermination nd reproduction,and are associated ith rnfer-

tility. Therefore, c is rare to see amilial transmrssion f a Y-

linked disorder Advances n assisred eproductive echnologresmay makepossible amilial lrarismission f male nfertiliry

Figure 80-6. Pedigreedemonsnating Xlinked recessivenheritance- (From

Nussbaum RL, N'lclnnesRR, Vitlard HF, ThorllPson & Tboh'Pson Gehetics

in Medidne,5th ed. Philadelphia, rB Saurders, 2001.)

TI



496 PAETX r HumanGerctics

IB f f i g H,xe x-x" X.Xo X.Xo

/ ' \

/ \

H HX.Xp x*4

H Bx.x" x-x, X.X

H Bx.xo x_x"

X X, X-XU X.X.X.X,

x.xo x,xo x.x x.x, X.Xo X.Xo

X. X., X.XN X.X. X.X,,

Figure 80-7. X inactivation.

Mitochondrialnhelitance.An individual's mitochondrialgenome s entirelyderived rom the mother (Fig,80-12). Spermcontarn ew mitochondria,most of which are shedupon fertil-ization. Mirochondrial disordersexhibit maternal nheritance;woman with a mitochondrial geneticdisotder will have onlyaffected ffspringof eithersex,while an affected ather will haveno affectedoffspring (Fig.80-13).Although suchan inheritancepatternca n be explained y autosomal ominantor X-linkedinheritance, t suggescs mitochondria l basis Table80-1).

The mitochondriaare the cell! suppliers f energy, o that theorgans hat are most affectedby the presence f abnormalmito-

Figure 80-8. Pedigreepatrern demonsrratingx-linked dominanr inheritance-

lFrorn Nussbaum RL, Mclnnes RR, Wrllard Hr: Thompson It Thonptu11

Geneti.s n Medicine,6rh ed. PhiLadelphia,WB Saunders, 001.)

chondria are rhose that have the greatest energy requireme

such as the brain, muscle, heart, and liver (see Chapters 8

358, and 598). Common manrfestationsnclude developm

delal seizures,cardiac dysfunctron, decreasedstrength and c

as well as hearing and vision problems. Examples include MEL(myopatby, encephalopathy, lactic acidosis, and stroke

episodes), MERRF (zryoclonic epilepsy associated with rag

red flbers), and Kearns-Sayre syndrome (ophthalmoplegia,

mentary retinopathy, and cardiomyopathy) [see Chapter 5

Mitochondrial drseases an be hrghly variable in clinical mfestatrons. Cells may contain a mixture oI mutant and nor

mitochondria, referred to as heteroplasmy. Unequal segrega

of mutant and normal mirochondria (rephcative advantage)

result in signilicant drfferences n expression of a mirochond

trarr ,n the ovum and different cel ls of an individual or diffeoffspnng of a carrier mother. Becauseof rhis, the mother nia

asl'mptomatic. In affected offspring, diseasemanifestations t

ro occur when 50-507o of mrtochondria carry a single large d

non or when 80-c0o/ohave a poinl murarion.

TriFletRepeatExpansionDisordeis. Triplet repeat expansron

orders are distinguished bv the special dynamic nature of

diseasecausrng mutation. Triplet repeat expansion disor

include fragrle X syndrome, myotonrc dystroph)', Huntir8t

disease, spinocerebellar disorders, and several others (Table

21. These disorders are caus€d by expansion in the numbe

three-base-pair repeats.The fragile X gene, FMRI, normally

between .5and 50 CGG rriplets. An error in replication can re

ln expansion of thar numbeq referred to as premutation.

fragile X, premutation comprises 50-200 repears. Individ



ChdFe.m . Prltemsol G6r6ticTlrlsnissiol r

Figur€ 80-9. Pedigree f an X-link€d dominant disord€r with male lethaliry, such as incontinenla pismenn-

with a premutationareat risk for having hegeneexpand urtherin subsequentmeiosis,crossing nto the range of full mutation.In fragile X, that boundary is above 200 repears.Wirh rhisnumber of repeats, he FMR1 genebecomes ypermethylated,

and protein production s lost. Somemale carriersof the premu-tation develop a syndrome as adul ts characterized y ataxia,tremoq and cognitivedecline,

The effectof theexpansions different n othergenes.n Hunt-ington disease,he expansion auseshe geneproduct o haveanew, oxic effecton the neuronsof rhe basalganglia,For most

tripler repeatdisorders, here s a clinical corelation to theof rheexpansion, ir h a greater xpansionausingmoresand/or earlier ageof onset or rhe disease. he observatiincreasing everity f disease nd earlyageof onset n subse

generalionss termedgeneticanticipationand is a deliningcacteristic f triplet repeatexpansiondisorders Fig.80-14).Geletic mp ntittg.The two copiesof most genes re func

ally equivalenr. n a small number,only one of the pair isscribed.The activegenewill be that inherited from a spparent,and the other copy is silenced ssociated ith met

Figure 80-10. Ylinked inheritance.Blue, aflecredpadenr.



498 r PARTX r HunanGenelics

F'igurc80-ll. Digenicpedigre€.

tion of DNA (epigeneticmodification of a gene not due to a DNA

mutation). In imprinting, gene expression is dependent on the

parent of origin of the chromosome (seeChapter 81). Imprinting

disorders result from an imbalance of accive copies of a given

gene, which can occur for several reasons- Prader-Willi andArgelman syndromes, whrch are two distinct di sorders associated

with developmental impairmenr, are illustrart ve. Borh are associ-

ated rvith microdeletions of ch(omosome 15q11-12. The

microdelerion n Prader-Wrllisyndrome s always on the pater-

nally derived chromosome 15, u'hereas n Angelman syndrome ic

is on the maternal copy. UBE3 is rhe specific gene for Angelman

syndrome, and as expected, rhe paternal copy of UBE3 is tran-

scriotionall v silenced in the brain.

Uniparental disomy (UPD), the rare occurrence of a child

inheriting boch copies of a chromosome from the same parent, is

another senetic mechanism thar can cause Prader Willi and

Angelman syndromes. Inheriting both chromosomes 15 from the

mother is fuflctionally the same as deletion of the paternal 15q12

and will result in Prader-rJ7illisyndrome. About 30% of casesof

Prader-Villi syndrome is caused by paternal UPD15, whereas

macernal UPD15 accounts for only 3lu of Angelman syndrome(seeChapter 81).

A mutation in an imprinted gene is another cause. Mutations

m [IBE3 account for almost 307. of patients with Angelman syn-

drome and also result in familial transmission. The most uncom-

mon cause is a mucation in t he imprinting center, which resul ts

rn an inability to set the imprint. In a woman, the inability to

reset the father's chromosome 15 imprint will result in passing

oo ro active copies of UBE3, and the child will have Angelman

syndrome,Besides 15q12, other imprinted regions of clinrcal interest

include rhe short arm of chromosome 11 (where the genes for

Beckwith-Wiedemann syndrome and nesidioblastosrs map) and

che ong arm of chronosome 7 (maternal uniparental disomy of

7q has been associatedwith some casesof idiopathic shorr stature

and Russell-Silversyndrome).

Imprinting of a gene may occur during gametogenesisor earlv

embryonic development (reprogramming). Genes may become

rnaclive or active by various mechanisms inc|.rding DNA methy-

lation or demethylation (or histone deacytylation) with different

patterns of (de)methylacion noted on paternal or maternal

imprintable chromosome regions. Some genesdemonstrate tissue

specific rmprinting. There is an increased ncidence of imprinting

disorders ssociated ith in vitro fertilizatron r intracvtoolassperm injecrion (Beckwith-Viedemannnd Angelmansdrome). Retinoblastoma as also been reported n associawith assisredeproducriveechnologies.

MULTIFACT0RIAUPOIYGENICNHERITANCE.ultifactorial inhetance efers o traits thar are causedby a combinationof inhited, environmental, and stochastic factors (Fig. 80-1Multifactorial traits differ from polygenic nheritance,whrefersro traits thar result from rhe additive effectsof multigenes.Multifacrorial traits segregate i thin families buc do nexhibit a consistent r recognizablenheritance attern.Charteristics nclude he following:

l. Iherei a imilarate f €(uen(etypitally-5%)mongll st-degreeelaliverpariblingg,off5pdngI he ffertedild).lt r un|llualtondasubrtaltialnfie e n kl

rclativegelatedore ittnntlythannd eg.eeo he nder a5e.

2. lhedrk fn(ufien(er related0 he nddeftefthe ise e.

3. SomeirodeE ave s€x edilection,r ndiaatedy nunequalale emalen(id

Pyloft eno9k moreommon0males,herearongenitalislo(ationfthe iprirm(ommonn enaler.Whereherer analtepd lx la1i0,hedrk 9higheror he elativ

an ndex(deinthele$connonlyaffectedtex.Ihedsktohe onofanf{ededemal

infdntileylod(lenoeis318%ompandith fie5%uk or he on fanaffe(ed

lhe emalear asrednagreaterenetku(eptibility0hpr ffrpng.

4. lhe ikelihoodhat othdentiolwins illbe ffectedith he ame alfomatior

than 00%ut u(h reaterfianhe hancehat otfinembeBofaonidenli(alwin

willbe ffeftd.lherequen(yf(on(odan(eor denti(.ltwinrngetfioml%to6

Thit ittdbutionontras$ithhat fmendeliannhe an(e,inwhi(hideaticiltw

thare dkorderuato ingle utantene.

5. Ihe rhl of rc(u[en(er increaredhenmultipleamily nembersre af{e

therengtaneale oftenhe mortproblenatkor dirtinquirhingnuhifactol f

mendeliantiology.simplexanpl€r that he igk frc(ufienceorunilaterale

and alates496ora(ouple,ithone ff€ctedrildand nsea'tr o 996 ith rvoaffe

d\ildren.5, Theiikof eorren(e ay e nater henhedisodermoreevere,henfant h

long-tagmentlirsdlrprungireaseas greateran(e fhavingnaffe.tedibling

the nfant fio utshort-regmQntiuchsFungieease.

There are two cypesof multifactorial traits. One exhibits co

tiriuous variation, with normal defined by a statistical range, a

outliers of that range, usually two standard deviations, are co

sidered "abnormal" {intelligence, blood pressure, heigbr, he

circumference). Offspring represent a modified average of th



Ch|[to.8o . P.ttornsol Genolic ransmiision

Aminoglycoside-inducedeaf ess12S RNA

s€nsorineuraleatness (A1555G)

12S RNA \ \(A7445G)

\v. l 12s

T

P

I\,1ELAS,PEO 16 5IRNA'E' \

(A3243G) \L

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t Q

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Nna - NADHdehydrogenase" Subunrt

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(Leu15 6Arg,Leu 156Pro)

c o l

co A8

S

D KI

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(A8344G,T8356G)

Figure 80-12. The hurnan mirochondrial DNA rnolecule,showing rhe tocation of genesencoding22 rRNAs, rwo rRNAs, and 13 proreinsof the oxidacivep

phorytarion (OXPHOA) complex. Some of the most common disease-causjnBubstitutions and deletions n the mtDNA genone are also illustrated. OH

OL are the origins of rep)icarionof the two DNA strands, respecrively;12S, l2S ribosomal RNA; 165, 15S ribosomal RNA. The tRNAs are indicated b

single etrer codefor rheir correspondingamino acids (e.9.,L for leucine,K for lysjne).The 13 OXIHOS polypepridesencodedby mrDNA includecompo

of complex I: NADH dehydrogenas€ND1, ND2, ND3, ND4, ND4L, NDs, and ND5); cornplex [: cytochrome 6 (Cyt ,)i cornplex V cytochrome c oxI, or Cyr c (COI, COII, COn); and complex V ATPase6 (ATP-6, ATP'8). SeeTabl€ 80 I for representadve iseases.Adapted from ShoffnerJM, \gallace

Oxidative phosphorl.lariondrsease.n Scriver CR, BeaudetAL, Sly wS, er al [editors]: Tbe Metabolic and.Molealar Basisof lnheti4d Disease,Tth ed.

York. Mccraw-Hrll, 199-9; nd Johns DR: Mirochondnal DNA and dise se.N Ensl I M?i 1995;333:638-544. Frorn NussbaumRL, Mclnnes RR, Willard

Thomfrson 0 Thoh'bson Ceneti.s in Medici'e,6th ed, Philadelphia,WB Saunders, 001 )

Fisu.e 80-11. Pedigree of a mitochondrial disorder exhibi.ing

marernal nheritance. Btu€, affecredPatient.



DlStASt PI{EN0IYPE M05I ntQUEllT UTATlotlll MTDNA,!ott(Utt Holtl0PLASMYvStftnoPrAsMY l]HfRITAN(t

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l,tumpath!tax ret t , qmenl]!i,Eveloprnil Po imJtalionsnAlh5e . ir 16qene |]eteropsr l,4atena

dea); , ienta.a ai01 ct i i ai l . .mi

,1.1ahoncrlpni.phalom/olitii;ldrt ,( d0! , rnd Poifim aiionn q:iA" |].teropsft Matemal

nrokelikep odei;nav ar n cn ardirbetes

rne I'J5MERBf ,{1!oc)nrr p Fy' ,rqqed€l] lbersf mu5rle,tax , Poifim taticnn R\A' |]etfi0psh Matema

!ensoreuraledlxe!

Deafnei! rroq|e!!'ve5en5orcuralean.'55,oftencLtedy A15556inut]tonlT5rRNA |]0roplasmii L4atena

am oglrc5ident olcs

llonsyndrom5en50reuraleaFnesj(hmni(ror_tresl/e {sna ?:ogrl]s!:vehraines5le)lta0(urmu(ej

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Ai445Gutdton ll! rRNA |]olropl;s mi.

The(ormonIELASclr irJta1i0nn RNA arqp |]eter,lpa5mr

0clProirsi .niaro 55

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| , . imN-'bz[ IRL'! t | i |$iR! ' lLidt | i 'et |o| \ )|h|N\0, ln|11h'npJrn| : |4l l r.J] i ,1cf6€,5rh?dPhadehh,r\ ' l8rd| [ ]0] ,p;46

p a r e n t s ! wi t h l t U t r i t i o na l a n d c n \ .l r ( D m e ] 1 ta l i a c t o r s p [ ay i l r g a n t r i L l t r ri o r l | l i l b i | i t y

inportanr role. popuianorr. Lrdivjdurls wh o cxceed a thrcshold liabiliry

l(ith other muLrifactorial rl irs, thc discinction )er$-cen onnel affectcJ bi the treir.

anclabnormal s clearer pyloricsrcnosis, curirl uL)e lefect5,(Jn-' l 'hc

h.rl-rLr..hrnr.rr ' grrr.rre nnd Lvir()nlnental actor

gcnitalheart dele*s, al<l cleft l ip, clefi palacc). Lrchrarts ollorv clenronstratecll neural rube defects.Cleneric acrors are ima fhreshold nodel (t-ig. 80 l6). Thcrc is postulareclo be a clrs- cated bv fhc increascd ccrrrrcnce isk for partrrts of ln affe

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A41 yl

Figure 80-14. A, Myotonrc dysrophy pedigree llustrating anricipation ln rhis case, he age of onser or family

membersaffectedwrth an autosomaldominant diseases lower in rnore recentg€nerations.Blue, affecredparients.

B, An autoradiogram frorn a Sourhernbtot analysisof rhe myoronic dystrophy gene n three ndividuals. Individ

ual A is homozygous or a 4- ro s-repeat rllele of 175 repeats; his indrvidual has myoronic dystrophp lndividualC is also affecredwith myotonic dysnophy and has onenormal alleleand a disease ausingallele of approximately

900 repea6. (4, Counesy of Drs. Kenneth and Elaine Lyon, Universityof Utah Health Sciences enter.From JordeLB, CareyJC, BamshadMJ, et aL Medical Genetitr, 3rd €d. sr. Louis, Mosby, 2006, p 81.)

child compared o the generalpopulation.This risk is 3%, less

than what would be expectedf the trait was caused y a singlegene.Further emphasizinghe role of nongenetic nvironmentalfactors s that the recurrence isk can be owered by vp ro TOyo

Cho olm . Prnemsof Genelic lansmission

if the mother-to-be akes olic acid at 4 m9lday starting 3prior to conception-Another example s that a sequencetion in the nterferon egulatory actor 5 gene sassociatedafl increasedisk for cleft lip and palate.



502 PAnTX r HumanGenelics

Nalure snurture

FiBure80-15. The progressive ecreasen the genecicoad contributing ro che

developmenrof a disease reatesa smooth transitron rn the djsribution of ill-

nesses n an etiologic diagjam. In theory,no diseases re completely ree rom

the influenceof both genetrcand environmental facrcrs. (From Bomprezzi R,

Kovanen PE, Marrin R: New approaches o Inveshgating heterogeneiry n

compl€x rraits. Med Genet 2003t4U553-559. Reproducedwith permissron

from the BMJ Pubtishing Group.)

HighLiability

Figur€ 80-16. Typical hnear erythemr and bliscering n a female nfanr with

incontinentiapigmenrj.As the child grows older, he skin lesionswill become

flattened,pigmenredstreaks. (Photographcourtesy of Mrginia Sybert, Uni-versity oI\0ashingron, Seatrle. romNussbeum RL, Mclnnes RR, Wrllard HFr

Thompson d Tbompson Genetics b Med.icine,6th ed. Philadelphia, WB

Saunders. 001.)

Many adult-onset iseasesehaveas f causedby multifacial inheritance.Diabetes,coronary artery disease, nd schphreniaare examples.

Allegrucci C, D€nning C, Priddle H, et aJ:Srem-ceJl onsequences f emb

epiLgeneticdeferts. Lancct 2004;364 206-208.Bomprezzi R, Kovanen PE, Marnn R: New approaches o rnvestrgating

erogeneity n complex tfttts. I Med Genet 2003;40:553-559.

Clayton-Snirh J: Genornic imprinting as a cause of disease. B

2O03;327 1121-1122.Gosden RG, F€iDbersAP: C€neticsand epjsenetics-naore's pen-and-p

ser N Engl l Med 2007;3561731-733.

Jacob S, Moley KHr Gam€les and embryo epigenenc eprogramming af

developmenraloutcome: mplication for assisred eproductive echnoto

Pediatl Res 2005,5 *437 446.

JacquemonrS, Hagerman RJ, Leehey MA, et al: Penetranceof rhe fra

X-associated remor/ataxia syndrome n a permutatroncarrier populat

JAMA 2004:291:460468.

Maher ER, Brueron L\, Bowdin SC, et al: Beckwith-Viedemann syndr

and assisted eproducrjon technology(ART). .l Med Geftet 2003i4U62-

Teebi AS, El'Shanti H: Consanguinity: mplications for practice, esearch

oolicy. IaRcet 20061367'9 7 0-97 1.

Clinicalcytogeneticss thestudyof chromosomesiheir structinheritance, and abnormalities. Chromosome abnormaloccur n approximately% of livebirthsand are esponsiba largeproportion of early fetal losses,multiple congenitalmformations,and cases f mental retardation.They havea sigicant role in the development f neoplasias.

Chromosomeanalysis s indicated n dre child with multicongenitalanomalies nd/ordysmorphic eatures, t is indicafor the pregnantwoman with advancedmarernalage >35yr)

is also warranted n patientswith (1) two major malformatiand/or threeminor malformations; 2) problemsn earlygrowand developmenr,ncludingambiguous enitaliaor mental edatioo; (3) fertiliry problemsor recunent miscarriage )3), sbirth, andneonataldeath; 4) a first-degreeelativewith a knoor suspected tructuralchromosome bnormaliry.

METH0DS F CHR0MOS0MENALYSIS. ytogenetic tudiesusually performed on peripheralblood lymphocytes; ultufibroblastsmay also be used.Prenalalchromosome tudi€sperformedwith cellsobtained rom the amniotic luid, choriovillus tissue,and fetal blood,or in preimplantationdiagnosisanalysisof a blastomere.Cytogenetic tudiesof bone marrhavean mportant role in tumor surveillance, articularlyamoDatientswith leukemia.

Chromosome nomaliesncludeabnormalities f number astructureand are the resuhof errols in cell division. Theretwo typesoI cel l division:mitosis,which occurs n mostsomcells, and meiosis,which is limiced o rhe production of gecells,

In mitosis, wo geneticallydenticaldaughter ellsareprodufrom a singleparentcell.DNA duplicationhas alreadyoccurduring interphase, o at the beginni[g of mitosis the chromsomesconsistoI two DNA strands oined together at the ctromere.Mitosis as oursrages:rophase,ne;phase, naphand telophase. rophases characterized y condensation f DNA. Also during prophase, he nucleai membraneandnucleolus isappear nd he mitotic spindle orms. n metaphthe chromosomesare maximally compacted and are clea

Low -

Environmentalffect



Figurc 8l-1. A, Centromereposition determining the rhree types

of chromosome seen n rhe normal human karyorype-metacen-

tric, submetacentric,and acrocentric.B, MorphoLogic landnarks

use{ul n chromosome d€nrification.

Chapter l . Cytogonolics

fi=ifuxSatellites

I- secondary onstriction-i

ttSecondaryonstrictions

ii.. l- /''1 I 1 6

B

I

I

l sfltt

Metacentric

Submetacentric

l AAcrocentric

vrsibleasdistinctstructures. he chromosomeshgnac he center

of the cell an spindle ibers connect o the centromere f eachchromosome nd extend to centnolesat the two poles of the

of two chromatids, n meiosis,a diploid cell (2n = 46 chromo-somes)divides to form haploid cells (n = 23 chromosomes).Meiosisconsists f two major roundsof cell drvision. n meiosisI, eachof the homologouschromosomes air preciselyso thargenetic ecombination, nvolving exchangeberween wo DNA

itrands (crossing ver),may occur,This restrltsn a reshuffling f

alleleson rhe recombined hromosomes. acbdaughtercell henreceivesone of each of the 23 homologouschromosomes.n

secondpolar bodn eachwith a haploid (z = 23 chromosomes)set.Consequenrly, eiosis ulfills rwo crucialroles: t redrlceshechromosome umber from diploid (45) to haploid (23) so that

upon fertiliza tion a diploid number s restored, nd it allows for

genetrc ecombination.Two errorsof cel l divisioncommonlyoccur duringmeiosrs r

mitosis,and both can resulc n an abnormalnunber of chromo-somes.The lirst is nondisjunction, n which cwo chromosomes

fail to separate nd thus migrate rogether nto one of the new

cells,producingone cell wrth two copiesof the chromosome nd

another with no copy, The second s anaphaseag, in which a

chromatidor chromosomes lost becauset fails o movequickly

enoughduring anaphaseo becomencorporated nro oneof the

trypsin-Giem which producesG- or GTG-bandrng, uniquecombinarion dark (G-posirive) nd Lighc G-negatrve) ands

Many other banding techniques and special stains includ

qurnacrrne Q-banding), everse R-banding), nd cencromer

bandrngl are available for use in certain circumsta

Metaphase chromosome spreads are 6rst evaluated microsc

cally, then thei r images are capcured by a video camera and sto

on a computer Homologous chromosomes from a metaphspread can be paired and arranged sysrematicall y into a ka

orype. The chromosomes are arranged by size n pairs, the lar

autosome being designated chrornosome l and the sma

chromosome 22. The sex chromosomes (X and Y) make up

23rd pair A description of the karyorype includes two or th

parts: (1) th e number of chromosomes, 2) the sex chromos

constitution, and (3) any abnormalities noted. A normal ka

otype is 45,XX for females and 45,XY for males (Fig. 81-3

present, abnormalities are noted after the sex chromoso

complement.

While the internationally accepred system for human chrom

some classificatron relies largely on the length and band

Daughter ells..> -oo

Miloticnondisjunction

ZySote\

..> -?tQfigurc 61'2. Formation of mosaicism.The X and Y chromosomesare

ro illusrrace wo common errors eading o chromosomaltyabnormal cell

ulations. In normal mitosis /topl, duplicared chrornosomes separate

become ncorporated nro daughrercells. f one replicatedchromosome

to separate,mirotic nondrsjuncdonoccurs zrtldlel. Occasionall-v,ormal

aration occurs, bur one member fails to misrate. This is knorvn as anap

lÊ (bottom) (Used,wirh perm;sion, Iron wxnrewski LP, Hirschhorn

Glide to Huffian Chromosome Defec*,2nd ed. Whjre Plains,NY, Nlarc

Dimes Birth DefectsFourdation, Birth Defects:Orieinal Articl€ Series, o

'ec 6. 1980. )



504 PARTX r HumanGenetics

of the 24 differcncchtomosomepaints s labcled$.irh a clit fe

coflbinarion of the -i f luorcscentdyes (u'hich cmir ar diifcn'avelengrhs). lch oi th e 2. 2dutosomes.nd the X an d Y crnosornes ave fheir otvn Lrnique pectraof \\ 'avelengths f fresceDce. pecial i lfers.clnteras, and imageprocessing ofrwar c requireclo iclcnrif.vach chromosonrc.SK Y and M-Fl5Hespeciaily useful for rdenrifl'rng tire complex chr{}lDosrearran[jemcntsoLlnQ ll manv tumors.

Comparative genonrich,vbridization CGH) is a FISH bmethod fhar call be usedas a Henome-&'idecreen () neasur

ierencesn copy uLrrnbcr f a particular )NA sequence r cmosomirl segmcnl beru.cen u'o diffcrcnt DNA samples.tcchnique nvolvcs.li lferenrially abelin!ipatrerltDN A u'irh a

orescent le (green an d normal reference )NA rvirhanotheorescent ye (red).F-qual mounts of the tr,vo abelDNA sa|nare mixed and fhen lsed es a painting probe for FISH r

nornal met.lphase hromosolllcs. he ratio of grcen o red ffescences measured long cach chromosome.Regionsof amfication of patient DN A u,ouJd ciisplay a exccss oi gliuorescencc,vhi lc regrors of loss of paticnt D\A rvould sexcess ed f luorescence.f parient and control D^_A are eqlreprcscrltcd, hc green-to-red ario would bc 1 : I rnd th c cmosornes \\1)r.rldappear yellow

High rcsolrrrion (-(iH-bascd microarr:rys (alrlv (l(lH) hth e probe preparatioD hrt is dre same es rra(lit ionel CGH,

rether thrrr hybridizing th e probe to rnelaphase hrornossprcads, arge' inscrtclones (such as bacrerialart if icidl chro

somcs; lACls) pottedon nicroarrays serveas rh c targcr. hc

oluoon of array ( lGl l is Limited nl _v y thc sizeoi thc inscrt

thc distancc bcrrveen lones, vhcreirs hromosomc CCH h

resolutioDof only -5-ltJMb. Targeredarray basecl lGH is

Ijgu.c 31-3.(arvotvpcf norrnalnale ithchronrxonresn ht e prophxre.Lhc hromosomesre onger,r|rd greirer unrb.f oi b^ndsft.s.endrtrn

wherchronxxomesrephorogrephcrlr nrcraphrsc

pattern of each chrol' lrosome.he posif ion oi thc ccntromere el

atir.c o fhc cnds of rhe chromosomealso s e usetul distinguish

ing Fcature (scc fig. l l1-1). l 'he centrrnere divides rhe

chromosornc n trvo, rvirh the short arnr designared s fhe I ar mand rhe ong arnr designated s rheq ann. A plus or minus signbeforc the nrLrnbcr f a chromosome n(licafes haf rhere s ane\tra or nlissing chronrosome, cspcctii,cLy. aLrlc ll-1 shows

somc of thc abL)re\'ranons sed or the descnption oi chromosomesand rheir abnormalit ies.A rnccaphaschromosomcsprcdd

will usuallv shorv.150-500 balds. Prophase nd pronefaphase

chf(rnos(xnes are k)nge! are less condensed.and ofren shorv

500 850 bands. High resolution analysis s uscfLrl or dercctirg subtle chromosomc abnormalirics he r mrghr ofherwisc l jounrecognlzcd.

The fluorescencen situ hybridization (FISH) rechnrques uscd

ro ideLrrify he presence, bsence,or rearrangemcnrof specif icDN A segmenrs. ISH involves using a unique f)NA sequence

labelcd rvith a f luorescent d1e, rvhich is exposed ro single

srrandedDNA on a microscopeslide-Th e probc pairs rvirh i ts

complementarl D\A scqucnce nd call be visualizedbv lluores-cence mcroscopy Fig. I | 4). In interphase cLls. hc number ofcopies of a parricu)ar f)NA segment can be dcrcrmined. Innletirphasc hromosome spreads, he number of copies of theDNA sequence s \ 'ellas he exactchromosornaLocation of cachprohc copv .an be documenfed.FISH is particularlr uselul forderecting erl. smxll deletions hat might escnpe olicc wirh C;-

band anirl-"sis.{r i rh high-rcsolutionchromosome anal,vsist isi 'ery dif l icult to rccognrze elenons ess hal 5-10 miLlion hasepl irs {5 10 \1b) in sizc; FISH can reLiablt derecr delerionsas

small a 1 Nlb. This has allorvcd checlinrcalcharacrerizarion f a

number of njcrodelcrion svndromcs. n addrtion to laenc-or

locus specif icprobes.complex mixturcs of DNA from irne part

of a chromosomearm, an elt ire chromosomearL-n, r an entirechromos()me re available or f luorescencerainingof largechromosomeseclions r entire chromosomes- he prohe mixturcs arcrcfcrrcd to as chromosomepaints (lig. 81--5).

Spcctral aryotyping (SKY) and mult icolor FISH (N4 FISH) aresimilar molecular c-vtoljencticechliques that use.].4 difterentchrom()some ainting probesand -5 luolochromcs o simuirancousJl' ,Jsuali zc velv chrdnosome in a metaphase pread. -ach

\

.l6

tq

r t

l iE a l

l 8

"

f . li . I t l ; ' r .; ; i i ? lr i i : : i f t

7 I 9 1 0 1 1

i l . :r a G li . i I a r t J

. j i ; : t ' t

: ,

3 1

9 ){ ,; l

6

! ta a

t 3

f :1 9

1 4 1 5 1 6 r /

' aa l

20 21 22

XX Female

IY [,lale

l i i l Nurnber{ tot(e 5

ten [ef0ome0del Deetion

der Dervaiive

dJ! Dup,ld1ron

nJ Inse{on

nv Inyercn

eh Lr'euphaseilsP

i,l( 5h lnterphasels|]

nat L,laer

m05 lrmia|{

c0NDm0tl

lla'malema hr',1]i,ne

Nordlrale a'yotype

NJmberfr e 5 ed(h1]

5epardteine' fdone5ftmalewrhr omy ll\ ale /th oonosoml'l

kf

+

5hortamrLonqrnRinq(hmmolome

Ilansloction

Termninal5a5htuin fL0s5l



Chapter8lr Cnogenetics

ChromosomalNAon sltde

Denaturaln

-- ,r-

cGTT _ A

A _ T

c - G

A _ TcG

B

-

Renaturationi lhtluorochrome-labelled

DN Aprobe

c

TT

Gc

cG

Probehybrid ation

D C

o n c i r g e n t t i c s l i d e p r c p a I , l ] o n s 1 A ] i n t o s i l r g l e - \ t r l n d e d D N A 1 B T h t

c o p i e s o f a s n r g ] e s r r J n C | e d , i l u o l l c h l r n r e L a b e l e d D ^ v A b , l s e p [

BangsCl), ct al : FISJln

Dtsaf t lercn At lolesrents rate f rhe Art Rerlews Adolescenr ' lerl ieinc ht ladelphLr, rnler an d Bel fus, 002,pp 105 i1. ] )

2 ] - s p c c i f c p r o b e I h c 3 r e d s r g n a l s n r a r k r h e p r c s c n c e o i . ] c h r l n o y m e s ] 1 t . } I s H e n a 1 v s r s o f a r r r e r a p h a s e c h r o m r l v l l c s p r e a d i r o n l r c n i c a |

rndlvrdual using a rvhoLc-chromosome a

Chromosome ilhfluorescentprobestgnal



5m r PAnTX I Human orelics

NormalGhromosome21.8

1.51.2

0.9

0.6

0.30.0- 0,3.0 .6

- 0.9- 1.2. t.5. {.8

DiGeorge yndromedel(22Xq1.2q1 .211

0.30.0

.0.3

.0.G

.0.9

.1 .2

. t .5- 1.8

Figure 81-5, Representative rray CGH plocs rom a norrnal control and frorn an indMdual with the 22q11,2 deletior seen n Diceorge syndrohe. Each c

is arranged along the *-a-'ris according to i* LocatioR on the clEomosome *'ith th€ mo6t distalhelomeric p-arrn clones on the left and the most disraVtelomq-arm clones on the right. The blue line plots represent the ratios from the fust slide (control Cys/patient Cy3), and the pink plots represent the ratios obtai

from the second dide in which the dyes have been reversed (pati€nt Cy5/control Cy3). The mp panel is a norrnal plot for chromosome 22. Th€ lower plo

fron an individual with DiGeorge syndrome ir whom clones in the critical del€tion region a-redeleted (dt/ou). (Plots cou{tesy o[ BA Beiiani and LG ShaSrgnatureGenomic Laborarories,LLC.)

ocE=

ooGt

tJ

6coo-

ooGu

I

,t.81 .51 .2

0,90.6

effective and efficient techniquefor detecting cryptic chromoso-

mal aberrations, hich rnaybe an mportantadlunct o FISHandconventional hromosome nalysis Fig.81-6),

ABNORMATMESFCHROMOSDIIIE{UIDERAnsuploidy nd Polyploidy. uman cells contain a multiple of

23 chromosomesz = 23). A haploid cell (n) has23 chromosomes(ovaor sperm) . f a cell'schromosomes re an exact multiple of23 (46, 69,92 inhumars), the cell s referred o aseuploid.Poly-ploid or heteroploidcells are euploid cells with more than thenormal diploid numberof 46 (2n)chromosomes, hilepolyploidconceptionsare usually not viable, the presence f mosaicismwith a karyotypicallynormal ine mayallow for survival.Abnor-mal cells hat do not containa multiole of 23 chromosomes retermedaneuploid ells.Aneuploidy sihe mosrcommonand cUn-

ically significant ype of humanchromosome bnormality, cc

ring in at lea6t3-4% of all clinicallyrecognized regnancieTiiploid cells, hos€with three setsof chromosomes3n),

viable n a mosaic orm. Trioloid inlants can be livebornbutnot survive ong. Triploidy ii frequendy heresultof fenilizatby fwo sperm dispermy). ailureof one of the meioticdivisioresulting n a diploid egg o! sperm,can also result n triploiThe phenoqpeof a triploid conceptiondepends n the originthe extrachromoso$eset. f the exua set s of patemaloriginwill result n a hydatidiform mole.Those hat have an extraof marernalchromosomes re soontaneously borted.

Aneuploidies suallyconsistoi monosomy nd risomy.Monsomy,which may be completeor partial, occurswhen only oinsteadof the normal two chromosomess present n an othwisediploid cell, n humans,a1l omplete utosomalmonosom



Chapler 1 . Cytogenetics

appear ) be Le rha l a rh in deue lopm enr ;u rv iva l s poss iL r l . ' i n

mosaic orms, An enccption s monosomy for fhe X chronlosonte

farlure of chronosorres to disjoin normally durtlg mcit>stsse e

Fig. 81-2). No n di s r.LnctLonan occur durilg mclosis I or l l or-

dur ng nirosis. Aitcr meiotic nondrsjunction, hc result inggrnlctc

eirLreracks a chrornosome r has 2 copies, esult ing u e nrttncr

\ r m l L , 1 ' i n ' r n l r \ B ' , r e . ' c ' l \ l ' l l \ ( l ! ,Trisom,r., haracrcrizccLr the prcsclce of 3 instead ol thc

cel lsor ir may bc in mosarc orrn. N'{osrndividuals ' tth tr strrnr

exhibit a consisrcntand spccilic phenolypc depen<1irrgrr thc

chromosonrc nvolved. FISH rs c()mrtonly r.rlcd r rhc l)rendreLdetectionof fetal aneuploid,v nd rn tLre apid diagnosisof neu'

borns suspectcd o have a crtsotny,

Th c major nu c'ncal lisordcrsof chromosonres re -l rtLrtoso-

rn l l t r i so rn rest r i l om y l , u i son ty l l , t r i som y 3 ) , and 4 f l pes

of scx chrcrnTosornal neuploidics:I irrner

s,vndrone iusuallv

45,X); Klinetelter s\ 'ndrorne 47.XXY); 47,XXXr and'17,XYY

B,v ar the ilost conmon type oi rrisun-v n livehorr infants is

frisonly 21 lkaryotypc 47.XX,+21 or 47,X\+21) or Dou'[ s-vn

drome.' lr isom-v 1li irncl risorny li are also rclativeLY ornnlou

and are associared ' ith a characcerisricer of congcnital r[onr

al icsald nental rctardarion (Tablc t1-2).l)own syndrome s rssociated vith cognirivc mpairncnr en d

characterist icacial and orher dtsnorphic fearures Figs i l l -7 ft )

81-9). Affecred ndividLrals re nore prone to congcniralheart

defeccsatrior.entricul;rr eptaicletecrs, cnrrtcuLat eprdlciefects.

isolared ecunclum trial scpraldefecrs, DA. rerralogyoi fallor).

sY[DRo

Tr50myl,PataLl

5yndrome

I[ 5omy8, dmri]s

iyndrcme

[{cDt}tG

1/10,0{00fth5

l/6,000hs

Ir 5omy,mo5asm l /20, 000ifrh!

(trilt(ALANtFtsTAIt0lrS(leftlo lfrenmdlin,otflexednge6wihp0/da,:1y,J4tua

hypoteorm,bulbouroJe;w e tmalfomlpdar9

abn0Imakur;(ercbrdlfralfomat0n,e5pe

holo | ) ro5en(eohay;nrrophf l d,cdrdra(maf

icalp ei?cB;hyp0plrsrorab5enbs,vi5(erandgeni lalafomale5

Low thwl:igh[,c05edstiwlrrndex nger\€rapp

ld cal

andhe th 9{ cvrddpog he th, arcw

\rft |m pi labdLjctrcn,5hoernum,r0rker-bo

1r(mrepl;)' , romenicdput,m oqnath, dbc

r€namaiomaton5,dndmertactrdat0n;95%0

are than he l yr

Hypolonia,atlace.upl/lardxd dntedalpebiass!e5

epicinthfolds,speakledrue5Erushield$0n5);$rdeEeesi nentalandm!Vthiardirof;dysp! cf

Flv 5,l:adDr alfomatirnr,andinanredse;sh

handl,hyl)opgiafnr dle haanIi5th ing4du

aftesa,a"dqhar(hedaale:596fpatient5!rthDc

tndromerehe esull0faft!solntcn (l4q2lq

(l5q2lq),and{llq2lq)- i wi ch he hen0t}Ts

s,rmes ruomy?1own/ndmme

Longa(e,ghprorheqlorehead,\{,ideprurnei0jer

everted0llrPl ,mlooretruqnalhia,wsettars,gh

arched,50metme5:lell a te;0iteDdrtcufanornd

(0mm0n,mooetaleenla lanlit n

Ir5oni r,Down5yndlonr

t/5cc 00Dtnnl



500 PARTX r Human enetics

Figure 1-8. Characterisri cerrnal anerns f thepalmof a childwirh Downsyndrome, single lexioncreasesirnian rease), xial tlnadills (anol!) indislalposirion, patrern rea n rhepalrnbetweenhe hird and ourthdigirs,andulnar oopson all 10disjts. FromNussbaurn L,Mclnn€sRR,WillardHl Thoftpsob6 TbonpsonGenetics Medkire, 6rh ed.Philadelphia,rBSaunders,004, 160.)

gastrointestrnal anomalies, leukemia, Alzheimer disease, mmune

dysfunctroo, hypothyroidism, diabetes mellitus, ard problemswrth hearingand vision {Table81-3),Most maleswith Down syn-

drome are sterile; some females have been able to reproduce. Indi-

viduals with Down syndrome often bene6r from programs aimedat stimulation, development, and education. They also benefitfrom anticipatory guidance, which establishes the protocol for

screening, evaluation, and care for patients with generic syn-

dromes and chronic disorders. The lile expectancy for childrenwith Down syndrome is approximately 50 yr,

Down svndrome is the most common chromosome disorder

and the single most common genetic cause of moderate mentalretardalion. The incidence of Down syndrome in live birrhs rsapproxrmatel;r 1 rn 750; the incidence at conception is more

than rwice that rate, The occurrenc€ of tr isomy 21 as well asother autosomal trisomies increaseswith advanced maternal aee

12J5yrl. Due to this rncreased isk, women at thir age should 6eoffered genetic counseling and prenatal diagnostic tools (serum

screening, ultrasonograph)', ammocentesis , and chorionic villus

sampling) [see Chapter 96].Even though younger women have a lower risk, they represent

half of all mothers with babies with Down syndrome becauseoftheir higher overall birth rate. All wornen should be offeredscreening or Down syndrome in rheir second ffimester by meansof 3 maternal serum tests (free p-hCG, unconjugated estriol, andc.-fetoprotein), Even more efficient, with a detection rate of 95ol",is a method of screening using maternal age and fetal nuchaltranslucency (NT) chrcknessalong with maternal serum p-hCG,

PA?P-A (pregnancy-associatedplasma prorein-A), unconjugatedesrriol. and o.-fetoDroteln. Increased levels of maternal serum cr-

Figure 81-9. Prehensile oor in a l-mo-old child.(Frorn

WiedemannKunze J, Dibbern H: Atlas of Clinical Syndrones: A visual Cuide to D

, 'osrr,3rd ed. Sr.Louis,Mosbl ;1989.)

fetoprotein MSAFP)are also inked o orherabnormal etalcditions, ncludingopenneural ube defects nd defects f thetrointesrinal ystem nd genirourlnary ystem,

In approximately95lo of the cases f Down syndrome hare 3 copies f chromosome 1. Theparentalorigin of the sunumerarychromosome 1 is marernaln 977o of the casesresult of errors in meiosis. The maionw occurs rn matemerosis (78%). Approximately 1% of individualsare moswith somecells having 45 chromosomes, hile anorher47

individuals havea translocation hat involveschromosomeThe majority of translocationsn Down syndromeare fusionthe centromere etween hromosomes 3, 14, 15, or 21, knoas Robensonian raoslocations.The cranslocations an benovo or rnherited.Veryrarely s Down syndrome iagnosedparienrwith only a part of the long arm of chromosome triplicate (partial trisomy). Down syndromepatientswithouvisiblechromosome bnormaliryare he leastcommon.

&



ChapterSl Cylogenetics

DISORDENARYO]YPT

l$omy 4],XX/XX+8

\lanlg 1/,XXIX'1,+9

Irsomy6 47,XX/XI+16

Tetrarrmy 7,XX/XX+(12p)

(Ltr{tcArAfittsTATroxs

Grorrh ndmentalell(ienryre arrablehemallrrtyfpaten15

diem05a,Ihe

ptesen(efdeepaknarfld dntarfu,ovA

lt (naEcteI5l:c

Ihen40r{ydi rtr€rti ar6 oeirs (l,licaicatuts rilrde(an0fad3hiqhoreheadmi(mphthdlm,lowrel dl[orme,l

ea6, ulb0,rsoielandkelelaj0ifi onraturea)altornalnl

dnd eJrt efecls6096)

Them05tftequenty0b5erven,ruto50nilaneLrploldyspontaneous

abonronsheeturenelsk nElige(rownd5Pal inerl lnrtndrome5paxelnierf frapharr ,

eldrcw5,nd ye ihe5,ominentoPhead,hubbyheek5,nq

ph1rurn h hDupperpdndrpd bowonfiqurdror

Polydacryand reaksfhyper/hvcop!rnenlationavee€f

reFrreo

I t is not possible o disr inguish he phcnotypesot inLli\ ' r( lua

u' ith full tr isom,v l ald rhose \ ' ifh a lransl()cetiorr. xtlcntswb o

are nosaic tcnd ro havc r mikler phcnotvpe.(lhrorrosome arallsis is rnclicatcdn indivrdualssrLspectedi

havitg Dou'Lr ,vndronre.f a rranslocarion s idcnril ied,plrenral

chromosomesrucljesmrLstbe periorrned to deccrnrrne vherhcrone ol the parcLrtss:t translocatiol cirrrier, vhich carrrese hrgh

recLrrrenceisk ior havilg another rifccted child. Thar parerrt

lnirt dlso have orhcr farnrly nlenlhcrs af risk. Trarslocetiorr

l-11;21) afriers havc r l{)0'ra reclr'rcn.c risk lbr a chromoso

nrallv abnorrral chiL,:1. cnomic dosage rnbalanceconcribures

through direcran J indJrecr arhwa.vs r rhc l)or'n syodrorne hc

notype and it s phenotlprc variatior.

TebLes81 4 arrrl l l l-5 providc urorc trrfotnrariol on othct

aneuploicLiesnd parraL autosomalancrrploidies l ig s li I lt) rrr

l. t - l.

ABNOBM ATIT IESTCHFOMOSOMETsUCIURE

Translocaiions. ransloclt ions, r,vhLch rvolr'c the tralsfer oi

rnltcri: l frrur one chrorrosonre o aLrofhcr, ccur wrfh r trc

quenc' of 1 in 500 livcl.or:nhunran nfalrs. Thq mav l.e inhcr

TRISOMY] Tfl150['tY8

I , 'l l r i , Facrr lappcarancc i .1 .ht ld wrfh rr l somy 13 (From Wnrrnn I l { . KnDrcJ,DibhenrH. ,1/ ld. , , /Ol t rtLLalyndromes: Ysual (

n, l ) r r ! !osrs . rct .d St l -ouLs, osb! . 1989

Headndira Sc;p efe.r5eq,(utiapldl ) Smaind rem,rturerppearanie

M lophlhdia,orneabnomar5 llghtpapebra55Lrnl

[kfr pa u dalen 6096-80%fci5e5 Na.mw05e]nd ypoplarna5dlae

Miiro(epy

llcrochtharia

5otn9 thead

Ho po5en(ephrlyft nen(ephaiy)

[ar ]4ry emanqnmas

Deafnel5fhesl Ccnge,r13ea ni5ed5eeg,/ iD,PDA,

and ICJrn0% fcae!

Th rpot teicrD5m!5nqib5l

Erlftmrte5 0vedaooq 0fh0qer5ndce5dincdactyy)P|)ydanyly

lypopd5t(d ,hypPrc,invera,

Proff entoccul

1,4oliafi a

l :el po r a te

Mlc|o(ephaly

l.orEenil hed( 5ea5e9,V5D,lA.

and !D)

5hl]nternum,smallrpdP5

Lr|red ipabdu. rof(l'rodacryind verappingirlE15

ndex\rr d, 5ih ver ,c iei h5t

ffoil3f-botomeet

Hnooast(Jr l r

[enerd seveftpvelopmenla]delaysnd nnaEl ser'erelve pmentael 5.rdprctur:

and rlsinarairowthetardalcn and stm(a rouh elarcalon

Refalbnoimalities Premdt,r,?th, 0yhyd?Tniosi i lcrcarpmlei t$rsineuvophrls fqJrni lorabdo|I ' , ] lhernia5

f ty t% veofger lhdnrn o 0n1y5%rwonqerrhanlwa'

nomhb.mdRt,(kqrirnl!1l?iJcnfJrflrrollftdr,rrfteiPh delphi,WB5r!nde62002l4i A5D,dLridepl;]

delerr,DA"aknLu(L!:rter 5ur5D.nmolirtla denr

rfed t 'rom a carricr parc t or i lppcar'de novo, n' ith ncr orf iected fanril\ ,mcrnbc. Translocationsmal, be elther recjpror roircrtsonian lig. lJ1 1,1).

Reciprocal translocations rrc thc rcsLrltof brc:rks l nornrokrgous hrornos<nnes,lth reciprocalexchange f the bro\egrrlents. larricrs oi e rcciprocal rransk>catiou re usuallyllorvprcaLl}'nornlxlbur.re lt irn rncreased isk both for misriagcdu c ro unbalxnced ccipr<>cirlranslocatior and for beachronrosoarallyabnornral olfsprng. Unbalanced rans]oca.| e rhe resLrlt f xbnoromlit ies r rhe secregatiortcrossovertreLrslocirf lonarrler chtonlosornesn rhc gcrrn ccLls,

Robertsonian ransJocationsnvoh'c trvo acrocentricchro5orncs chro[losorDes .], 14, 1.1.21,ancl22) that fuse neirccnfrorneric egion wirh e subsequcnt oss 01 the shorr elJecausehe shorr arrnsol r l l -5pairsof acroccntric hrornoshave mult ipLecopresoi gcLresor ri l,osomal RNA. loss of

!h(rrt rrrr of 2 rcr()cenrnc hronosonteshas no deletcriotLsfThe resulring arvotvpe hr s on1y,1-i hromosomcs,ncludingrrnnslocntcd hromosome har is macleup of rhe oig lrm ofrn'o tused hronrosorne!. )rricrs of Roberrsonidn ranslocairrc sua]lv phenof,vpicalll orLrel. lotvever, he,v rc at increrrsL irr niscarriage nd u bdlinccd aLrnormal ffspring.

Inversiolts \ lt xlversion re(lurres hJt a single cbromosbreak et tu<r poinrs; he broken piece s rhcn nvertedan d jo

llrt(J the s;lnrc chronr(Jsorne,nversioLrs ccur ln 1in 100

l>rrr lrs. hcre are t\\1) types of rnversions: e.icentric and p

ccntric. lr pericentric nversions, he hreaksar c in the trv<>

srtc arnls of lhe chromosonre rnd rrclude hc ccntr()mere..1reLrsualLy iscoverecl ccausc hc_v hrnge rhe posirion ofccnrromcre. I he bre:rks n palacentric nvcrsionsoccur i[



510 PARTX r HumEn enetics

Figure 81-11. Trisomy l8; overlapping ingers and hypoplasricnails- (From Wiedemann HR, KunzeJ, Dibben ft Atlds of Clinrcal Syk*omes: A visual C

to Diagnosis,3rd ed. St. Louis, Mosby, 1989.)

one arm. Carriers oI inversions are usually phenotypically

rormal, but they are at increased risk for miscarriages and chro-

mosomally a bnormal offspring.

Deletioffi ald Duplications. Deletions may be simple, wich a

piece of the chromosome missing, or rhey mav occur along with

a duphcation of another chromosome segment, resulting in an

unbalanced reciprocal chromosomal translocation. The latter is

r-:suallydue to abnormal crossover or segregation n a tra[sloca-

t10n ot lnvetslon carrlet

Deletions may be located at the end of the chromosome or in

interstitial segments,A carrier of a deletion is monosomic for the

generic nformatior of the missing segment. Deletions are usuall,v

associatedwith mental retardation and malformations- The most

comrnonly observed deletions in routine chromosome prepara-tions ioclude 1p-,4p-, 5p-, 9p-, 11p-, 13q-, 18p-, 18q-, and 21q

(Table 1 5 andFig.81-15). eletions aybeobservedn rouchromosome preparations,wich deletions and t ranslocalarger han 5-10 Mb usuallyvisiblemicroscopicalll'.

High-resolutionbanding echniques, ISH, and DNA stucan revealdeletions hat are too small o be seen n ordinarroutine chromosome preads.Microdeletionsare small chrosome delerions, he largesrof rvhich are dececrable nly wprophase hromosome tudiesand./orDNA probes.For sucroscoprc eletions,he mrssing iececan only be detected FISH or DNA-imolecular tudies.

The presence f extraSeneticmaterial rom the same hrosome s referred o as duplication,Duplicationsor partial (mental) trlsomles are less frequent than rvhole trisom

Duplicationsmay be sporadicor result frorn abnormalsegLion n translocationr inversion arriers.

Fisure 81-12. Trisomy 18: rocker-bottom feet lprotruding calcanei). Frorn V/iedemann HR, KunzeJ, Drbbern H: Atlas of Clinical $,ntuomes: A Visual G

t^ DMEh^<t<.rd ed.St .Lous. Mo\bt . lc8'



Chapter 1 . Cytogeneficr

Figure81-13.Male nJentwirh trisomy78 ar age4 days.Norepromin€ni

occiput,mlcrognathia, ow-s€l earsrsholt stemum,narrow pelvjs'prominent

calcaneus,nd ler.ion bnormalitiesf the ingers.

E

A

13 ta

Ids(13;t.l)

BFigur€ 81-14. A, khematic djj?.F/zm left) and panial G-banded karyotpe (ri8ht) ot a rcciprocal Eanslocarion between chromosome 2 (blue)and chromo

8 (pink). The breakpornmare on the long (q) arm of both chromosomesat bands 2q33 and 8q24.1 with the reciprocal exchangeof material between he

ative (der) chromosomes2 and 8. This translocation s balanc€d,with no net gain or loss of malerial. The nomenclature or this aychange s t(2;8)(q33:q

B, khenetic d|agr^m (W) and paftial c-banded ka.yorype (ight) of a Robensonian translocalion between chromosomes 13 (blue) and 14 (pink). The b

points are at rhe cnrromere (band q10) of both ckomosomes with tusion of the long arms into a single derivative chromosome and lo6s of the shon (p

mac€rial.The nomenclature or rhis exchange s der(13;f4)(q10;q10).



512 PARTX r HumanGenetics

\

cFisureSl-l5.A,Chi ldwi thvelocardiofacialsyndromc{delet ion22ql l .2).B,Chi ldwi thl r: rdeGVit l is,vndrome(delet ionl5ql l -13) C, Chi ld wnh A nge

syndrone deledon iql1-13). D, Chi ld ui th \ i l l ia mssvndrome delerion ql1.23). Fronl Lln RL. CherryALI, BangsCD. et al ; Flsrl ins for ansrver

use of moJecular -vrogenericechniques n adolescentmedicnc practice. n I{yme HE, creydanus D [edirorsl: Ceneti. Disoders in Adolrsrent' Srafeof rhe

Re' ie\r 's. dolescenr edicine.Phj ladelphia, an leyand Bel fus,2002, t 305-31i . )

N'Iicrodelerions ard microdupl ications usDally involve regions

rhat include several genes,so that the affected indivrduals have adisrrnctive phenotype. When such a deletion involves more than

a single gene, the condirion is referred to as a contiguous gene

svndrome(Table8l-7).

Subtelomeric regiofls are ofien involved in chromosomal

reauangements that cannot be visualized using routine c_litoge-

netics.Telomeres, 'hich are the distal endsof the chromosomes,

ar e gene-rich egrcns,Small subtelomericdeletions/duplicacions

or rearrangements translocations,nversions)may be relatively

common in nonspecific mental retardation wirh mjnor anomalies.Subrelornericearraneements ale been found in 3-7?. of chil-

dren r.r'ichmoderare to mild mental rerardation and 0..5% of chrl

dren rvirh mild menral retardarion. Clinical iearures >30includeshort stacure,microcephah;hypertek>rism, asalaod

abnormaliries,and cryptorchidism m males. Thrs group is acharacterized y' 'a iamiLy hiscory of mental retardarion andincreased Likelihood of retarded gro\4'th beginning in the pre

tal period. Both rhe suhtelomeric rearrangements and

microdelecion/microduplication yndromes are diagnosed

FISH or other molecular means.Insettions. Insertions occur rl.hen a piece of a chromoso

broken ar trvo poincs is incorporared inro a break rn another p

of a chromosome.A total of threebreakpointsare then requiand thev mav occur bet\\,'een llo or vvithin one chromosome

form of lonreciorocal translocation. insertions are rare. Insert



carriersar e ar risk of having offspring wirh delerionsor duplica-

t ions oi rhe rnsetted ellrnent.

lsochromosomes.sochromosomcs onsistof two copresof rht

same chrornosomearnl loined through a singlecenrrolnerealtd

lbrning rnirror images of one another. Th e most frequcntlr '

reported aurosomal rsochronlosones cnd b involvc chronro

solneswi!h sma]l arms. Sone of chcmote colnnr()n hromosome

arms nvohed in thjs formation Lnclude p,8p, 9p, l2p, lt ip, rnd

sornic or the genespresent n thc isochronosorne.

MARKER ND BINGCHR0MOSOMES. arker chrornosonres rc

rare and are usual[ychromosome ragmelrs tbar ar c f(x) sn]all c

be idenrif iedbv bondedc,vtogenericslhc yusually occur rn addi

t l(r1 ro the normal .1 6chrontosomes. ' lost arc sporadic (709i,);

Lnosaicisms often (.50%)nolcd becatseof th e mirocic rtscabi[-

ity of rhe marker chromosonle.The incidence n neu horn infants

is 1 in.l, l00. and rhe ncidencc rr ndividuals vith nrelrt ir l erar-

dation is 1 in l(10. Their phenotvpe rarlgesho m normal lo

s rve re lv bno rm a l .

of a chrornosorne re delcrcdand the endsar e he n oincd to f irrrrr

a ring. Depcnding on rhe atnount of chromcrsomc narerial haris lacking or in erccss (i i rhe ring is in cddit ion ro the nornral

chromosomes),a patient wirh a ring chrotnosolrte an afl)ear

normai or nearl-ynormal or may have mental retarc]arron nd

multipie congcnitalanorll.r l ie .

SEXCHR0M0S0ME NEUPLOI0Y.bout 1 i n ,100 ta lcs nd 1 rn

6-50 cmales hare some lorrn of sex chrotrosome abnlrrntalitr"(-onsidereclogerher, ex chromosonrc bnormaljtres,rrc he uosf

connron chromosonreabnornrlit ies seen in lireirorn rnlents,

childrer, and adults.Sexchromosorleabnorrnaliftes ln b.'erther

Chapter 1 r Cytogenetics

MRYOTYPT APPNOIIMAITI.I(IDEIJORDTR

Ki ehllerFdrcfire

IYYilndrcmeOtherorYchmmc4omeabnolnalle5XXmaes

Tumeriyndofire

TrisomyX

47,XXY48,XXXY0lher48,XXYY,9,IXXYt

m0$1rt47,XYY

46,XX

45,X

1/5/5-li ,000l,lar

li 50,000/80,000lvidb

l/80C ,0lllNb 5

I / 500,rld s

l/20,011[4alrJ

l/2,50J1/5,C00;ema

0lher hmmosomebnomtaiel

XYenae5 46,XY

Variail5nd rolai(s47,UX l/1,000emales48,UXXnd 9,XXXXXRarc

l/1,000malesl/20,000ulralet

stmcturaL or numerical and can be prcsent in all cells or i

rrosaic form. Those aficctcd rvirh theseabrrormaliriesmav h

r L u r r r r r , l h r , s r r , r l' r J c r c . ' p m e n r . r lr o h l e r n sl . r h l e l - t r .

TurnerSyndrome. urncr slndrome, a coldit ion charactc

Lrr rhr complere or partial aLrsence f rhe sccondsex chro

some. s definedb- va conrhinationof phenotypic eaturcs T

81 9t . Hrlf oi rhc patienrs rvirh Turnel syndromehave a 4chronrosorne omplelrrenf. he other h:llf cxhibits nosaicrsnrane.l stmcfural abnorrrir l ir ics oi the X or Y chromoso

I)arentalage s not a factor in the 45,X abnornahty; its vari

occur rn approxintately I in .5,000 ernale rve hirrhs. n 7-l%

prrLenrs, he lost chr()mos()mes of parcrrralorigrn, 4-5.X s

of rhc chromosorrc a[.normalit ies rrrost frcquentl,vassoc

rrirh spontancoLrs borrion. lt has been esrimared hac 9-5-9

ol ,15.Xconceprions rre rniscarrieclTh c phenotype irr rh e ncrvborn can includc shott stat

prr)rnrner!eirrs,ucbhing of rhe neck. and edema of thc ha

Dtttltoil

lpl65ql56p257q1'1.))

JY DNOMI

lpdeldion

-bto550%)

Axenfed-Riegel

8D1l

rype

9ql4 eeton

D6eoqe

Poro([-5haffer

ldoDsen

Pradef-Wii

Ar4eman

l5q2ldel..tlon

Fubin5rein-Taybi

sfiith Magerf

t{llerDeker

Al iqi le5yndrome

Ve (ardEfa(idDGeorgeyndmme

cL r(AtMAl, tSlAIl0N5

Growthretardaran,dysmorphr(fearurc5wlhflatndiabdqe,,rbrcrmaear,deep-iereyet0yergrohlh,acrocphaly,aqe andind€pl islinrtiwa(idlearures,ieftal isabilric5Arenfudieqeralfornrdton,eannqrs,r0ngenrlaearldefe.ttdent?n0ma5,develo!menhldeay5,fadal5morphi!$

RaUndfac€WithfL]LChe€l5ancipl'5teldtepafefn|r'$labhmL]5,5|]po\'J|V!ar.]0I| it5temmtalrtardatn,l ndpeBonalty

Kallmansyndrcme2,5phem(ylosr5,mLrtrpeongenrla,rnomaie5,mefiaretard,itron[,1i(rcepha, ewlopnrentaleld]5,SD.VSDulmonrrteno5i5,nqenibehdvclabnormater

pir tum. r,lpaotrudg a6,md en(a elalrjatn

Ilu ple ,]5ael(arclnomas,odontoqenrreratol:y(!dlmopantari$ , ( ficatonak erebr

DI l ln(facW]lh5/nophry5, lnlevaledndIe5'tentedupperiDprot |LldingtongUe,mrdfatehypopa5id,

l\/lanyofhpCiGeorqelndvelocardi0facalfeatLrres

Multiphxo5toses,nlargedareldlforamd,(dn 5yn0sfo5fucla ysmorDhi5m,e0c aid :ap

N}peinephromdlW|mslUnrol),anrda'ma|eqent i |hyoopa5iaoIvaringdegees,gonadob|a{0rna'on

0to!r5,e,rkedo3e,lowet corlyoimedun( s,menlaeiada{on

Meniand rowtterardat;oi,ordarnd qit nonrlie5,hmmboqlopen

Seterehyp0t0nratbnh,obesrry,5h0rtitatJrere5pon5iveoqrowlhormoI1e),s,naandsndeet,ypogoiladr'r, entalrcladaiicn

HypoIonla'fai|ha|I'midb(ehypop|a5d,pm9n.]lh5m,5ezUre5'jeiqa1axitm4emefl'unconI@llab|eb0U]5o

Gmu]lhtadaton,aked 05e,rhupperip,5mailhandsId e4ment]leladalron

l\,1.forephal)1tori5,eaked05e ithowlynq h Irunr,roadhLrmb5ndargelrs,mentaletardalr0n

Brachxephaly,drar lhrpopla5d,pralndthm,myop,deh a tg$o( alure,ehavoraroblem5,enDlretadat0n

l.,1(|orPph,r|y,i59enGphay,padygyra'nar|oWlofheadhyp0p|anicma|eeX|erna|ge01a9,9lot{hre|ard

Bkdu(paucqwf{ho|e5i ]55;heande|ec| l 'pani0|ar|ypLrmoadIydt teIyJteno5i5;o(ulalabncmaitelo

ru(h 5 unerllyeltebneinq 05e hbmad id-nole

Hyp1jpa5iaofa9ene5i5oi lFethymL]5andNrdthyroidq|a0d5'hypopd5iofaui(eandextema|a]drIy

5hoatiaturc,ehavrocioberns

Hypoion,dpvel0pmentildey,n0rmaior((eehledmwth,ptori5,dyspft tornas,abnormilea[,poinledhin

Du(henneuscurdystrophy,ltl1iipigrnento5a,adrenalhypoFla5ia,menbetrrdatn,gly(erclkna5ede6oenq

dthyosi5,ai in 5yndtorne,efa eudat 0,cho0dr0dy5Dtapun(ati

lUcro0hthalrna,Lnedrikindereds,p0rkl0dem,r,i:ooqenihlhedrtdefe(1s,sezureS,mentaetadatn

Spl l

8p2l

8q24ql4 l l

9q22

tt4l0pl2'plll l p l l 2 -p l4l lp l l

11q24lllqlel15q11'q1lar )l5qllq1 l ma U

15q21l6plll1/Q1111/pll20p12

22qll

22q1l.le t,orXp21'p2txp .) )lIl/t1 ltl r0llldlrr4 l- hPardet''I\Vl5)



51 4 ' PARTX r Human enetics

:|l0rtrlrture

Lonqenitdmphedemi

Paiela5oct cn

ncrea5edryinqanqle];ebcw

illaielLlrgef0rmiyrh0ndrcdysps cfdina dalep hy56)

[onqei : i lhdJc(aron5ro r5'y'/

de5preadpFe!5hedheet

Eedundantfui [ ,1( r uiproiy$i lE ]0rnd)

Lcw o5terrha ne

[oardal0nlao{a

Ei(u5pido' i {a e

Lardr ordLrrtonbnotrute5

Fyp()plaqi{Pir ea'irfdrorel

:0radaidt\!leire!ilinil'l)1pindrlamenorrhea)[0nad0bl{ lmal 'Yihomo5cFremrieridlpreserl )

Lean q b rrll]snonverbaaceprudcrornd 5105pd1:alk15ln 70%]

ie!eloprnentalea)"n 10%)

ioca dL!klvddre55

iypothyrcd5ma.qu,,.d15 l]-lr6)Ii0e2ddbete5el ur{riurn et6lal)ej

5trJbriLrj

[aia,r(

Red reenclcioIndnessa5n n; ejlReaurien:trtlm'd,l

serioxn.rn Parnqss

Inflamm?toryowe sei5e(, ,8(l i reasg?

a n d f e e f , ) t m r ) n c $ ' h o r n s a f c f h c n o ! \ . p i c a l l v r r o r m a l l l g . l J 1 -'|

61. Oldcr chi lcl rerr rnd adul ts have shorr s tacure anc l exh ib i t var i

able d,vsnorphr c ieatures. (i rngrni tal hcart dcfccts (40%) anr l

5 t ruct r r r i r l renai d.omal ies (607.) are coLunolr Thc most

connon heart defects are bicuspid aorr i c r ,ahcs. coarctat ion ol

th c aorta, lorric srcrrDsis) nd mit ral valve proLapse.The gorrrds

are gereral l , \ 'st re aks of l ibrous t issuc (gonadal dysgenesjs). Ihere

is pr imarv aurenorrhea and lack of seconclarv scxual characrer ist ics. These chi ldr en shoLrid recerve re l lu lar endocr inr>1ogic cst ing

isee Chapter 587). Pat ienrs tend rcl be of normal inrel l igcnce bu r

are at increased risk for beh ar. ioral problcms ancl clcl iciencies n

spat lal an(l mofor fercelron.(iuidcl incs for hcr l rh supen' ision

ior chi ldren u'rfh' l i rner sl rrdrome arc publ ishcd br' the AAP

Approximarcly l0% of pdtienfs wirh 4-5,X,/46,XYmosa

have extemal geniralLahar are crthcr ar.lbiguots or femalercmxining 90-9i' v i l l have nornaL appearin[jcxternal n1.rletalia. I his va.raLlf s esrirnared rcprssent pproxinately 6prrt icnlswith nrosricTurLrer _vndromc.om cofthe patienfs'Iurner

sl.ndromephenor,vpe nc la Y cell l ine lvil l exhibrr culinizatiorr. Phcnocyprc lnaLes rvirh 4.5,X/46,XY irosaihave a 15 .10')1,lsk of clcvclopine onadoblastoma. hc ris

fhe patients i ' ifh a nele ph.notlpe an d exfern.ll testes sso high. but funlor sLrrvcillarcc s nevertheless ecomrne

The A,A.P :rs ecornmer(Le.lhc usc of FISH anaLrsis t) L(x

Y-chromosorre mosaicism n lll 4-5.X patients. I i Y chrosornc mntcr rl is idcnrii ied. laparoscopic gonadectom

rccom m ct )oeo ,

\oonan syndromc s arr aLrtosorlal lominanrclisorcler usolnepatienfs 609i,) tr a rnulation in PTPN/, n-hich elcodnon recep to rv ros inc inase SL l l ' - 2 ) n ch rom oso r re 2q

Features onmon to \oonal s,vndrornertclr.rclehorf starureposrcrior hxirl ir rc, shicld chesr,cougenitaL eart discirsc,

sho r ro r r vebbed eck I lab le 8 l - -10 ) . l con f r r s f o I u rne r. l r r r r c .N , ' , ' r . . \ r , d n , n r cr i t c c r ' . , r h r r . ' , r ' d \ . r , . r d i i lpaftern of coLrgeniral eart diseasc-

KlittelelterSyndro e. F.ighrl-percenr i childrerr$' ith l(hn

ter syndrorrc hevc a m,rlc karyotype n'rrh an exfra ahromosX-47,XXY1 thc rcrnainlng 09i,havea higher grrdc oi scr cm osom e i l r l cL rp lo id r , 43 ,XXXI ' 18 ,XXYY; 49 ,XXXX

mosaicisrr 46.XY/.17,XXY1,or srrLrcrlrrall_r-bnorrnal X cmosomcs.Thc grcalcr rhc dnetlploidy, he more scvcre he seand rncntal impairnrcnt arrd dvsnlorphisrn. Indivicluals

5M[5tat",re

Fa ' reo hrive

tpcntha cidr

fuo\i5

nypenef!m

Low a5dlbrdqe

DoLlnladlanlinqa ebri5iu.€5r,lpp

\ynaqtrr$-0w-5elaLllaes

Denla dDrilLl5on

Lowosrerio,a r

Snorrebbedc(k

5hieliht5t

P€rius(ov3iumrGanaiumS(olosi5

[ub us aq$

PLironJfyalveteio!i

llypertrophkrdiomyocahy

Atdlseph elerl (A-iDl

lelriloqyf r ot(ry!rcrchrrSmal e is

Bhednq trde[, (irdng tromboqt

Nfrgi , l ,VtJ2004i1.51:12 2--. -12i8 oplr ighr O20r)4 \ . lassrchrLsc trs.{edr. : r locrei}Al l r iel i ts cscricf



Klinefelterar e male; his syndtome s the most common causeot

hypogonadisman d nfertil ity in malesand the most common sex

chromosomeaneuploidy n humans (seeChaprer 584). The rnci-

dence s approximarely1 in 575 liveborn males.Errors in pater-

na l nondisjunction n meiosis (MI) account or half of the cases.

pr()gnosis for testicular function. Although individuals with

Klinefelter do not have a reduced intellect. rle)'show deEcits in

language and executive funclions.

47,XYYThe incidence of 47,XYY is approximately I in 800 to

1,000 males,with many cases emainingundiagnosed, incemosl

affected individuals have a normal aDDearanceand normal fer-

I igencebu t are at nsk for learning disabilit iesan d hyperacrive

behavror

fBAGltE SITES.Fragile sices are regions of chromosomes that

show a tendency or separation,breakage,or aftenuation under

parricular growth conditions. They appear as a gap in the stain-ing- At least120 chromosomal oci! many of rhem heritable,have

bein idencrfied as fragile sites in the human genome (seeTable

80-1). One fragile site hat has clinical signif icances that on the

distal long arm of chromosome Xq27.3 associatedwith tbe

fragile X syndrome. Fragile X accounts for 37" of the cases of

males wich merrtal retardanon. There is another fragile sitc on

the X chromosome FRAXE on Xq28) that ha s also been mpli

cared with mild menral retardacion.The FRA11B (11q23.3)

breakpoinrs are associatedwirh Jacobsen svndrome- Fragile sires

may also play a role in tumorigenesis.

The main clinical manifestations of fragile X syndrome rn

affecred males are mental retardation, autist ic behavjor,

macroorchidism, large size, and characterisdc facial fearures.The

macroorchidismma y not be evidentuntil pubertp Th e facial ea

tures, which include a long face and prominent jau', become moreobvious with age. Females affected wich tragrle X shorv varying

degrees f menral retardatronand/or learning disabilicies- iag-

oosisof fragileX is possible y irs molecularcharacterizarion nd

by the observation hat rr is associatedwirh an expandedDN A

segment. The expansion involves an area of the gene thar con-

rains a variable number of trinucleocide CGG) repeats.

MOSAICISM, {osaicismdescribes n individual wrth 2 or more

different cell lines derived from a single zygote and is usuaLly he

result of miroric nondrsjunction seeFig 81-2). Scudyof placen

tal tissue from chorionic villus samples collected at or before the

10rh wk of gestationhas shown rhat 27o or more of all concep-

trons are mosaic for a chromosome abnormalitt-. !(/ith the excep

tion of chromosomes 13, 13, and21, compJete aurosomal

trisomiesare usuallynonvrable; he presence f a normal cell in e

early embryogenesis, osaicismmay be present n some trssues

but not in orhers.Germline mosaicism,which refers o lhe Pres-ence of mosaicism rn the Eerm cells of the gonad, is associated

with an increased risk for recurrence of an affected child.

PallisteFKill ianSyndrome,This disorder rs characrerizedby

coarse facies, pigmentar,v skin anomahes, localrzed alopecia,

diaphragmatic hernias, cardiovascular anomalies, supernumerary

nipples,and profound mental retardatjon.Th e svndrome s due

to mosaicism for isochromosome 12p. The presence of the

isochromosome 12p in cells gives four copies of 12 in the

affected ceils. The isochromosome 12p is preferentially r.rltured

Chopter8l Cytogenolics

from fibroblasts and is seldorn present in lymphocltes.

abnormalit iesseen n affecred ndividuals probably reflecpresence f abnormal cells dunng early embryogenesis.

Hypomelanosist lto. This entity is characrerized y unila

or bilateral macular hypopigmented whorls, streaks, and pat(seeChapter 652), Abnormalit ies of the eyes, musculosk

sysrem!and central nervous system may also be present. Pat

wirh hypomelanosis of lto have rwo genetically distinct cell l

The mosaic chromosome anomalies that have been obse

involve both aulosomesand sex chromosomesand have

demonsrratedn about 507o of patients.Th e mosaicismmay

be visible in lymphocyte-derived chromosome studies ; it is m

lkely ro be found r .yhen chromosomes are analyzed lrom fibroblasts. The drstinct cell lines may not ahvays be duobservable chromosomal anomalies but to single gene mutat

or other mechanisms.

CHBOM0SOMENSTABIIITY YNDBOMES. h.omosome nsta

iry syndromes, formerly knou'n as chromosome breakage

dromes,are characterized y an increased rsk of malignanc

specificphenot,vpes.They display autosomal recessivenhenta

and have an rncreased requency of chromosome breakagear

rearrangement, r,r,'hether pontaneous or induced. Thev r

from specific defecrs n DNA reparr, cell cycle control, and a

tosis.The result ing hromosomal nstabilicl ' eads o he ncrerisk of developrngneoplasms, he classic hromosome ns

ity syndromes are Fanconi anemla, ataxia celangiec

Nijmegen svndrome, ICF (immunodeliciency, centromere in

brlrty., and facJal anomalies) syndrome, Roberts svndro\ferner syndrome, and Bloom syndrome.

UNIPARENTAIlS0MY Uniparenral drsomy (UPD) occurs w

both chromosomes of a pair of chromosomes ilr a person w

normal number of chromosomes have been inherired from

one parent. Uniparental isodisomy means lhat che cwo chro

somes are identical, whereas uniparental heterodisomy m

rhat the two chromosomes are different members of a pair.

o[ which were nherired rom nne parent. l he phenorypical

of UPD varies according to the chromosomeinvolved,

rhepa

who contributed the chromosomes, and whether it is isodrs

or heterodrsorny, Three types of phenotypic eifecls are see

UPD: (1) those relared to imprinted genes, hal is, the absena gene that is expressedonly when inherited from a parent

specificgender, (2)rhose related to autosomal recessivedisordan d (3) rhose related to a vestigial aneuploid produ

mosaicism se eChaoter 80).In unipareocal isodisomn boch chromosomes (and thLr

genes) n tbe pair are i dentical. This is particularly impo

when the parent is a carrier of an autosomal recessivedisoIf the offspring of a carrier parent has uniparental disomyisodisomv for a chromosome that carries an abnormal gene

abnormal gene will be present In rlr.o copies and the pheno

wrll be rhat of the autosomal ecessrve isorderi he chrld ha

autosomal recessivedisorder even though one parent is a ca

of tha! recessivedisorder. It is esrimated rhat all human becarrl 5 to 8 abnormal autosomal ecessrveenes. he autos

recessivedisorders sprnal musctrlar atrophy, cystic 6brosis, clage-hair hypoplasia, cr- and p-thalassemias, nd Bloom

drome have occurred because of uniparental disomy'.possibil ity of uniparenral sodrsomyshould also be considrvhen an individual is affected with more than one recessivorder because the abnormal genes for both disorders coul

carried on the same isodrsomic chromosome. Uniparental i

som-v s a rare cause of recessively nherited disorders.

Matemal uniparental disomy involving chromosomes 2, 7

and l5 and paternal uniparental disomy involving cbromoso

6, 11, 15, and 20 are associated ith phenotypic abnorrna

ofgrou'th and behavior.UPD maternal7 is associatedwitha



516 PAnT t HumanGon€tics

J--- +-.'-

Figure 81-17. In pediBrees uggesrive f parernal mpnnnng, phenorypiceffects occur only when the gene s transmitred rom the mother but not when tr

nnred frorn the facher.Equat numbers oI matesand femalesare affectedand not affectedphenotypically n eachgeneration.A non manifesring ransmitrer

a ctue co rhe sexof the parent 11hopasseshe expressed enetic nformation; in other words, in paternal mprinrinB, here are "skipped" non manilesting em

notype similar to Russell-Silver yldrome with intrauterinegrowchresrriccion.Thesephenotypiceffectsmay be related oimprinting (see mprinting, below).

UPD for chromosome 5 is seen n somecases f Prader-!7illi

syndromeand Angelman syndrome. n Prader-Willi syndrome,abow 60o/" of cases ave maternalUPD (missingche paternalchromosome 5). n about 5% of individualswith Angelman yn-drome,paternalUPD of chromosome 5 s observedmissinghematernalchromosome 5). The phenotype or both Prader-!(illisyndromeand Angelmansyndrome n cases f UPD is thoughtto be due to the lack of the functional contribution from a oar-ticularparentol rheirchromosome 5. These indings uggesrtherearedifferencesn functionof certain eeions fchromosome15 .dependingn wherher t s nheritedroir rhemother r fromtbe father,

Uniparentaldisomymost ikely ariseswhen a pregnancy tartsoff as a trisomy.Most trisomiesare ethal,and rhe etussuryivesonly if a cell hne osesone of the extrachromosomeso becomedisomic.One hird of che ime, he disomiccell ine s uniparental.

Usually the viable cell ine outgrows he trisorniccell ine.Whenmosaic risomy ls foufld at prenatal diagnosis, are should betaken o determinewhetheruniparentaldisomyhas resultedandwhether he chromosomenvolved s one of the disomies nownto be associatedwith phenotypic abnormalities.There mustahvaysbe concern hat some esidualcells hat ar€ trisomic willbe presenrn some issues,eading o malformatiols or dysfunc-tion, The presence f aggregaresf trisomiccellsmay account orthe sDectrum f abnormalities een n individualswith UPD,

IMPBINflNG.Genomic mprinting occurs when the phenotexpression epends n the parentof origin for certaingeneschromosome egments.Whether hegeneticmaterial s expredepends n the genderof theparent rom whom rt was deri

Genomic mprinting s suspectedn the basisof a pedigreeF8L-1.7and 81-18)with unusual ransmission.mprinting probly occurs n many differentparts of the human genomebuthought to be particularly mportant in geneexpressionelto development, rowth,cance.,and behavior.

Imprinting in humans s noted by phenotypicdifferencesrn Prader-Williand Angelmansyndromes,which are assocwith deletionand uniparentaldisomyof the same egionof chmosome15. Thus, in uniparentalmaternaldisoml chere s lack of rhe parernal segme[t of chromosome15, resultinPrader-Willi syndromeas well, In Prader-Vill syndromedeletion,when t occurs, s alwaysof thepaternallyderived hmosome15, suggestinghat thephenotype f Prader-\(illi sto a lack of paternallyderivedgeneticnformationcarriedon tsegment f chromosome 5. In contrast,when there s a del

chromosome 5 n Angelman yndrome,he deleted hromosis alwaysmaternal n origin, and he JPD s alwayspaternal,is, there s lack of maternal nformation.There are ikely tomany other disorderswith this type of parent of origin effec

ACOUIREDYTOGENETICBN0RMAUTIES.cquired clonal)geaetic hanges an be found in most tumor cells.Chromosanalysiss an mportant tool for the classilication f manyherologicdisorders.Most leukemias isplaynumerical hromos

-+--r--.,-l---.''-.'

Figurc 81 18. lD pedigrees uggestive f maternal imprinting, phenotypic effects occur only uhen the gene s transmrtted rom the facher but not when tr

mitced from rhe morher Equal numbers of males and fernalesare affecredand not affectedphenowpically in each gener3tion.A non-manifesting ransm

grvesa cJueco the sex of the parent *ho passeshe expressed enetic nformacionj n orher words, in mateinal imprindng, rhere a.e "skipped" non rnanife



abnormalities, structural rearaanSemenrs mairrly trans]ocations),

or borh (see Chaprer 495). Many of rhe chromosomal abnor-

malities are nonrandom and have been shou'n to be useful in

diagnosing rhe leukemia subtype afld predicting treatmenr

outcome, This has been especrally rue in the case of acute lym-

phoblastic eukemia (ALL).

PREI{ATAL IAGN0SIS.Prenaral diagnosis is indrcated q'hen there

rs a familial, marernal, or fetal condition that represents an

rncreased rrsk for malformation, chromosome abnormalitn or

genetic disorder. Advanced maternal age (235), whrch is associ-ated with an increasedrisk for aneuploidies, rs chemost common

reason for prenatal diagnosis. Chromosome analysis and genetic

counseling are also warranted in the event of (1) an abnormal

screening result; (2) a chromosome abnormality in a previous off-

spring, parent, or close relatrve; (3) a previous offspring with mul-

tiple congenital anomalies on whom no chromosome study was

obrained; 4) th e need or fetal se x determjnation n pregnancies

ar risk for serious X-linked disorders for which speciflc prenatal

diagnostic tests are nor available (seeChapter 83).

Prenatal diagnosis usrng cell or rissue samples for chromoso-

mal, biochemical, or molecular genetic str.rdiesmay be performed

using a number of technrques, ncl:ding transabdomin amnio-

centesis, chorionic villus sampling {CVS), fetal blood mpling,

and preimplantation genetic dia8nosis (PGD). In addirion, fetal

cells and free fetal DNA have been detecred n the mother's cir-cularron and can aid rn the prenatal diagnosis of fetal condirions(seeChaprer 96).

Alfirevic Z, Neitson JP: Antenatal screening or Down\ svndrome BM"/

2004;329:811 812.

Anronarakis SE, Lyte R, De.mnzakis ET, et al: Chronosorne 21 and Dorvn

syndrome, From genomics to parhophysiolog-v. Ndt Rev Cenet

2004;5:725-738.

BandyopadhvayR, Heller A, Knox DuBois C, el at: Parentalorigin and timinB

of de novo Robertsonian rranslocarion formation. Am I Hun Ceflel

2002;71:7456 1452.

Beiiani BA, Srleki R, Ballit BC, er at: Use of targeredarray-basedCGH lor the

ctinical diagnoslsofchromosornal imbatance:k lessmorcl Am I Med Genet

2A05:r34A:259267

Bondv CA, Van PL, Bakalov VK, et al: Prolongation of checardiacQTc

inter-

val in Tu.ner svndrome.Medicine 2006,8s:7S-81.

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by rapid aneuploirly resrins bf chronosones 13, 18, and 21 by FISH or

PCR without a full karyotype: A cyrogenetic .rsk assessmenr La,.ef

20O5;366:'t23-128.

Carrel AL, Moerchen V Myers SE, er al: Grolr'rh hormone improves mobil-

iry and body composirion in infan$ and coddterswirh Praderwilli syn-

&ome. I Pediat 2004:145:744-149

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chemical screening or trisomy 21 using feral nuchal rranstucency, bsenr

fetal nasal bone, {ree 0 hCG and PAPP-Aat 11 co 14 weeks Pleut Diagn

2003i23:306-310.

CrolJaJA, Youings SA, Ennis S, et aLrSLrpernumerary arker chromosomes

in man: Parenralorigin, mosaicismand maternal aee rcvtsied. Eur I Hum

C enet 2OO l 3 7S4-l 60.

CuDnrffCr American Acad€mvof P€dialricsCornmitreeon Genetics;Prenaral

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telomericrearrangenents:A checklist. Med Gezar 2001;j8:145-150

Douglas SD: Down svndrome: mmunologic and €pidemiologjcass,xiarions-

Enismasrenaln../ Ped,.rtt 2005;r47:723-725 .

Dyken ME, Lin'Drken DC, Poulron S, et al: Prospective olysomnographic

analysiso{ obstructivesleepapnea n Down synd ome.Arch Pediztr Adolesc

Med 2003 1. 7 655 460.

Garrison MNl, Jeffr;esH, Christakis DA: Risk of death for children with

Down syndromeand sepsis. Pediatr 2005;147:748-752.

Gibson PA, Newron RW, Selby K, et al, L:ngitudinal srudy of rhyroid func

rion in Down\ svndrome in rhe first rwo decades.Arch Dis C,h d

2005r90:574-578.

cicquel C, RossignolS, Cabrot S, et al: Epimutarion of the telomeric mprinr

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Chapter12 r Genetics ol Common0isorders: 0iagnosis and Management r

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and fragile X associated rernor/araxia syndrome: rwo faces oI F

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.etarded patients: Implicarions for routine DNA dta9nos.j'cs. ur JGenet 2004112124-28

Lanfranco 4 KamischkeA, Zirzmann M, ec al: Klinefeiter'ssvndrome. d

2004.,364..273-283.

lvlalone FD, Canick JA, Ball RH, et al: Firsr trimester or second-rrim

screening, or both, for Down's syndrome. N Ensl J M€d 200.52001-2010

MassaC, Verlinde De Schepper , er a| Trends n age at diagnosisoI T

syndrome.Arci D,s CDild 2005;90)67-268.

Mazzan.i L, Cicognani A, BaldazziL, er al: Gonadoblascoma n Turner

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Rappold GA, ShanskeA, SaengerP: All sbook up by SHOX deficie

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10% of crypric snbretomeric earrangemenrsn idiopathic s,vndromicm

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Robin NH, ShprinrzenRJ: Defining the ctinical spec(um of delerjon22q

J Pediatl 20Q5t147 90-9 6.Roizen NJ, PatrersonD, Downt syndrorne Laftcet 2003\36111281-12

Schubbert S, Zenker M, Rowe SL, er al: Cermline kR,4S mutarions

Noonan svndrome. ar Cer€t 2006:38:331- 336.SchwartzS, Graf MD: Microdelerion svndrom€s:Characteristics nd dia

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1227-7238.

Tarraglia M, Pennacchio A, Zhao C, €r at: Crin-of-tunL-tionSOSI mL,r

causea distinctiveaormoiNoonan syndrorne.Nat Genetics2007,39:75

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Vhpner R, Thom E, SimpsonJL, er al: Fi.st-trimesterscreening or rris

21 and 18. N Ersl.J Med 20033411405-1412.V'arburron D, Dallaire L, ThangaveLuM, e! al: Trisomy recurrenc€:A r

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Geneticstudiesare useful n diagnosingand trearing are patric conditions,ofrenalleviaring uffering,e)rTendingife, anthe case f neonatalmetabolic cre€ning,reventingnjury besymptomsdevelop,Ceneticstudiesmay also rdentify he caof more commondiseasesuchasasthmaafid obesiry,An unstanding of the complex and potentially multiple pathwleading o disease s crucial ro rhe development f appropprevenlion strategies including screeningof presymptomparents), s well as effectrve nd specific herapies.



518 PARTX r Humon onotics

Commonpediarricdiseases re often multifacrorial,with thecombinationof manygenes nd eflvironmental actors riggeringa complexsequencef events eading o disease. ach ndivrdualhas variations n his or her set of genes;he interactionsof theindividual'sgenevariantswith eachother and with the environ-ment determinesusceptibilrty o disease. he complexiry n thecombinationoI facrors ncreaseshe challenge f iinding genericvariants hat causedisease.Genetic ools include he completedhuman genomesequence, ublic databases f genericvariants,and the human haplotypemap. The incorporationoI these oolsinto largewell-designed opulatronstudies s the field of geneticepidemiology.

82.1 MAJORGEI{ETIGPPROACHESOTHESIUDYOFCOMMONEDIATRIGISORDERS

A model for the genetic conuibution to health is shown in Figure

82-1. Genetic liability is present from conceprion in all persons.

Sometimes this liability rs predominant and results in a srngle-gene disorder such as cystic librosis or si ckle cell anemia, In most

the liability is latent at binh but over time contributes to theemergenceof spec ific medical conditions, particularly upon expo-

sure to envrronmental factors. The goal in medical genecics s toidentify the generic factors in che hope of preventing the occur-

rence of disease,erther by avoiding inciting environmental factors

or by instrturing trearmenrs that reduce risk. For individuals who

cross the threshold of disease, he goal is to better understand theparhogenesis n rhe hope that this will suggest better approaches

to rrearmenr.

A srarting pornt in the genetic analysis of a complex trait is to

obtain evidence n support of a generic contriburion and co esti-

mare the relacive strengrh of genetic and environmental factors(Fig. 82-2), This rs done by determining u'hether a trait clusters

in famrlies and is seen amons related individuals more often chan

in the general population. Possible nheri tance models are delin-

eated by such segregation analyses, The relative st rength ofgenetic and nongenetic risk factors can be estimated by variance

compoflents [alysis,atld the amountof variabilityof a rrai tis due to inherited factors s termed the heritabilitv of a tChromosomalegions irh geneshat mayconrribuieo dissusceptibility an be ocatedwith lintage mapping,which locregionso{ DNA that are inherited n families with the spdisease. enedc ssociation tudies eek o determine elativeof diseasen individr:alswith specific enetic ariants.Dereof the modesteffect of eachvariaff and inreractionswith eronmental actors eouireswell-oowered tudies.

Both linkagemapping and association tudies equiremaralong heDNA rhatcan be ascertained, r genotyped, ith lascale aboratory echniques.Markers that are typically usein the form of microsatellites nd single-nucleotide olymphisms (SNPs) Fig. 82'3]. rVhile humans all have the sgeneticmaterial, everyperson'sgenome s shghtly differencomparison f any two copiesof the same egion of genomereveal that about one in every 1,200 baseswill be diffeusually n the form of a SNP Most SNPs dentifiedby comirtg two chromosomes re common and areessentiallyhe eqalencof geneticdialect,or random differencesn coding withsignificance r functionalconsequence, few of thesepolvmphismswill alter the biologic unctionof a gene,either by afing the structure of the protein or by altering rhe locaamoun!.or time atwhich theorotein s made.Some f these tional alterationsmay affect usceptibllty !o disease.

Outcomes n genetic tudies reclinicalphenoqpesand caa clinical iagnosisf a diseaser a discrete easurementr related o disease. phenotype an be measured y the presor absence f a disease s aquahtative rait, or by usinga maof disease, uch aspulmonary function tests n asrhmaor bmass ndex in obesiry as a quantitative rait. A homogenphenorypes ideal to avoid conflicting esults rom rhe scua trait that has tt'o or more etiologies.Geneticheterogerefers o a trait resulting rom more than onegeneticmechanThe develooment f a trait or diseaserom a differencmecharesults n iphenocopy, the occurrence f which would dininthe detectibilityof theresponsible ene,A pafticular genevarmay not cause he sameoutcome,and rhis pleiotropiceffeeachvariant depends n other geoetic ffectsand environmexposures.

t . iguIe82-l .Model fortheinf luenceofgenetrcsonheal th.Everyoneinheri rssomegenet icl iabi l i ty{ordiseas€risk,buriornut t rfactorialdisordersthist

ficienr ro produce disease n its own. Over time, exposure o environmencal acrors eads rom a presymptomaticco a disease tate. dentificatron of rhe g

responsible or risk can lead to orevenrionstrateeres r treatments.



Chalter82 r Genetics f Common isorders

GeneticEnvironmental 4easurementvariance variance variance

v P : v A + v D + v E + v t + c o v c E+ v M

VA=Addit iveenetic a anceVD Devialionue odomindnce ndepistasisVE=EnvironmentalarianceV :lnteraction arianceCoVcE:Covarianceot genelicsand environmenii igu,c S2 L Heri t ibi l i ry cr)ncept henoqvpic ar iance an be part r -

ttuned into gererrc uararce, ervrronmentalvariance,rhe covanance

benveel rhe tlvo. and measurement ariance. Genericvariarce can

Lreurrher partitnrncd nro addirrveatfectsand gene gere interactrons(epjstasist invi ronmental anance an ikervtse e pant r ioned nro

addnive atrd nreracriveeffecrs.HerLtabilitv s defined as the propor

tion of phcnotlplc veri:rn.e dc.ounred ior by genenc variance. One

caD esrimate hentabilirv in the ndrfow sense ron corrclation of .t

quanrirarive .ait betrveen elatives,as sho*'n in the table

There are many factors that may colnplicate scgrellarion and

heritability srudres.Many disedseshat are found to crack n fam-

ilies rna,vappear to skip a generation; a person could inherit an

allele (inherired unir, DNA segorent, r chromosome)and not

show any sign of the disease, phenomenon called ncomplere

penetraflce. om edLseases anifesrsignsonly larer in li fe, u'hile

orhersbecome es sobvious as rhe child grows olderi study pa r

ticipanrscould be misclassi6ed s unaffected gho actuallv have

the d ise . r se - l r ' r duc rngcne . M a r rv L " m nru r rd rsease \m d t r l t e \ t

with varying severit,vl families,and this variable expressivitys

another actor that could causemisclassif ication f People.Tb maximjze rhe ability ro derecra genewirh disease ssocia-

tron, environmelral exposures need ro be measured andaccoulted for in a populatlon.The interactionberween enes nd

Relationship

i,lonozygoticwins

Sib-sibor Dizygotic wins

One parenFOne offspring

l\,'!dparenFOtfspring

Firsl cousins

Uncle-Nephew

Hedtability

h2:2r

h2:2r

h2= 105=to.7o71

h2=8r

h2:41

the environment s called cpjstasis.Epistacic f lectscould a

the expressivity f a rrait as well as rhe penetrance. n era

of this is G6PD deficiency. n individual could carry the algene aod be deficient n l he enzyme.1e r would never hahemolyriccr is isunless xposed o an oxidative stress. eople

inherited propensity for malignant melanoma lr.ho live in dageographic egionsor limir their sun exposuremay neeercxth e phenoc,vpef cance. Asthma in some susceptible eople

developonly afl er exposure o cerlaln antigensor pollucanLinkageMapping.Linkage studies rvere used in the pa

isolare eneshat cause are genetic vndromes;modrfiedmehave been used to identi$ chromosomal regions linked to

common diseases. rnkagesrudies nvolve taggrngsegmenperson'sgenomewith markers thar allow identil ication of

Whal s an SNP?

Differentpeoplecan have aditferenlnucleotideor base ala given ocationon a chromosome

What san SNPmap?

GGTAACTG

GGCAACTG

Figu.c 81.-:i. Ditfercrt combinarions oa single nucleoljde

polymorphisrns SNPs)are found in different indn'iduals.

The locations oi rheseSNlrscrn be pinpointed on Drps oIhumangcnes. ubsequerr t l ) ,hev an beused o creet tpro-

files that are assocjrred rvrrh difference Lrr esponsckr i

drug, such as eificacv and nonei6cac-v.Adapted rt{,m

RosesA l'hafmacogenerics nd the prd.hce ot rnedrcrne-

Ndt'/zd2000;40J 857-865 Copvrishr 2000 Rcprinred b1

permission or Llacmillan Publ,shersLrd )

iff,llii""t'^l["

fi EHow can an SNP mao be used o oredictmedicine esoonse?

oction f SNPgqnoype rof

T|_ImTIlmatientsYi,ith llicacyin clinicalials

Patientswithouteff cacyin clinicalrials

Predictive f efficacy

Predictive f no etficacy



520 PARTX r Hurnan enelics

menls that bave been inherited through the famrly along wrth

disease, The markers are typically microsatellites or SNPs that

define u'hich tvpe of an allele any person carries. The type of an

allele is referred ro as a genotype. Linkage anal,vses f commondiseaseshave shorvn inconsistent results. Facrors sucl as hetero-generty,plerotropy, variable expressivitl'. and reduced penetrance

in addi tron ro varrabiliry in envrronmencal exposures \l,eaken theporver of linkage studies in complex craits.

GeneticAssociation. or mult ifactorial common diseases, sso

ciation analyses mav be better suited to detect small effects than

linkase studies. Genetic assocratron srudies are simrlar ro rradi-tronal disease ssociation tudies,with a person's enoc,vpeeing

used as a predictor of a disease or trait. The goal is to identifv

the actual allelesat a locus that confer the risk f or a disease.Three

basic designs re used: 1) a case-coltro] design,with a compar

ison of che frequency of an allele in affected people compared

with unaffecced people, (2) a population based studl', in u'hich

an inc rea \en J quan l r la l r vera r to r con t inuousmea\urement\

correlated with genotype, and (3) a family-based test, in which

cransmission f alleles o affecred and unaffected offspring is

cested. hjs lasc ype of anah'sis,known as a transmission ise-quilibrium rest (TDT), looks for an allele hat is cransmictedo

an affected person more often than rhe other allele. lf there is nc>

assocrarron etween an allele and disease, he transmrssionof

eachalleleshould be equaL,with eachhaving a 50/50 ratio. If an

allele confers risk of disease, he rransmission rario rvill be drs-rorted, u.irh one allele showing higher transmissron ro affeced

chrldren,The uccess f all 3 typesof associatxrn nalvsrs epends

on the desiEn f a well-poweredstudn wrrh enoughsub;ects, nd

atr accuratelymeasured rait ro avord misclassif icatron ue tovariable expressivit,v r reducedpenetrance nd ro minimize th e

effect of genecic heterogeneitv and pJeiotropl.. In large popula-

tion-based studies, confounding bv erhniciry or population strar-

ificarion could distort results. Some senenc varlanrs are more

lrequentlr round rn people rom a p.rrricularethnicgroup. rvhich

could causean apparent association f a r.arianrwrth a disease,

when the disease ate happens ro bc higher in that group. This

association would not be a true associalion betrveen ao allele and

a djsease,as the association *'ould be confounded bv ethnicitl',rl,'hich s oftel re(erred to as population strarification. The famil,v-

based cestsusing the TDT are immune co population stratificatiofl because he association s rot wich a soecif ic l lele.bu t rvith

a d is ro r r ion l r ran \m i \ \ i on n a t f e . t edpeop le i rh ina t . rm i l1 .

Assocrarion srudies should be a powerful rool to find genecic

variation that confers isk ro an rndividualt rhe effecrof any one

genetic varianr rvill be a verv small conrrlburion ro the complex

diseasepathrvay. Genetic variants have been found that impl icate

a novelgene n a process,modvating more in-depth esearchnr o

svstems hat &'ill affecr diseaseoutcome. Assoc iations such as theApoE4 variant with an increased risk of Alzheimer drseaseare

nored by many sr udies.Many published association esultsar enot reproducible; insuflicient pow'er and stratl6cation may

account fo r rhe inconsistencies.

Genetic discovery is also possible by focusrng on specrfic can-

didate alleles. There are 5 10 million SNPs across the genome,

far more chancan be cestedn any singleassociarion tudy'.Can-didare SNPsar e identrf led rom genes hat are suspected o con-

tribute to risk, perhaps because of a known phvsiologic or

biochemical role in che disorder A major limitarion is that unex -pected genetic contributions will be missed, leading to fai lure to

take advancage of the potencial power of rhe generic associalion

approach to uncover ner! 'disease mechanisms.Sequencing feach rndividual's genome u.ould detect all variants but is rmprac-

tical and expensive. However, by using known patterns in thegenome, lhe rnajoflty of vaflants can be assessed or each individual rapidly.

SNPs are arranged n the genome on blocks of 10,000 basepairs or more that have nor been interrupted by recombinatron

through generations;he SNPs n a block iorm an inheritedunit

called a haplotvpe. The HapMap proiect has delined these bloin four populations around the world, providing measurem

of the relationship betrveen SNPs in the blocks. This al lowsrhe selection f SNPs hat are proxies or "tags" for a haploblock. Genotyprng chis smaller subset of SNPs captures mos

the common variarion in a regon with far fe*er genoty

Current estimares show that 500,000 SNPs are sufficient to resent about 907n of variation in th e human senome. HapMap is a ra r lab le : a pub l i t Ja raba ' e . . ; l uab le res .for the design of association sudies that can be tailored to s

crnc Popularrons.

82.2 CURRENTrrrorRsrnnorrucFGENErrcsFCOMMONIsoROrRsNCHITDREN

The impacr of generic scudies of common pediarric diseas

being reahzed. Prevention and incervention may soon be poss

usingval id genecic ssociation esults o identif,v hildren at rThreeexamplesof diseases nder ntense crutiny or genetic

factors are tvpe I dlabetes mellitus, asthma, and obesit,v.

TYPEDIABETESELTITUS

Type I diaberesmellirus T1DM) is the best characterized f poJygenic,mult ifactorial pediatric llnesses sceChapter 590is a common diseasewith a well-defined phenotype and evide

of environmental and geneticcomponents. Linkage studiefamilies vith an affectedchi ld yield many loci thac appear o

consistently inked to rncreased isk for Tl DN{. A |:ewgenevants have been found rhat confer risk for disease,and some eronnental factors have been idencilied includrne vrral infecti

rriggering rhe autoimmune process.While rheie are rare '

dromic forms, such as Wolfram syndrome, resulting liom knomonogenicmutations,most childrendiagnosed vith T IDN{ ba currently unidentrfied etiology.

Heritability estimates for T1Dtr'l are cst imated bet\r' een 6and 72o/., u.irh trvin concordance of 307. to 50%. Althou

these studies ma,v be confounded by shared environmenr, ievident that, at least in part, there is an inhericed componen

T1D1!{ risk. The relative risk to a child in chegeneral populat

is 0.47", whereas or the sibling of a child with drabetes r rs

trmes higher ar 67". The Type 1 Diabetes Consortr(wtuw.tldgc.org) has undertaken a meta-anal,vsrsof all of

l inkage dara. They have also devised a uniform nomenclas1'stern, uch that promising linkage regions have been assignumbers, designated DDN{ 1-18. lt ' {any early scudies etelinkage at the MHC locus on chromosome 6p21 u.ithin the Hgene region. A meta-analvsis f these inkage studiesshonevery srrong [nkage signal wirh a LOD score of 65 at this locnhich has beendesignated DDM1,

'$(rhrlerhe HLA-{DDM1 locus has been studied extensiveJ

presents many chalJenges n dececting causal genetic alteratro

Many of the genes n the region have sjmilar functions and in coflcett in tbe Th2 immune system, The region also has h

linkage disequilibrium (LD); many of the proposed risk alleles

inherited together, making it di fficult ro isolate a srgnal from

one as being drrectl,v responsible for the rncreased risk. Thpercent of children diagnosed with TlDNI have rhe combrnac

of ailelesac rhis locus hat code for HLA-DQ2/DQ8 (genoc

Cornbinatrons of alleles (haplorypes) at two loci in the Hregion ar e risk alleles;none of these has pinpointed discinccausalvarlants.

The IDDM2 locus encompasseshe insulin 11NS/gene.Asciation studies idennfied varianrs rn this sene thar conferred

f o r T ID \ | . A r rpeat reg ion kno t rn a ' r VNTR. or va r i

number tandem repeat) near the INS gene has been associ



with diabetes risk, with a longer repeat correlated with increased

risk for T1DM. The mechanism of gene dysfunccion due to the

repeat is unknown, an it rs very likell, that rt is in LD with

arother \.ariant thar do alter funcoon or inreraccion to predis-

pose an individual to diabetes.

A varianr of the CTLA4 gete is found in the coding region of

this gene, suggesting hat a firnctional change n the protein could

cause suscepribility. Additional studies found a variant in rhe 3'

untransLated region in LD with the coding SNP ro be an even

better predictor of risk. Thrs SNP was in chepromoter region of

th e gene,whjch could also suggest functional role in ttanscription regulation. The mechanism by which alterations in this gene

increases susceptibiliry ro TIDM reguires a thorough search for

regulatory genes hat may interact with rhe promoter region.

OBESITY

Childhood obesity n rhe UntcedStates s increasing t an alarm-

ing rate (seeChapter44). Obesity s a multifactorialdisease, ith

man-v of che conrributing factors still unknolr'n. Ic is likelv a het

erogeneous phenorl.pe resulting from dysfunction many dif

ferent parhways. Concributing factors ma,v inclu a modern

environment of plentiful calories and low phvsical activitn whrch

combined rvirh inherited risk genes esults in obesiry

Prevrousll.,childhood obesity was rare enough that a severel)'obese child warranted consideration of rare syndromes such as

POMC (proopiomelanocortin) deficiency,Prader-rJ0illis,vndrome,

an d Bardet-Biedlsyndrome.A few studieshave suggested hat

childhood obesrty s due to rare geles lhat act as a recessiverait

and can explain a larger fraction of tAe variation in body mass.

Melanocortin 4 receptor (MC4R) rs an exampleof a genewrth

recessive urations hat are found in 3% of children with severe

early-onset obesity. Polymorphisms in MC4R have not been

found to be associatedwith more common polvgentc obesity

observed n th e generalpopularion.

Common forms of obesiqv show a complex pattern of family

segregation. Family srudtes and twin studies yreld estimacesof

heritabrlrty ranging from 3Oo/" o 70y", $.ith the t,vpical estimate

at 5070, meanjng hat about half of the variation in body mass

within apooularion

is due to inherited factors-Body mais index (BMl) is a phenotype obtained in many

cohort collecnons. Whole genome linkage studies have shown

evidence i l inkage egionson everychromosomeibu r a number

of regrons ave beendeteced n several tudies ha t hold promise

for genes associated with common obesiry. Linkage studies in

children have resulted in the discovery of rare mutatrons in genes

such as leprin and melanncorrin thaf account for some of rhe

severe arly-onset besity; hesegenes av enot beenconsrstenrlv

found ro conrribute to comrlon obesrt)..

Studies have also focused on candidare genes thougbr to be

involved in obesity-related athways, such as tnsulin signaling,

fatty acrd oxidation, an d appetire regulation, N{ore than 10 0

genetrc assocrationswith obesitv have beenreported in posirional

and funcnonaLcandrdace genes, ier verv few of these indings are

reproducible; none have led to a novelprevention or therapv for

common obesity. Haplotypes in rhe ghrelin recePtot, ENPPI,

leprin. and insulin signalingprotein 2 are reported o he rssoei

ated with. common obesrty', et only rhe /NSIG2 finding has been

repllcareo.

ASTHMA

Asthma is a common childhood condit ion; rr is increasrng t an

epidemic rate (seeChapter 143). In rhe United Srares,asthma is

more orevalent in Hispanic and African American chiLdren.

Atopy and aschmaare heritable. Asthma is a heterogeneousdrag

nosrs and is delined as reversrble airway narrowing with obs-

truction associated wirh small airlt'av bronchospasm and

Chapter 2 r Genelics f ComnonDi$o.deF

inflammation. It mav resuft from dysregulation of the Th2 infla

macory cells with hrgher serum levels of IgE . Children with

parents affected with asthma have a 507o increased risk of atoThe odds of asthmadragnosis n children aged 3 to 6 yr incr

by 2-fold in children u'ith two rather than one affecred par

Twin studies rn S$,eden and Finland bave found asthma h

tability esrimates of 80%, ',r.ith much hrgher concordancemonozygocic twins than in drzygotic rwins. Children of asthmmothers have a higher risk than those wirh aschmatic athers,

gesting the possibilit_vof in ureto mechanisms nfluencing risk

deveJopingdisease.In utero exposure to tobacco and maternal aslhma are ass

ared with jncreased IgE leveLs n infants and a higher rate

asthma. Early pulmonary infectrons wrth respiratory synry

virr.:s (RSV), rhinovrus, and Chlamydia pneumonia have

been mplicated in rhe developmenr of asthma. Associations h

been demonstrated wrth enviionmental exoosures such as en

to r in , . ock roach nddusrm r tean r rgens .ndd ie te l a r r i c les

lack of exposure to a differenr set of pathogens has been shoto inctease mmune deregularion and asthma, as proposed in

hygiene hypothesis. Exposure to parasites n early childhood beeo correlated with prorection against asthma and atop,v.

Asthma has quantifiable markers such as pulmonary functcests, inkaee studiesof asthma an d its markers have dem

srratedsomi overlap of DN A regronson chromosomes5q,

12q, and 13q. Linkage ro 20p13 ha s motivated associastudies n the geneADAM3.3 la member of the a disintegrinmetalloprotease domain farnily); this finding has not been re

ducible. ncerleukins and 13 are associated ith rncrease

levels. ,rhrle L-4 and l0 are assocrared ith airway rersra

as measured bv FEV,. Increased TNFo levels in bronchral se

tions led ro a str-rdyof polymorphisms in that gene wrth le

and asthma severitv.ln childhood asthma rhere is great variability in respons

medications. arge cohorc srudies n children (suchas he Chhood Asrhma Managemenr Program and che Tucson ChildreRespiraroryStudy)have provided evidence f subgroupsof cdren with asthma that drffer in the natural historv of the disas w.ellas in drurg response. Cbildren vary greatlv in responsleukotriene inhrbrtors and corticosteroids, another hetero!!en

aspect of rhe asrhma phenotype. Varratron in the []j-receptorbeen shou'n to influence response ro $ agonist therapy with particular genotype in rhe receptor causing reslstance o the

bi[zrng and dilating effecc of the drug.

SUMMABY t is clear that there is much yet to be discorcred abthe common drseasesffectingmosrchildren.Successfulheraand prevention strategies will depend on the dissectioncomplex pathways in whrch many small changesan d envimenlal interaction\can acl rn urder for a per*on fo enc(,unthreshold for drsease development. Gene therapy techniqcould be applied as treatmen! focused on modif,ving rhe acgenetjc risk facro! bur will reqr.rire dentilication of specilic tarin diseasepathwal's. Efforrs rn the past to supply a gene to tth e placeof a mulated geneha d some success, ut were lim

bv hrrst re;ection of the vectors. New discoveries promise mprecrse modulation of gene products using techniques suchRNAi (RNA interference) with synrhetic RNA molecules tar

ted for specific genes.

Th e ne w tools available o researchers ave allowed detecof a number of novel genesand pathways for common diseaand the adveot of whole genome association studies promise

acceleration f these esults. nteractionsbetw.een eri6ableallelesan d environmental actors as uell as epistaric nteracwiii be increasingly possible. Whole genome association stuwill provide vast amounts of data, requiring new anal,vtrc

to dissect the true effects and inreractrons, Whole senome ac ia r ion e \ f ingp rom iseso h igh l igh tmany gene l i ca r ian r \ lin relation to each other and environmental factors wrll eluci



522 PARTX . HumanGenotics

the pathlvavs leading to common disease, eading to rreatment

and ultimately preventiol of disease.

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2005;437:r299-1320

Balicki D, Beuder E: Gene therapy oi human disease. Medirme

2002181:69-196.

Bracken NlB, Belanger K, Cookson ViO, et al: Genetic and perinatal risk

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demia Rer 2002,24,L75-1 89.Carroll W, ,{sthma generics:Pit{alls and triumphs. Paediatr Resph ReN

2005;5:6874.

Cavazzana'Calvo 1, FrscherA: Efficacy of gene therapt for SCID is bejng

conf'tmed. Ltln.et 2004\364:27 5J1 56.

Escolar DM, ScacherjCC: Pharmacologicand genedc herap). or childhood

musculardvstrophies.Cwt Ne rol Newosci R€p 2001,,11158-174.

Ferry N. Heard J\.{: Liver direcred gene rransfer veaors. Hum Gene Ther

1998..9:1.975-1981

Frsch€rAr Gene herapy oI tympboid prinary rmmunodeficiencies. rr Opi'

Pediatr 2000,12:s57-552.

Crimm D, Kay MA: TherapcutLc ho.t hanpin RNA expression,n the liver:viraL argetsand lectots. Ce11e henpy 2006j13(rt):563 575.

High KA: Gene transter as an approach ro rreating hemophilia. Cil. Rrs

2001i88:137-144

Hirschhorn JN: Genetic epidemiolosv of qpe 1 diabete!. Pediatr Diabetes

2003;4:87-100.

Kaiser J: Seekins he cause of induced leukernras n X SCID trial- Sciezce

2003j299:495

Kozarsky KF: Gene herap_vbr cardiovasculardiseaseAtrr Opin Pbarmacol

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Ttends Mal lvled2002;8-.62-68.

GENETIC ESTING.Genetic testing involves analysis of genetic

material to obtain information related to an individualt health

status using either chromosomal analysis (see Chapter 81) orDNA-based re5ring.

0IAGN0STICTESTING.Diagnostic generic resting helps explain aset of signs and/or symptoms of a disease. The li st of disordersfor which speciEc genetrc tesrs is avajlabLe is extensrve. The,Nebsrte Lrtu)ta-gefietests.orgrovides a database of available tests.

Single-genedisorders can be tested by two approaches: hlkage

analysis aod direcr mutation analysis. The former rs used if the

responsible gene js mapped bur not yer identified, or if impraccical ro frnd specificmurations, usually becauseof chesiTe and Iarger number of differenr murarion' in some gDrrect mutation analysis rs Dreferred and is facilitated ahuman genome sequence s ftrrther elucidated a[d cechnofor mutation analysis improve.

Linkage testing involves tracking a genetic trait rhroufamily using cJosely inked polymorphic markers as a surrofor the trait (Fig,83-1). t requires escing n exrended amily

is vulnerable rc' 5sveral pitfalls, such as genelic recombina

genelic hererogeneirr,,and incorrect diagnosis in che probGenetic recombination occurs betrveen any pair of loci, thequency being proportional to the distance between them. problem can be amehorated b,v che use of very closelv li

markers, and, rf possible, using markers that flank the spgene, Genetic heterogeneity can be problemaric for a linkbased test rf there are multiple distrnct loci that can caus

same phenotype, resulting in risk that the locus tested rs noone responsible for disease n the family. Incorrect proband

nosis also leads to tracking the wrong gene. Linkage ceremains useful for severalgenetic conditions. I! is critically imtant that genelic counsehng be provided to the familv to exrhe complexities of interpretatron of test results.

Direct mutation testing avoids chepitfalls of linkage restir

detection of the specilic gere muration. The specilic appr

used s customized ro the biology of fhe gene beingtested. In sdisorders one or a few distincc mutatrons occur in all affe

individuals. This is the case in srckle cell anemia, in which

same single base substitution occurs in everyone with the d

der In orher conditiols, there may be many possible mutat

that accoun! for the disorder in different individuals. Cfibrosis is an exampler over a lhousand distinct mutathave been found rn the CFTR gene. Mutalon analysis wichallengrng becauseno single cechnique will decect all pos

mutations.Direct muratlon tescsare interpreted in llght of 3 factors:

lytical validrry clinical validiry, and clinical utilitl-. Analyvalidity is test accuracy-does the lest correctly derect the

enceor absenceof mutation? Most genetic tests have a very

analvtical vahdity, assuming that human error such as sa

mix-up has not occur red. Such errors are possible, and u

Diseasegene

2 2 2 4

Figurc tll-t. Use of linkage analysis n prenaral diagnosis oI an aurorecessive isorde.. Both parents are carriers, and rhey have one alfecre

The numbers betow the symbols ndicate allelesar 3 polvnorphic Loci:

and C. Locus B resjdeswithin rhe diseasesene The aflecredson inherne

1-2-2 chrornosone from his facher and the 2-1-2 chromosome fror

mother.The fetus has nherited rhe samechrornosome rom the father, b

3-2-4 chromosome ron chemother,and rheretore s mosr ikely to bc i ca

c

2 2



most medrcal tests, a genetic cest s unlikely ro be repeated, since

ir rs assumed hat rhe resuft will not change over time Therefore,

human ettors may go undetecced or long periods.

Clinical validity is the degree ro which the test correctly pre-

not prove rhat rt is the causeof the individual's disorder Various

lines of evrdence are used to establish pathogeniciry These

include: finding rhe variant only in ffected individuals; inferring

that the variant alters rhe funcrio of the gene product; decer-

mining whether che amino acid alcered y the mutatron is con-

served in evolution; and determinin rvhether tbe rnuca

incidental.

False-negative results reflect n inability to detecr a mutation

in an affected indrvidual, Thi occurs principally in disorders

gene, since mutarions can be varied both in locatron *'ithin the

genean d rype of mutatron,Direct sequencing ill missgenedele-

t ions or rearrangements, nd mutations ma y be found wrrhrn

noncodingsequences uch as ntrons or the promoter; a negalive

DNA tesc does not necessanly exclude a diagnosis.

Clinical utility is the degree ro which cheresults of a test guide

clinical management. For generic testing, clinical utilitv includes

establishinga diagnosrs hat obviales che need for addit ional

workup or guiding surveillance r treatment.Test results may

also be usedas a basis or genetic ounselingThere ar esomedis-

orders for which genetic rescing s possible but in whrch the test

resultsdo not add ro the clinical assessment.f lhe diagnosis nd

genetic implications are already clear, it ma,v not be necessary o

pursue geneltc tesnng.

PREDICTIVE ESTING.Predictive genetic testirg involves perfor-mance of a tesr rn an individual who is at risk of developinga

genetic drsorder (presympromatic), all,von the basis oi family

hisrory; yet does not manrfest signs sl/mptoms. This is usually

done for disorders thar display age-dependent penetrance; the

likehhood of manifesting ignsand symptoms ncreases"ith age,

concern hat a posit iveDN A restma y reslrlt n stigmarizationof

an rndividual and may not as yec provide ioformation that rvi l l

guide medical managemenr. Stigmatization might include psl'

chologJcal tress,buc could also include discrimination, ncluding denral of heafth, ife, or disabil itv rnsurance r employmenr

(seeChaprer 78). lt is generally agreed har predictive genetic ests

should be performed for children if the resulcs of the rest will

beneft the medical management of the child. Otheru'rse, che est

should be deferred until the child has grot'n up to the point of

underscanding rhe risks and benefirs of resting arrd can provide

rnformed consenc. ndivrdual states offer varyrng degreesof pro-

rection from discrimination on che basisofgeneric resting; federa)

legrslation as noc yet passed hrough the U.S. Congress.

PREDISP0SITI0NAtESTING.t i s expected ha cgenetic estsma y

becomeavarlable ha t will predict nsk of disease. ommon dis-

orders are multifactorial in etiology; there may be many differ

Chapter 3 r Integration f Gerelics ntoPodiatricPraclico

ent genes that contribuce to risk of any speciflc condrtlon

Chapter 82). Mosr of rhe genetic vananrs that have been fo

to correlate wrth risk of a common diseaseadd small increm

of relatrve risk, probably in most cases oo little to guide m

agement. lc is possible, however, that further discovery of g

lhar conLribute !o common disorders will reveal examples of

ants thar convey more significant levels of risk. It is also pos

that testrng several genes ogether will provide more informa

about risk chan any indrvidual gene variant would confer.

rationale for predispositional cesting s tbat the results would

ro srrategiesairned ar risk reducrion. Thrs mighr include av

ance of environmental exposures that would increase ris

disease,medical surveillance, or, in some cases,pharmacolog

lreatment. The vah.reof predispositional tescing r'ill need t

cfltically appraised through outcomes studies as these tesr

deveLoped,

PHABMAC0GENETICESTING. olymorphisms in drug metabo

genes may result in distinctive pacrerns of drug absorp

mecabolism, excretion, or effectiveness seeChapters 56 and

Knowledge of individual genotypes will guide pharmacolog

therapy, allowing customuation of choice of drug and dosa

avoid roxiciry an d prurrde a rherapeulic esponse.

83.1 GENETICOUNSELII{G

Genetic counseling is a cornmunicarron process in rlhich

genetic contribudon to health is explarned, along with sp

risksof transmissionof a trart, and options !o manage he

dit ion and ts inheritance Table83-1).Tb e counselor s exp

to oresenr nlormation in a neutral. non-direcrive nanner an

pro,ride support to che individual/f amily to cope with deci

t|lat are made.

Genetic counseline has evolved from a model of care that

devek;ped n the contexr of prenatal diagnosis and pediacrics

Table 83-1). Fo r prenatal diagnosis, he task is to assessis

a couple of havrng a child with a genetic condrtion and a

the couple about options to manage that risk, including reductive options such as artiEcial insemrnarion and prenala

preimplanration genetic diagnosis. In pediatrics, the task

establish a diagnosis in a child, provrde longicudinal care fo

chrld. and advise he Darenrs bouc isk of recurrence s r.e

options to deal with that risk,The generic counseling role has expanded, particularly

advances n understanding the geneticsof adult-onset or com

disorders. Genetic counselng has a major role in risk asses

for cancer,especially breasr and ovarian cancer or colon ca

for which rvell defined genenc tests are avai lable to assess is

an irdividual.

TAIKING T0 FAMltlES. The type of information provided

family depends on the urgency of the sit uation, che need to m

decisions, and the need ro collect additional informatThere are 3 srtuations in which genetrc counseling is parhcu

rmPortant.

The lirst is the prenatal diagnosis of a congenital anomagenetic disease. The need for information is urgent becafamill musr ofcen decidewherher to continue or to termin

pregnancy. Risks to the mother must also be considered.

second rvoe of situarion occurs when a child is born wit h a

threaremng congenital anomaly or genetic disease. Deci

must be made immediacely with regard to holv much sup

should be provided for the child and whether certain type

therapy should be artempred. The rhird situation arises lat

life rvhen (11a diagnosiswrth a genelic mplication is rnad

a couple rs planning a family and there is a family history



524 PABTX r HumarGenetics

(onranguinity

Terat0genxposureo(upational,bure)

Repeatedregnancyors rinfe ility

Pregnancy(reeningbnolmality

MitenJl5e:ufrletcpr,rn

MatemalIi ! ( r?enr ,J l ] f lhJi . , i tltlal ullaronoErfiy

fetd aryotipe

Heterozygotecre€ningased n€thnk itlS d , . a l i r e m d

IJr. ;clt aJrrir!ar,JL(h.{ aiia!

Iha 5gem5

F0llow-upo abnormale0natalenetkesting

genctic pfoblem. includrng rvhethcr on e member oi a couplecarriesa translocationor is a carrier of an abllorlna]gene or anautosomaL ccessive r X-Llked disordcrl i3 ) ao adolescent ryoung adulr has a family historv ot an adult-onser cnelicdisor-de r iHuoringtoo disease, reastcancer); 4) unrlslral eaturesar e

presentand a (llagnosis s wanting or not possiblet rf ld (5)thereis suspecred xposure o a loxrc subsrance r tcratogen. f is oftennecessirrvo have severalmcetings vicha famiJl. n this third cat-egorl' . - lrgcnc,vs ooc as much of an issucas being sure hat the,vhave as much iniormation and as many options as are available.

GENETIC 0UNSEtING rovrdrng ccuratc nformacion o familiesrequires (1) raking a careful famrly historl. and constructing lpedigree rhat l ists rhe patrenr! relatives (including abortions,sril lbirrhs,deceasedndividuals)n ith tlreir sex, age,and stateofhealrh, up ro and ircluding rhird-degree clativcs; 2) garhering

informatjon from hospital recordsaboLlt he affecred rdividual(irr sorne cases,ahout orher famiLymembers); 3) d()curnenringpreretal, pregnancl; :rnd delverl.histories; (4 ) rcvierving chelarestavailablcmcdical. aborarory., nd genetic n[ornratioucon-

cerning the disordcr; i5) careful phvsical cxamilarion of rhealfected ndividual (photographs, neasuremenrs) nd of apparentl)runaffecrcd ndividuals n rhe amily; (6 ) establishing r con-firming the <iiagnosis v the diagnosrrc esrsavailable;17 )grvingrhc family informatron abolrt sLrpport roups; (8 ) providing neu'information to the family as it becomesavailable a mechanismi i ' r upd r t ingneeJ ' . ' h r < .Lab l i rhed ) .

Counseling essrons us! include the folkrt ' ing information:Th e Specif icCondit ion r Condit ions. f a specilicdiagnosis s

rnadc and confirmed, that should be drscussed ' ith che familynnd inlbrmation provided in wrrtrn€!, However. ofcen the disor-de r firs ittto a spectrum (1 of manv types of arthrogryposis)orrhe diagnosis s clinrcal ather rhan aboratory based. n thosesi ruarions, the famil,v needs to undersfand fhe limits oi preseDt

knou-ledgcand rhrr addit ional research vill probabll, leabetcer nformation i n th e future.

Knowledge f he Diagnosis l the Pa.ticularCondit ion. lrhoit js not aiu.ayspossible o ll lake an exact diagnosis,havinaccuralea diagnosis s possible s important. Esnmates |: ercnce risk ir|r.ariorLs family mernbers depend on an accudiagnosis. 0hen a specilic iagnosis annot lle made (a s n ncasesof mult ipie .ongen ta anomalies), he vari<>us iiferediagnosesshould be discrLssed ' irh the iamilv and empiin [u rm ar io r

5 ' r

r rded . f ' p cL f i d ragn , ' soc , " , t r r re" t r ' l "thcv should be discussed.

NaturalHistoryof the Condilion. t rs very important to disthe natural history of the specif icgeletic disorder n the famA le r ed nd i l i du r . l nd t he r r am i l i es i l l ha . . t uc , r inn . estng hep roAn ( , \ l s l | dpo fen t i J lh r r Jp \ rh . l t . l n b r r , \ c rcdwith knorvledge of fhe ritlrral hiscor,v. f rhele are other posdrffercntial iagnoses,heir naturalhistory ma,vdlso be disculf rhe disorder s associaredvith a spectrumof clinical ourcoor complications, he worst and best scenarros, s \,r 'ell s trmen! and referral to thc appropriate specialist, shouJaddressed.

Genetic Aspects o{ the Csndition and BecurlencB Eisk. Tinformation is ilrrporfant for the family because all farmernbersnecd ro bc mate of their reproductivechoices.generics f rhe drsorder an bc explarned virh visual aids

figof chromosornes).c s inrportant coprovide accurare ccurrand recutrence lsks for various members of rhe farnill ' , nciLrg naflectcd ndividuals. f a de6nitediagnosis annot Lr cmir is recessary to use empirical recurrence risks. CounseshouLdgivc th e individuais the necessarynfonnarion to rrnscancl he varrous oprioos and let th e patientsnake their oinfonned dccisions regarding pregnancl,, adoptr<>n, rri6inseminarion, renrraldiagnosis, cr eening, arrierderectionlennlnatiol of preenancv. It ma,vbe necessar,vo hirve more fone counseling essi()n.

PrenatalDiaqnosis nd Preventi0n.r. ' lan,viffercncmerhodprenatalcliagnosis re available, epending n drc specilic endisordcr seeChaprer95). The useof ultrasonography l lovr.snatal dia8nosis of auatornic abnormalit ies such as congeheart defccts.Amniocentesrs ld chorionic vrllus samplinqus . ' d u oh t . r in e r , r l r ' . u c t . r . rna l l s i i ' f ch |on ro .on r i labmaliries, biochemicirl disorders, and DNA studies. Mateblood or s erumsampling s used or some ,vpcs f scr eenrng.cells can be rerrieved from the urnbilical cord or from matebltxrd or tcsting.althoughnothers may harbor cells rom all vrouspreSndncreS,

Thetapies nd Beferral.A number of genericdisorders eqlhe careof a specialisr.ndividualswirh Turner s,vndron,tesuneed R) be evaluated y an endocrrnologist, reventionof knoconlpLcations s a priorir,t. The psychologicadjusrmenrof family may require speci6c ntetveDtron.

SupponGroups.A large number of communitv Iay supgroups have been iormed ro provide informarion and to fresearch n specif ic eneric nd nongenetic oldit ions. An imptanr par! o| .genetic ounselil1gs to glve nformarion rl)oLrt hgroupsro individualsand to suggest contact person or the fi l ies. Many groups have establishedwebsitesu' ifh ver,vhclrntormatron.

Follow-up.Families shorl]d be encouraged o continoe to questionsand keep up u' irh ne w information about thc spedisorder. Nerv developnents oitcn influence the diagnosistherapv oi specilicgenericdisorders.Lay supporr !(roupsagood sourceof nerv nfornation.

NondirectiveCounseling.ienetic counseling s usually norecrive; hoices bout reproducrionare eft to the familv to dewhat is t ight for thern. Ttre role oi rhe coulselor (physic

gencuccounsel()r, urse,medical geneticistl s ro provide inmation in undersrandable erurs nd outline the ranseof oDtavaiiable



83,2 MAI{AGEMENTt{DTREATMENTF

GENETICISOBDERS

Genetic onditionsareoften chronicdisorders;ew are amenable

ro curativeherapies. evertheless.herear emanymanagement

oprronsavailable. ll individuals/familieshouldbe provided

rnformation about the disorder,genetrc ounseling, nticrpatory

manrpulations, uchas avoidaace fphenylalanineor indrvidu-

al s with phenylkeronurra;oenzymeuPplementarionor lomeparients ir h merh lm aon cacidemal provision { substrateso

ixcrete ammoniafor thosewith urea cycledisorders;bisphos-phonate rearment or rhosewirh o\teogenesismperfeccao

ieducebone racrures; nd avoidance f cigaretre moking or

PHAffMACOLOGICHERAPIES.any physiologic therapies use

it is highly effective n rreatmentof CML and severalother

malignancies.

REPTACEMENTHERAPIES'Replacement rherapies include

reDlacement f a missingmetabolite,an enzyme'an organ, ol

evena specific ene.Enzyme eplacements a comPonent f the

rreatmenc f cy'itic6brosis o manage nteslinalmalabsorPlion.

Chaptor } | htegralioft l GeneticsntoPodiatricPractice

Pancreatrcenzymesare easily administered orallJ, since rhey m

be delivered to che gastrointestinal tracr. Enzyme replacem

strategies are effective for some lYsosomal storage disorde

Enzymes are targeted for the lysosome by modification w

mannose-5-phosphate, which binds to a specific receptor T

receptor is also present on the cell surface, so lysosomal enzym

wirh exposed mannose-6-phosphate residues can be tnfused in

the blood and are taken into cells and EansDotted to lvsosom

olism, and hematologic or rmmunologic disorders A succes

rransplant is essent ially curative, though there may be signifi.c

risks and side effects (seeChaprer 134).

Replacement of a defective gene (gene herapy) may offer a

invasive means of achieving a cure of a genetic disorder (

Chaoter 82).

Alliance of Genaic Supp rt Gtovps Directory of Ndtio,Bl Genetic Volun

Orsonizatiots, 35 Wisconsin Circle, Suite 440, Che\'! Chase,

20815-70r5.BarrelsDM, LeRoy BS, Mccarrhy 4 et at: Nondirecdvenessn genelicco

seling: A survey of practilione..s.Am J Med Genet 1997;72:172-179

Bowles'Biesecker , Marteau TM, The fuure of geneticcounseljng:An in

national persp€ctive,Nat Cenet 1999;22:133-137.

Burke w: Genetic tesrins.N Engl I Med 2002i347:1867-1876

Farrell MH, Certain LK, Farrell PM, Genericcor:nsetingand risk conmu

cation services f newborn screeningprograms.Arcb Pediatr Adolesc M

2001r155:120-125.

Frver AEr Clinicatgenetic ervicesr criviry, outcome,eff€ctivenessnd qua

Summary of a report of rhe Clinical Genetics Commifte€ of the R

Coljege of Physicrans- Roy Coll Physidans Lond 1997\3r:624-621.

ceneclinrcs:[email protected].

Hayflick SJ,Eiff, M?, CarpenterL, et al: Primart care Physicians'ut,liza

and perceprionsof genetics ervices.Genet Mea 1998\1:13-21

Holornan NA, Watson MS: Prornoringsafeand effectivegeneric esting n

United Srates:Final report of the rask force oD geDetjc esting, Bethe

MD, Human Genome Resea.ch nsrilute, 1997.

Hubbard R, Lewontin RC: Prrfalls of genetic testins N t,gl / M

199ti:3i4:1192-1194-

Preimptantationgeneticdiagnosis-For or a8ainst humamty? Ldn.et 2O

364:1729-1730.

PressN, Brown€r CH: Characterrsrics f wornen who refusean offer of

natal diagnosis:Dara from the California marernal serurnalpha fetopro

blood tesr experience.Am I Med Geftet 1998;781433445.

Sermon K, Van SteineghemA, Liebaers : Prermplantariongenetjcdiagn

Laicet 2004,363 1633-l 640.

ve.linsky Y, Rechitsky S, SharapovaT, et al: PreirnpLantationHLA tes

I AMA 2O04;291:2O79-2085

Ve.linskv ! Rechrtsky S, Verlinsky O, er al: Preimplantat,ondiagnosj

sonic hedgehogmutation causing amilial ho{oprosencephaly r" EzglJ

2001r348:1449-1454.

1

v



Part(.Vletabulic

errorsof metabolism.Most mutations are clinically inconseguenlral nd represent

may never ause linical iseasen e lifenme f the ndividual.

Potencialpsychosocial mplicatio of such findings can be

der.astatingand deservesserious consideratrons.ntrauterine

diasnosisf mosrgenetrconditionssnot' feasiblendha sbeen

usei routinel-vo Jetecraffected erusesn the population ar risk(seeChaprer 6) .

Childrin with inbornerrorsof metabolism ay present ithone or moreof a largevarier-v f srgns nd symptoms. hesemay

includemetabolic cidosis,ersistencomiting, atlure o rhrive,

diagnosis.

NEONATAf-ER|0D.nborn errors of mecabolism ausing linical

findings are usuallv nonspecificand simiLar o lhose seen n

infants ..ith epsis.n inbornerrorof metabolismhould econ-

sideredn the differennal iagnosis f a severelyll neonatalinfant,and special rudies houldbe undertakenf the ndexof

susprcions high(Fig.84 1).Infantswichmecabolicisorders re usualLy ormalat birrh;

I seasBscalcium and response to intravenous injection of glucose

calcrum usually establish hesediagnoses.Becausemost inb

errors of merabolism are inherited as autosomal recessive ra

a history of consanguinitvand/or death in cheneonaralpe

should increase suspicion of rhis diagnosis. Some of these di

ders have a high incidence rn specific population grou

Tyrosinemia 1'pe1rs nore common among French-Canad

of Quebec than in the general population. Therefore, knowle

of the echnic background of the patient may be helpful in d

oosis. Physical examination usually reveals nonspecifc 6ndin

with most signs related to rhe central nervous s,vs

Hepatomegaly is a common finding rn a variety of inborn er

of merabolism. Occasionally, a pecuhar odor may off-eran rnv

able aid to the dragnosis (seeTable 84-3). A physician caring

a sick infant should smell the patient and his or her excretr

for example, patients with maple syrup urine disease have

unmisrakableodor of maple syrup in their rrrine and on t

DOOleS.

Diagnosis usually' requires a variety of specrfrc laborat

st dies. Measurements of serum concenlrations of ammo

bicarbonate, and pH are often very helpful initialLy in differe

acingmajor causes f metabolicdisorders seeFig. 84-1). El

t ion of blood ammonia is usuall y causedby defecrs f urea c

enzymes. nfanrs with elevatedblood ammonia le"els from u

cvcle defecrscommonly have normal serum pH and bicarbon

values; rvirhouc measurement of blood ammonra, they m

remain undrasnosed nd succumb ro their disease,Elevatio

,...,. u-.oii" is also observed rn some infants with cer

organic acrdemras.These infants are severelyacidocic becaus

accumulationof organic acids n body Ouids.

When blood ammonia,pH , and bicarbonate aluesar enorm

other aminoacidopathies (such as h,vperglycinemia) or ga

tosemia should be considered;galaccosemic nfants may

manilest cataracrs, epatomegalr' , scites, nd jaundice.

Most inborn errors of merabolismpresenting n the neon

penod are lethal il specific redtffient is not iniriated rmmedia

Specilic diagnosrs, even in an infant in rvhom death se

inevitable, is of great importance for genetic counseling of

familv (seeCbapter 83;. Every effort should be made co de

mine the diagnosrs while the infant is aiive; postmortem exa

narion is noc ah,r'avs helpful, A specr6c diagnosis may

esrablished -v measuremenrof abnormal metabolices n b

flurds, bv assay of the specific enzyme activit-vror by identil

r ion of chemutant gene.

CHILDBEN FIER THE NEONATAIPER|0D.Most inborn errors

metabolism rhat cause symproms in the 1sr ferv days of

exhibit milder varianc brms chat have a more insidious onThese forms may escape detecrion during tbe neonatal per

and the diagnosis may be delayed for months or even years. E

clinical manifestations in children wrrh rhese orms are commo

nonspeci6c and may be attributed to perinatal nsulcs.

Clinical manifestations, such as mental retardation, m

delicits, developmental regressron,convulsions, m,vopathr', e

rent emesis, and cardromyoparhy are the common finding

older children. There may be an eprsodic or intermiftent paft

with episodes of acure clinical manrfesrationsseparate

periods of seemingly disease-free tates.The episodes are usu

An inborn error of metabolism should be considered in anv c



5Ag PARI r MebbolicDi$€rs€6

Initial indingBncludeoneor moreot the ollowing:a) Poorfeedingb) Vomitingcl !'BthargY . Nor r€sDonsiveoo) uonvuElont intrave;ous lucose r calciume) uoma

Nomal

IObtain

bloodpHandCO2

Figure 8+1. Clinical approach co a new

infant wirh a suspectedmetabolic disorderschema s a guide ro rhe elucidadon of so

rhe metabolic disorders in oewborn inAlthough rome exceprjonq o rhis schemair is appropdate for most cases,

r-rr--l

Obtain

High

Obtain

bloodpHandCOz

Normal Normal niongap



with one or more of rhe following mani{estations:-rnexplained

mental etardation,developmenral elay ot regression, r motor

deficitor convulsions; nusualodor,particularlyduring an acute

illness; ntermittentepisodes f unexplained omiting, acidosis,

menral deterioration,or coma; hepatomegaly;enal stones;or

muscleweakness r cardiomyopathy.

Grosse SD, Dezateux C: Newborn screenirg for jnherired metabolic disease

Lancet 2007;369:5-6.Marsden D, Larson C, Levv HL: Neit'born Screenihs o. rnetabolicdisorders'

J Pediatu2006;148 51 7 5 84

McBryde KD, Kershaw DB, BunchmanTE, er 1, Renal replacemenr herapv

in rhe rreatment of confirmed or suspected born errors of rnetabollsm.

Pediatr 2006;L 48:7 7 0-7 7 8.

Warsbren SE: Neuborn Screening for merabolid dtsorders -/AMA

)006;29 6:993-994

85.1 PHENvIALAI{INE.ra i Bezvani

viduals was found to be close o that of normal subiectswhen

Ch6pler5r Delgstin Metabolisnl ArDiro cids

studiedby magletic resor]ancepecroscopy MRS)and imag(MRI) echniques.

CtASSICPHEt{YLKETONURIA(PKUl.evere yperphenylalanin(plasma henylalanineevels>20 mg/dl-), f unrreated'nvariaresults n the development f signsand symptoms fclassicPKexceot n rare unDredictable ccasions

ClinicalManitestations.he affected nfant is rormal at biMental rerardation may develop gradually and may not evrdent or the 1st few months. It is usually severe, nd m

patients require institutional care if the condidon remaunreated. Vomiting, somerimes evereenough co be misdnosed as pyloric stenosis,may be an early symptom. Olunreared children becomehyperactive,with purposeless oments. hyrhmic ocking, nd arhetosis,

On physicalexamination, hese nfantsare ighrer n theircoplexion han unaffected iblings.Somemay havea seborrheeczematoidash,which s usuallymild and disappearss he chgrows older.Thesechildren have an unpleasant dor of phelacetrc cid,which has beendescribed s mustyor mousev. hare no consistentEndings on neurologic examination. Minfanrs are hypertonic wirh hyperactivedeep rendon refleAbour 25% of childrenhave seizures, nd more han 507" helectroencephalographicbnormalities.Microcephaly, rominrnaxiJlawith widelyspacedeeth,enamelhypoplasia, ndgro

rerardationareother common indings n unueated hildren TclinicalmaniFesrationsf classicPKU are rarelyseen n thcountries n which neonatal creening rograms or the detecof PKU are n effect.

MITDER OBMSO' HYPEBPHENYI.ATAI{EMIA" ION-PKU YPPHENYIAIANII{EMIAS.n any screeningprogram for PKUgror-:pof infants are identilied in whom initial plasma ccentrations of phenylalanine are above normal (2 mg/120 pmoleil) but <20 mgidl (1,200pmole/L).These nfantsnot excretephenylketones. linicalln rhese n{antsmay remasympromatic) ut progressive rain damagemay occul gra

ally with age,Thesepatientshave milder deficiencies f phealanine hydroxylaseor its cofaclor retrahydrobiopterin B

than rhosewith classicPKU. AftemDtshavebeenmade o c

sif,vhese atienrs n differentsubgro sdepending n thedeof hyperphenylalaninemia,ut such practicehas ittle clinor therapeutic dvantage. s with classicPKU, defciencyof Bshould be nvestigatedn all infants with milder forms of hypphenylalaninemiasee ater).

Diagnosis. ecause f gradualdevelopment f clinical mantarions of hyperphenvlalaninemia,arly diagnosiscan onlyachieved y mass creening f all newborn nfants(seeater)infantswith positive esults rom the screenor hyperphenynrnemia, diagnosrs should be confirmed by quanticameasurement of plasma phenylalanine. Idenctficationmeasurement f phenylketonesn the urinehas no place n screening rogram. n countriesand placeswheresuchprograre not in effect,however, dentificationof phenylkeconesn

urineby ferricchloridemay ofler a simple est or diagnos

infants with developmental nd neurologicabnormalities.Othe dragnosis f hyperphenylalaninemias established,eficieof cofacror BHa)should be ruled out rn all affectednfants wproper studies rer).

Neonatsl cre for Hyperphenylslaninonia.ffective ndatively inexpensivemethods for mass screeningof newbinfantshavebeendeveloped nd areused n the UnitedStatesseveral ther countnes.The bacterial nhibition assav f Guthwhich was the 1st method or thepurpose,has been eplacemoreprecise nd quanritativemerhods fluorometricand canmals specrrometry).ll thesemerhodr equire fe* dropblood,which areplacedon a filter paperand mailed o a cenlaboratory or assay. loodphenylalaninen affectednfantsw

PKU may se to diagnosticevelsas earlyas 4 hr afterbirth e



530 PARTX Metabolic iseasos

Protein ynthesis

I

in the absence f protein feeding. t is recommended, owever,that the blood for screemns e obtained n the 1st24-48 hr oflife after feedingprotein rJreduce the possibilityof false nega-tive results,especiallyn rhe milder forms of the condition.

Treatment,hegoalof therapy s to reduce henylalaninen thebody; formulas ow in or free of this amino acid are availablecommercially. he diet should be startedas soonas diagnosissestablished.t is generallyaccepted hat infantswirh persistentplasma evelsof phenylalanine 6 mg/dl (360 pmole/L) shouldbe reatedwith a phenylalanine-rescrictediet similar to that forclassicPKU.No dietary estriction scurrently ecommendedor

- Fumarylacetoacetate

Protein ynthesis

Succinylacetoacelate

iSuccinylacetone

Fumarate Acetoacetate

infants whose phenvlalanine levels are between 2 and 6 mPlasma concentradons of phen;rlalanine n treated patients shbe maintained as close to normal as possible. Becausephenynine is not synthesized by the body, overtreatment rnay leaphenvlalanine deficiency manifested by lethargy, failu(e !o thanorexia, anemia, rashes,diarrhea, and deathi moreoveq tyrobecomes an essential amino acid in this disorder and its adeqrntake must be ensured. Controversies exist regarding the "alable" degree of residual hyperphenylalaninemia rn trepatients. It is generally believed that plasma phenylalanine lshould be maintained between 2 and 6 mgldl- (120-350 prno

It

I

co2 + H2o

Fjgur€ 85-1 Parhwaysof phenylalanineand ryrosin€ metabolism. nborn effors are depided as bars crossing he reaction ato1r,(s). Path*'ays for synrhcofactor BH, are shown in rrlpl?. PKU. refen to defectsof BFli metaboLsm hat affect rhe phenvlalanine, yrosine,and tryprophan hvdroxylases seeFig2 and 85-5). Enzlmes: (1) phenylalaninehydroxylase,(2) carbinolamjnedehvdratase, l) d,hydrobioprerin reducrase, 4) 6,pvruvoylrerrahydroprerinsyn(J) guanosine rjphosphate(GTP) c-vclohydrolase,6) tyrosine aminotransferase, 7a) intranolecular reaffangernent, 7+7a)4-hydro4?henylpvruvare dio

nase,8)

homogentisicacid dioxygenase, 9) rnaleylac€toaceraresomerase, 10)fumaryLacetoacecateydrorylase.



alanine-restricted iet for l ife.

Oral adminisrration of the cofactor tetrahydrobiopterin (BH.)

through a regional reatmentcentet

Pregnancyn Womenwith HyperphenylalaninemiaMaternal KU).

nraiata-iledon a phenylalaninc-restrictediet before and during

ch e us cdescribed ongeniralanomahes n therr offspring

HVPERPHENYLATANINEMIARO MDEFICIENCYTTHE COFACTOR

BHa. n 1 2% of infants t ith hyperphenylalaninemia,he defecr

resides n one o{ rhe enzymesnecessatYot producoon or recv

transmitrersdopamine se eFig. 85-2) and serotonin seeFig. I l5-

Chaprer 5 r Delectsn Metabolism l AminoAcid$ .

5). BHr is also a cofactor for nitric oxide s-lnthase,hich

al,vzeshe generationof nirric oxide from arginine.Patientsw

BH1 delicienc,v re diagnosed er,v arl-vn life because llparie

u'ith PKU and hvperphenylalanirremja are rested or the poss

ir,vof this cofactor deliciency.

BH. is svnthesized rom guanosine triphosphare thro

severalenz-vmatic eactions (sce Fig. 85 1). Four enzvme d

ciencieseading o defectrve Hq fbrlnacionhave beendescr

.\{ore than half oi the reportedpatienrshave had a deflcien

6 pvrur.o,vhetrahydropterinynthasc PTPS).

Clinical Manifestations.nianrs with cofactor deficiencyidencif ied uring screening rograms or PK U because f evid

of hvperphenvlalaninemia. Lasma henylalanine evels may

as high as rhose in classic t'KU or in rhe range of nilder fo

of hvperphenylalaninemia. NeurologJc manifestations, such

.loss f }ead c ontrolr truncal hl,potonia (f loppy baby), drool

su.allowing diflicufties, and myoclonic seizures, develop a

3 mo of agedespiteadequare iecary-herapv.

0iagnosis. BHa deficiencv and the responsible enzyme de

mav be dragnosed by rhe following tests: measuremen

neoprerin (oxidarive product of dihydroneoprerin riphosph

and biopterin (oxidative producr of dihydrobiopterin

retrahydrobiopterin) n body fluids, espectallv nne (seeFig.

1). n patientswirh guanosine riphosphate GTT) cvclohvdro

defciency, urinary excretion of both neopterin and biopteri

very lorv. In patients wirh 6 pyruvo,vhetrahydropterin syntdeficienc,r', here rs a marked elevation of neopterin excretion

a concomiraot decrease n biopterin excrelion. In patienrs

dihydroptcridine reducrase eficiency, eoptern is normal,

bioprerin rs verv high. Excretion of biopterin rncreasesn

enzylrre deficiency because rhe quinonoid dih,vdrobiopt

cannot be rec,vcled nto BHa. Patients u.ith carbinolamine d

dracasedeficiency excrete 7-bioprerin (a n unusual isome

bioDrerin) n their urinc.llt{r l.OADlN-c I-I l5 . Ar oral dose of BH4 (20 mg/kg)

malizes piasma phenylalanine n parients * ' ith BHa defici

rr. ithin 4 to 8 hr The blood phenylalanine bould be elev(>400 gmole/L) to enable nterpretarionof che esults.This

be achievcd by discontintJng diet rherapy for 2 da1's before

tesr or by administering a loading dose of phenylala

1100mg/kg) 3 hr before tlre tesr.t\ lYN'll l ASSAY,The acci rity of dihydropreridine educ

can be measured n chedr,v blood spocson the filter paper u

Tyrosinase

DOPA

Tyrosinase

M elanosom e- - - - - -

Tyrosine

3,4,dihydroxy-

phenylalanineDOPA)

1 6 t

Dopamine

l oNorepinephrine

l ^| ( 4 1

Epinephine

HO cH2-cH cooHNH z

Tyrosine

DOPAQuinone

Pheomelanin(yellow-red olymer)

It

Eumelanin(black olymer

IThyroxine

L

Fieure 3 j t. Orher Frthwa"s in'olving t_vrosine etabol ism. KtJ' i rdrc . r re !hyperpheu,v la lancLrraut ro retrah,rdrobioptermBH!) dcl iciency sc

8j 1) [nzymes: t] r_vnrs ine_vdrrxi lase,2) arcm.ric L-aminoacr< l ccarboxr laseAADC), (3) dopamrnc vdrox l lase, 4) phenyLerhanolamlnem

!ranst i rasePNN{T).



532 PARTX MetaholicDisoases

for screening purposes. 6-Pyruvovltetrahydropcerin synthaseactivity can be measured in the liver, krdneys, and eryrhrocvtes.Carbinolamine dehydratase activity can be measured in the liverand kidneys. GTP cyclohydrolase activify can be measured in theliver and in cvtokine {interferon-y) stimulared mononuclear cellsor fibroblasrs (the enzyme activity is normally very low in unstimulated cells).

Ireatneol. The goals of therapv ate to correct hyperphenylalaninemra and to reslore neurotransmifter deficlencies n cheCNS.

l he con r ro lo f h lpe rpheny la lan inem ias m po r tan r n pa t ien rs

n'ith cofactor defciencl., because high levels of phenylalanineinterfere with che rransport of neurotransmifter precursors (cyro-sine, tr,vprophan) inro the brain. Plasma phenylalanine should bemairtained as close to normal as possrble (<6 mg/dl). This canbe achieved bv a combinarion of a low phenylalanine diet andoral supplementation of BHa, Intbnts with GTP cyclohydrolaseor PTPS deticiencies respond more readrly to BHa rherapy (5-10 mg/kgiday) than those with dihydropteridine reducase defi-crencl', In the latt er patient s, doses as high as 20 mg/kg/day maybe required. BHa for replacemencrherapy is commercially avail-able, although r rs expensive.

Adminisrration of defrcient neurorransmirrers iL-dooa and 5-hldroxvtryprophant ir recommended ve n when rrear;ent wirhBHr normalizes ptasma levels of phenylalanrne. BHa does norreadily enrer the brain to restore neurotransmitter production.

Supplemenration wirh folinic acid is also recommended inpatients \:r,lth dihydropteridine reductase de6ciencl..

Hyperprolactinemia occurs in patients with BHa deficrencyandmay be due to dopamine deficiency lwhich is the major prolacrininhibiting factor) rn rhe hypothalamic region. Measurement ofserum prolactin levels may be a convenient method for monitor-ing. adequac,v of rreurotransmitter replacement in affectedpanents,

Some drugs such as trimetoprin sulfamethoxazole, methofiex-atet and other antileukemic agents are known to inhibit dihy-dropteridine reductase enzyme activity and should be used withgrea! caurion in patients with BHa deficiencv.

Genetics and Prevalence. AIL defecrs causing hyperphenylala-

ninemra are inherited as autosomal recessive rairs. The oreva-len ie o i PKU in rhe Un i redSta res s es r im a red t l / 14 ,000 ru

1/20,000 live births. The prevalence of non-PKU hyperpheny-lalamnemia is esrimated ar 1/50,000. Th e condit ion is morecommon in whrtes and Native Americans and less prevalent inblacks,Hispanics,and Asians.

The gene for phenylalanine hydroxylase is located on chromo-some 12q24.1 and many disease-causing urations have beenidencified in drfferenr families. The majority of parients are com-pound heterozygotes for rwo different mulaflr alleles. The gene

for PTP synthase, the most common cause of BH4 deficiency,resides on chromosome 71q22,3-23.3, the gene for dihy-dropteridine reduclase is locared on chromosome 4p15.3, andthose of carbinolamine dehydratase and GTP cycLohydrolaseareon 10q22 and 14q22.1-22.2, respectively. an y disease-causrngmutations of thesegeneshave been rdenrified. Prenaral diagnosisis possible using speci6c geneuc probes in cells obrained from

chorionic vil l i hiopsl' .

TETNAHYDROBIOPTEBII{EFECTSITHOUTHY CRPHEIIYTALANII{ETJIIA

IIEREDITAEYROGBESSIVEYSTOI{IA,UTOSOMATOMIIIAIITooPA-sEsPol{srvEysToNrA,EGAWA|SEASESEEArS0GHAPTER 9t.3). Thrs rare form of dystonia, 1st described in

Japan, is caused bv GTP cyclohydrolase deficiency. t is inheriredas an autosomal domrnan! ffaic and ts more common tn femalesthan males (4:1)

Clinical manilestations usually occur around 5-6 yr of age andare heralded bv dystonia of the lorver Lmbs, which may spread

to all extremities wichin a few years. Torlicollis, dystonia oarms, and poor coordination may precede dystoma of the l

becoming worse by rhe end of the dav and improving with sParkinsonian signs may also be present or develop subsequwith advancing age.Patients may be misdiagnosed as havingbral palsy. Late presentation in adult [fe has also been repo

Laboratory findings shou. no hyperphenylalaninemia,reduced levels of BHr and neoptenn are found rn rhe spinal

Dopamineand t r s m erdbo l i re \hom ovan i l l r c c id ) m ly a lreduced in the spinal flLrid. lt is believed that the enzymeciency in this condition is less severe han that of rhe autosrecessive orm of GTP cyclohydrolase deficiency, which rs ciated wirh hyperphenylalaninemiase e arlier].The existenasymptomatic carriers indicates that other factors or genesplay a role in parhogenesisof the phenorype. The asymptomcarrier mav be rdentified by measuring the rario of plasma phlalanine to tyrosine after an oral dose of phen,vlal(100 mgikg); the ratio increases significantlv (=3 times ano fm a l va lueat 2 h r ) i n the asvm p lom a t t ca r r ie r .

Diagnosis may be confirmed by reduced levels of BH4neopterin in rhe spinal fluid, by measuremenrof the enzyme airr. and by idenrif icarion i rhegenedefectLsee arlrer].Clinicthe condirron should be differentiated fuom orher causesof

t on ias nd ch i ldhoodPark inson ism ,spec ia l l v) o \ ine hvdlase (seeChapter 85.2) and aromatic amino acid decarboxdeficiencies.The sriking diurnal partern of dystonra is an imran t c l in rca l nd ing n tavo ro i CTP cyc lohyd ro lasee f i c ie

Treaiment wirh L-dopa in conjunction with a peripheral ddecarboxylase inhibitor usually produces dramaric improvem

85.2 TyRosrNEGrant . Mitchell ndlraiBezvani

Tyrosine, obtained from ingesced proteins and synthe

endogenously from phenylalanine, is used for protein synthand is a precursor of dopamine, norepinephrine, epinephmelanin, and thyroxine- Excess yrosine is metabolized to cadioxide and warer (see Fig. 85 1). Hyperryrosinemia is obsewith de6ciencies of r_vrosne aminorransferase, 4 hvdroxvphpyruvate diorygenase (4-HPPD), or fumarylacetoacetate h1lase (FAH). Deficiencies of other enzymes involved in rvrodegradation cause iftle or no increase n blood levels of tyrosAcquired hypertytosinemia may occur tn severe hepatoceldys func t ion l i re r la i l u re t , cu rvy v r t am inC i r rhe o fac roche enzyme 4-HPPD), and hyperthyroidism; hyperc,vrosinema common artifact in blood samples obtained soon after eaThe clinical specrrum of heledltary byPertyro*nemias is not

wBosrNrMrAypE {wBosr osts, HEREDTTABYyB0stNH€PAT0RENALYE0S|NEMlAl.n this condition,caused y a ciencyof the enzymeFAH, a moderateelevarionof serum rsine s assocrated ith severe nvolvementof the liver. kidnan d peripheral erves. hese indingr may be due ro amulation of metabolites of tyrosrne degradation, espesuccrnylacetone.

ClinicalMaoifcstations. he affecred nfant rypically prebetween and 6 mo of agebut rarely may become ympromas earlyas 2 wks o{ ageor may remainseemingly ealthy or1st vr of life. The earlier hepresentation,he poorer rs hepnosis. The l yr morcality,which is abour 60y. in infantsdevelop5y11p1o-.6efore2 mo of age,decreaseso 47o rn nfwho become ymptomaticafter 5 mo of age.



The major organs affected are the liver, peripheral nerves, and

kidneys. An acucehepatic crisis commonly heralds the onset of

the diseaseand is usually precipitated by an intercurrent illness

that Droduces a catabolic state. Fevef, irritabiliry, vomirrng,

hemoirhage, hepatomegaly, jaundice, elevated levels of serum

transaminases, and hypoglycemia are common. An odor resem-

bling boiled cabbage may be present, due ro increased methion-

ine metabolites. Most heparic crises resolve spontaneouslt but

may progress ro liver failure and death. Berween the cnses,

varying degreesoffarlure

tothrive, hepatomegaly, and clotttng

abnormalties often persist. Cirrhosrs of the liver and, eventually,

heparocellular arcinomaoccur with increasing ge ;carcrnoma ''

unusual before 2yr oI age.

Episodes of acute peripheral neuropathy resembling acute por-

Dhvria occur in =407" ol affected children These ctises, often

iriggered by a minor nfection, are characterized by severepain,

often in the legs,associacedwtth hypertonic postunng of the head

and trunk, vomiring, patalytic ileus, and, occasronally, self-

induced injuries of the tongue or buccal mucosa' Marked weak-

nessan d paralysrs ccur rn =307oof the episodes, hich may lead

to resprratory farlure requiring mechanical ventilation. Crisescyp-

icallv lasr I to 7 daYs.

Renal involvement rs manifested as a FanconiJike syndrome

with normal anion gap metabolic acidosis, hyperphosphaturia,

hyp.,phosphatemia,nd vitamin D-resistanL ickets.Nephrome-

giiy an d .ome degreeof nephrocalcinosi' , re often found by

ultrasound examination.

Hypertrophic cardiomyopathy is occasionally seen in these

lnfants.Laboratoty Findings. In untreated patients, liver function tesrs

are perturbed in a characterisnc fashion. c feroprorein level is

incriased, ofcen markedln and liver-synthesized coagulation

factors are decreased n most parients; serum levels of transaml

nases are increased, parlicularly during acute heparic episodes.

Serum concentration of bilirubin is increased with hver failure.

Increased evels of cr-fetoprotein are present in rhe cord blood of

affected infants, indicaring intrauterine liver damage Plasma

ryrosine level is dependent on diet; tyrosine level has less diag-

nosdc value than that of succinylacetone (see ater) Elevations rn

serum concentratiorlsofmethionine and other amino acids, char-

acreristic of liver farlure, may also bepresent. HyperphosPhaturia

and hypophospharemia are common. Generalized aminoaciduria

mav occur. The urinary level of 5-aminolevulinic acrd is elevated

(due to inhJbition of 5-aminolevulinic hydratase by succinylace-

tone). The presenceof elevated evels of succinylacetone n serum

an d urine is diagnoscic seeFig. 85-1).

Diagnosis is usually established by dernonstration of elevated

levels of succinylacetone in urine or blood. Neonatal screening

methods detect h;rpenyrosinemra; only a minority of patjents

wirh ryrosinemia type I ate identrlied by these methods. Succ iny-

lacetone, whrch is not detected by the current screening methods,

rs rhe preferable initial metaboLite tested. Tyrosinemia rype I

should be differentiared from other causes of hepatitis and

hepatrc failure in infants, including galacrosemia, hereditary fruc-

toie intolerance, neonalal iron storage disease,giant cell hepatl

t is, and citrull inemia yp e II (seeChapter 85 11)

Treatmentand outcome. A diet low in phenylalanine and tyro

sine can slow down but nor halt rhe progtession of the conditjon.

The treatment of choice is nitisinone (NTBC, 2-(nitro-4-trifluo-

romethylbenzoyl)-1,3-cyclohexanedione), which inhrbits tyrosine

degradation at 4-HPPD {seeFig. 85-1), Thls treatment prevents

acute hepatic and neurologic crises. Patienrs treated wich nrtisr-

none are also prescribed a diet low in phenylalanine and tvro-

sine, Ahhough nrtisinone stops or greatly slows progression of

the disease, much preffeatment liver damage is noc reversible.

Therefore, patients must be followed for development of hepa-

rocellular carcinoma. On imaging, the presence of a liver nodule

usually indicates generalized crrrhosis. Accurace distinction

between benign nodules and malignant ones is difficult to obtain

ChaDter5 oelectsn Metabolisml Amino cids

through maging.Liver ransplantationsan effectiveherapyaalleviates he risk of hepatocellular arcinoma.The impacnitisinone rearmenton the need or liver transplantation s under study but dependson the stageof the drsease t whtherapybegins.

Genetics ld P]evalence. yrosinemia ype I is an aurosorecessiverait. The gene or FAH has beenmapped o chrosome15q;nunerous mutationshavebeen dendfied.DNA ansis is useful or molecularprenataldragnosis nd for rescingroupsat risk for specificmutationssuchas French-Canafrom the Saguenay-Lac aint-Jeanegion of Quebec.Tvronmra ype is panethnic;ack of FrenchCanadianor Scandinaancesrrydoes not exclude he diagnosis.The prevalence f condition s estimated o be 111,846ive births n the SagueLac Sarnt-Jeanegion.The worldwide prevalences estimarebe 1/100,000o 1/120,000. renatal iagnosisasbeen chiby measurement f succinylacetonen amniotic flurd, by enzymeassay n amniocyresor chorionic villi biopsv, andDNA analvsis.

TYROSINEMIAYPE I {RICHNER.HANHARTYNOBOME,GUTTANE0US B0SINEMIA).his rare aucosomalecessiveisois causedby deficiencyof ryrosine aminotransferase nzywhich results n palmar andplantar hyperkeratosis, erpetif

corneal ulcers,and menral retardation (seeFrg. 85 1). Ocmanifestations f excessiveearing, redness, ain, and phophobia ofrenoccur beforeskrn esions.Corneal esrons re psumed o be due to tyrosine deposirron. n contrast o herpulcers, orneal esions n tyrosinemiaype I stainpoorly withorescrn nd often are brlateral.Skin lesions,which may devlacer n life, includepainful, nonpruritic hyperkeratoticplaq

on rhe soles,palms, and fingertips.Mental retardation, whoccursn <507oof patients,s usuallymild to moderate,

Abnormal aboratory indingsare imited to significant ytyrosinemia 20-50 mg/dl; 110-2,750pmole/L) and tvroiluSurprisingly, -hydroxyphenypyruviccid and ts merabolitealso elevated n urine desprtebeingdownstream rom the mbolicblock see ig .85-1).This s presumedo be due o shing of ryrosinevia other transaminasesn rhe presence f h

ryrosine oncencrations,he condicrons due o the deficienche cyrosolic raction of hepatic tvrosine amrnofiansferascontrast o tyrosinemia ype , liver and kidney unction, asras serumconcentratlons f other aminoacids,are normal.

Diagnosis s established y assayof plasma yrosrnecontration.Susrained ypertyrosinemia n a nonrestncted iet s aseen n liver failure; the level of plasma yrosine is hrghetyrosinemia ype l and oculocu!aneous anifestat ions reabin liver fail-rre.Diagnosis f rype I ryrosinemramay beconfirby assay f ryrosineaminorransferasectivity n liver or bv Dana)ysis f the mutant EeDe.

Treatmen! wjth a diet low io tyrosine and phenylalaimproves he biochemicalabnormalitiesand may result n dmatic healing of the skin and eye lesions.Some observasr.rpporthe easonable laim rharmental erardationmay be

ventedby earlv dietary estrictionof t,vrosine. he gene or rsineaminotransferases mapped o chromosome 6q and sevdisease ausinemurarionshave been dentilied.About haltreported aseJare f Italiandescent.

rYR0SltlEM|AYP Ell {PRIMARYEFICIENCYF -HPPDl. nfew cases avebeen eported;most weredetected v amino adeterminations erformed or vatrousneurologic indings.This doubtas ro whether his enzyme eficiencyauses ny clinabnormalities. ge of onsethas been rom 1 to 17 mo, Devemental delan seizures,nrermittenr ataxia, and self-desrrubehavior are reDorted. No liver or renal abnormaliriespresent.Asymplomatic nfants have been dentilied n neonscreenlnSrograms,



53{ r PARTX MetaholicDiseases

The diagnosis is suspected n chrldren with sustained moder-ate iflcreases n plasma levels of tyrosine (350-700 pmole/L) andthe presenceof 4-hydroxyphen,vlpvruvic acid and rts metabolites(4-hvdroxvphenyllaccicand 4-hvdroxyphenylacecicacids) inurine. Diagnosis ma,v be confirmed by denonstration of lowactivir,vof 4 HPPD enz,vme n li ver biopsv or presenceof muta-tions rn the 4-HPPD gene.

Given rhe possibleassocrarion rith neurologrcabnormaliries,dietary reduction of plasma tyrosine levels s reasonable. It i s alsological co atrempt a trial of vitamrn C, the cofaccor or 4-HPPD.The condit ion is inhericedas an aulosomal recessive rait. Th egene for 4-HPPD rs mapped co chromosome 12q24-qter

TBANSIENT YR0SINEMIA F THENEWBORN.rl a small numberof newborns, plasma cvrosine may rise co as high as 60 mg/dl(3,300pmole/L)d uring r he 1sr 2 u'k of l i fe. Most affected nfanrs

are premature and are receiving high-prorein diets, The condition

is presumablydue to dela,redmaruratronof 4 HPPD enzyme see

Fig. 85-f). Lethargl' ,poor feeding,and decreasedmoror acrivityare noted in some patients; most are asympromatic and come tomedical attention becauseof a high blood phenylalanine evel,rendering rhe screening rest for PKU posirir.e. Laboratory find-ings rncludemarkcd elevationof plasma vrosinewlth a moder-ate increase n plasma phenylalanine,Th e presence i markedhyperty rosrlemia ditferenciates this condition from phenylke

tonuria. 4-H_y-drox),phenylpyruviccid and irs metabolires (4 -

hydroxyphenyllacticand 4-hydroxl'phenylacetic crds)are alsopresent n rhe urine. HypertJ'rosinemia sually resolves ponta-neously n th e 1sr mo of l ife. The condirion is often cottectedprompdv by reducing the amount of protein in the dier (t o

2 Elkg/24 htJ and by administering vitamin C (200-400 mg/24

hr). Mild incellectual ellcitshave been eporred n some ull-term

infanrs lr.ith this disorder, but rhe causal relationship to hyperc,v-

rosiiemia is nor conclusivelv scablished,

HAWKINSINURIA. his rare condit ion (named after the 1staifecced amily) is causedby a mutant 4-HPPD enzyme har car-alyzesa partial reactiolraDd releases n intermedrate ompoundused for diagnosis (seeFig, 8-5-1).This rntermediare s eitherreduced rcl li:rm 4-hydroxycyclohex,vlacetic acid (4-HCAA) orreacts with glutathlone to form the unusual organic acidhawkinsin (2-L-cysreine-S-y1-1-4-dihydroxvcvclohex-5-en-1-yl

acetic acid); secondarv glutachione de6ciency may occuf.Individuals vich hisdisorderbecome vmptomaticonl,vdunng

infancl'. The symproms usualLyappear after u.eaning from breasr-Feedingvith rhe nrroductionof a high-proteindiet. Severemeca-

bolic acidosis, erosrs, ailure to f ir ive, mil d hepatomegah;an d

an unusual odor (of a s&'imming pool) are described. N'lental

developmenr s usually normal.

Affected children and adults excrete the organic acids 4-HCAA, 4-hldroxyphenylpyruvic acid and its merabolites(4-hvdroxvphenyllaccrc and 4-hydroxyphenylaceric acids),.5-oxoprotine owing to secondarl glutathione deficiency),an dhawkinsil in rheir urine.Plasma ,vrosineevel s usuallynorma[.

Treatmcnt consrsts f a lor-protein drer breasrmilk) or a dietlorv in phenylalanineand t,vrosine.A trial rvi th large dosesoivLtamin C (u p ro 1,000 mg/24hr) rs also recommended. Notherap,v s needed after 1 yr of age. The same mutation, a substr-tution of threonine or the normal alanine codon a! posit ion 33of the 4-HPPD gene,has been dencified n unrelated patients wirhharvkinsinuria.

ALCAPT0NUfiIA. his rare (incidence =1/250,000) aurosomalrecessivedisotder is due to a deliciencl' of homogencisic acidoxidase, ra'hrch causes large amounts of homogentisic acid toaccumulate in the body and lhen lo be excreted il the urine lseeFie. 8-5-' l l.

tlinical manifestations of alcapronuria consist of ochronosisand archritis, rvhich occur in adufthood. The only sign of rhe dis

order in children is a blackening of the urine on standing.rs caused by oxidatron and polymerization of the homogenacrd. Urine uirh acrd pH may not darken even affer man,v hThis sign may never be noted, delaying rhe diagnosis unrrl ahood. Ocbrcxosis, seen clinrcail y as dark spots on rhe scleear cartilage, results from rhe accunulation oF the black polof homogentisic actd, Arthritis can be disabling and occualmost all affecredsubjeccswrth advancing age. t involvelarge oints (spine,hip, and knee) and is usuallv more sevm a le r . i l e rhsum a to id r rh r r t i s , he a r rh r i c i r

a 'acu re

\abations, buc the radiologic {indings are typical of osceoarthwith characteristic narrorving of the jornt spacesand calcificof the ntervertebra discs.High incidences f hearrdiseasem

an d aortic valvulris, calcif icarion f rhe heart valves, nd m,vdiaL nfarction) have been noted.

The diagnosis is confirmed by finding massive excretiohomogentisrc acid in urine. The enzl,me is expressed onl;' inliver and kidneys. Th e gene for alcapronuriamaps ro chrosome3q and several iseases-causingutations have beenti6ed, Alcaptonuria s most common in the Dominican Repand Slovakia.

There is no effecrive reatrnent for this disorder Nitisinonetreatment of tyrosinemia rype I) inhibrrs homogentisicprorioni its administration to patrents rvitb alcapronuria bplgment deposirionma1' be useful n prevention

ofarchntis

TYROSINE YDROXYTASEEFICIENCYINFANTITEARKINSOAUTOSOMATBECESSIVEDOPA-RESPONSIVEYSTONIACHAPTER 97.31. yrosine hydroxylase calalyzes thc formatioL-dopa from tyrosine (seeFig. 85-2). Deficiencr.of this enhas been reported in a felv chrldren r.ith dystonia and pa

sonism. The clinical picture resembles the aurosomal domidystonia due to GTP cyclohvdrolase deficrencv (see Cha85.1). The spectrumof the condit ion is nor full,vappreciat

Clinical manifestations such as jerky movemenrs of the lleading to spasriciry ard muscJe rigrdiry, expre$sionless ptosis,drooling, oculogyriccrises, nd parkinsonismmav sraearly rnfanc1.. Psychomotor rerardation has been secn in sparients. No diurnal variation of the svmproms has been uo

Laboratory indings nclude educed evels f dopamJne nmerabolice onovanrll ic acid (HVA) and normal concenrraof retrahydrobiopterinand neopterin n the spinal f luid. Sprolactrn evelsare usually elevated.

Diagnosisshould be considered n an y patients vichdysand parkinsonism. GTP cyclohydroxylase defrcienc,vshoulruled out bv proper studies seeearlier).Diagnosis s establbv che aboratory f indings (seeearlier)an d genestudy.

Treatment with L-dopa resufts in a dramatic improvemPatients unresponsrve to L-dopa have recentlv been repohora'ever,The cofldition is inhericed as an autosorlal recetraic. The gene for tyrosine hl.droxylase is rnapped to chrosome11p.

AIBlNlSM. Albinism is due to defecrs n the biosvnthesis andtribution of melanin (Table ll5-1). N{elanrn s synthesizemelanocyres rom tyrosine in a membrane-bound ntraceorganelle, the melanosome. Melanoc,vres originate from embr,vonic euralcrestand migrate ro the skin, eyes choroid

iris), and hair foll icles.The melanin n the eye s not secretethe adjacent issues,whereas he pigmenr n skin and hair fcles s secreted nto the epidermis and the hair shaft. The ramelanogenesis s ver,v low in the eye and very hJgh in cheand hair The bios-vntheticparhnay for melanin synthesis iscomplerelyelucidared seeFig. 85-2). The end products arepigrnetts: pheomelanin, which is a yellov,red pigment;

euffieldnin, a brown-black pigment.

Clinical rnanifesratiolls common in generalized albinismhvpup igm en ra r ronf t hesk inand ha i r .Pa t ren rs i rh nvo l r m



85-1), Attempts o differentiate ypesof albinismbasedon the

mode of inheritance, tyrosinase activity, or the ettent of

hypopigmentarion ave ailed to yield a comprehensivelassifi-.rtion. The followine classifications basedon the distributionof albinism n the body and the qpe of rnutatedgene.Not all

conditions associatedwith albinism are discussed nterested

readersare referred o more comprehensiveources see efer-

ences),0culocutaneousGenerslized)Albinism0CA). ack of pigment s

generalized, ffecringskin. hair, and eyes.Threegenerically is-iincr ormsexisr:OCAI, OCA2, nd OCAj. The ac kof pigrnent

is usuallymore severen patientswith OCAI; these ypesmay

nor be distinguishable linicalln however,becauseoI a great

in theseparients esidesn the tyrosinase ene,which is located

on chromosome 1q. Many mutant alleleshave been dentifred.

Most affected ndividuals are compoundheterozygoteor twodifferent mutant alleles.The condition can be subdivided o

OCAI A and OCAI B basedon enzymeactiviry and, to a lesser

er.:tent, linicalmanifestations.OCAI A (Tyrosinase-NegativeCA), A numberof mutations

in the tyrosinasegenerender the enzymecompletely nactive'Individualswith this form usuallyhave he most seve!€ as€ofgeneraUzedlbinism, linically,ac kof pigmenrn che ki n milky

whire),hair (whitehair).and eyes re dgray ridesl s evident tbinh and remainsunchangedhroughout life. They do not tan

and do not developpigmentednevi or freckles.OCA1 B. These mutations in the tyrosinasegene result in

enzymeswith some esidualactieities.Clinically these ndividu-

als, although completelydepigmented t birth, are capableof

GhaDtol86 Defccrsr llslrtolilm d Amino cids

developing omepigmentwith ageand become ight blond wlight blue or hazeleyes.They developpigmented evi and frlesand they may an. Thesepatients,depending n the degrepigmentation, trereonce subdivided nto different groupswere hought to begenetically ifferent.One nteresting ormthe temperature-sensiti ve lbinism in which the tyrosibecomesmore active n coolerpans of the body such as imThese ndividualshave no pigment n the scalpand uunk developsomepigment n arms and legs.

OCA, (TYROSINASE-POSITM OCA). This is the m

common orm of generalized lbinism. t i s particularlycomin African blacks.Clinicallv. hese ndividualsdemonstrate pigmentation f the skin and eyes t birth andcontinue o copigment hroughout their lives. The hair is yellow at birth may becomedarker with age. They have pigmentednevi frecklesbut do not tan. They may be clinically ndistinguishfrom OCAI B. These ndividualshavenormal ryrosinase ctiThe defect s in the p (pink-eyed ilution) gene,which is locon chromosome 15q. This gene produces the P proleinmelanosomemembraneprotein, the function of which is completely nderstood, atientswith Prader-Williand Angelsyndromeswho havedeledonoI chromosome 5 lack one cof the OCA, gene nd havemild pigmentary ilurion(seeCha80).

OCA3 (RUFOUSALBIMSM). This form has been dent

only in AIricans,African-Americans, nd natives f New GuiPatientshave eddishhair with reddishbrown skin as an adThe color of the skin is peculiar o this form. In the youngmanifestationmay be confusedwith that of oCAr. PatientswOCA3 can make pheomelanine ut not eumelanine. he mtion is n the tyrosinase elatedprotein 1 (TYRP1)gene, he furion of which is nor understood.

HERMANSKY-PUDLAK SYNDROME. This is a group oforders,eachcaused y mutation of one of the seven enesHto HPS7. Thesegenesare necessaryor normal sfiucturefunction of lysosome-derivedrganellesncluding melanosand plateletdensebodies. n most forms, a tyrosinase-poOCA of highly variableseverity s associated ith plateletfunction (owing to the absence f plateletdense odies)anaccumulation I a ceroid-likematerial n tissues, he cond

is transmittedas an autosomal ecessiverait and is mostprlent in Puerto Rico (types1 and 3, frequencyabour 1:2,0Bleeding endencies, ften manifesredas epistaxisand alonged bleeding imer are common. The ceroidJike materihistochemically imilar o that found in neuronalceroid ipocinosis.The accumulationof this material in tissues esulresrictive lung disease, nflammatory bowel disease,kidfailure, and cardiomyopathyn the 3rd or 4th decade f life.majoriry of patientshavemutations n IIPSl, which s locatecn

ASHI SYNDROME. Patientswith this autosomal ecessiveondition havepartial albinismand susdbility to infectionwith the presence f giancperoxidase-polysosomalgranules n granulocytes see Chapter 129), Tpatienashave a reducednumber of melanosomes, hich

abnormally large (macromelanosomes).atienrs who suearly childhood may develop a lympho{ollicular malignaMutadons in CHS1 gene locatedon the long arm of chrosome ) have been dentified n thesepatients,

0cularAlbinisn 041,Albinism s imited o the eyes.All th€frndingsof albinism see arlier)arepresent.The Xlinked resive orm (OAr) has beensegregated s a separate ntity. Mcases f autosomal ecessive cular albinism are Ielt to be mvariantsof OCA2.

OCULAR ATBINISM 1 (OA, NET'TLESHIP-FALLS TYOnly the hemizygotemale has he completemanifestationwsomeabnormal refinal pigmentation may bepreserf in hete-gore female carriers. The gene for this condition is locon the short arm of rhe X chromosome.An X-linl<edoc



536 PART r Metabolic isga6ss

albimsm with lare-onsetsensorineural eafness as also beenreporled.

Localized lbinism.This disorder s characterized y locahzedareas f hypopigmenration f skin and hair,whicb may bepresentat brth or developwith time,

PIEBALDISM. In this autosomaldominant inherrredconditron. che ndividual is usually born with a whrte forelock. Theunderlying skin is deprgmented.n addition, there are usuallywhite macules n the face, runk, and extremities. hewhite hairlock and che depigmented underlying skin are devoid of

melanocytes.Mutatlons in the KIT genehave been shown inaffecred atients.

\\,AARDENBURC SYNDROME. In this syndrome, aceraldrsplacement f inner canthi, broad nasalbndge,heterochromiaof irides and sensonneural eafness re associated ith a whiteforelock,This condirron s inheritedas an autosomaldominanttrart. !'our typesof this syndromehave been dentilied,Patiencswith rype have displacemenr f inner canthi, The condrtion scausedby mutations n rhe PAXJ gene.Type ll patientshavenormal innercanchi,and mutations n the MITI genehavebeenshown n somepatients.Patientswith type ll havealL he find-iogs seen n individuals with rype I, plus hypoplasiaand con-tractures of rhe upper limbs. The geneabnormalitv rs in thePAX3, Type IV is assocraredvrth Hirschsprungdisease,s het-erogeneous, nd mutat ions Lndifferentgenes EDN}, EDNRB,

or SOXl0) havebeen dentified n differentpacients.

85.3 METHIoNINE.lraiezvani ndDavidS.Bosenhlaft

The normal pathway for catabolism of methionine, an essentialamino acid, produces S-adenosylmethionine, whrch serves as amethyl group donor for methylation of a variety of compoundsrn the body', and cysteine, which is formed rhrough a series ofreacnonscalled rrans-sulfurarion Fig. 85-3).

H0M0CYSTINURIAH0M0CYST|ilEMlA). ost homocysteine,an

intermediate compound of mechronine degradation, is normallyremechy'lated o methronine, This mechionine^sparing reaction iscatalyzed by the enzyme methionine synchase,which requires ametabolite of folic acrd (5-rnethyltetrahydrofolare) as a methyl

donor and a metabolite of vitamrn Br2 (methylcobalamin)as acofactor (see ig. 85-3). Only 20-30% of r otalhomocvsternean d

ics dimer homocystine) is in free form in rhe plasma o{ normalindividuals. The rest is bound to proterns as mixed disulfides.Three major forms of homocystinemia and homocystrnuria havebeen rdentiGed.

Homocysliruria ue o Cystalhionine-Syntha$eCBS)Deliciency(Classic Homocvstinurial.This is the mos! conmon rnborn errorof methionine metabolism. About 40% of affected patients

respond to hrgh dosesof vitamin B{,and usuall,vhar.e milder clin-i ca l m an i f es ra r ion rhan hosewho a re un respons iveo v l t am in

B, rherapy. These patients possesssome residual enzl'me activiry-Infants rvith this disorder are normal at birth. Clinical mani-

festarions during infancy are nonspecifc and may include failureto thrive and developmental delay. The dragnosrs s usually madeafrer 3 yr of age, when subluxation of the ocular lens (ectopia

lentis) occurs. This causesseveremyopia and rridodonesis {quiv-ering of the iris), Ascigmatism, glaucoma, staphyloma, cararacts,retinal derachment, and optic atrophy may develop larer in life,Progressive mental retardation is common. Normal intelligence,however, has been reported. In an international survey of >600patients, IQ scores anged from 10 to 135. The higher IQ scoreswere noted in viramin 86 responsive patients, Psychiatric andbehavioral disorders have been observed in >50% of affectedpacients. Convulsions occur in =207o of patienrs. Affected indr-

viduals with homocystinuria manifest skeletal abnotmalresembling those of Marfan syndrome (see Chaprer 700);are usuaUy tall and thin, with elongated limbs and araodactyly. Scoliosis, pectus excavatum or carinum, genu valgpes cavus, high arched palate, and crowding of the teeth are cmonly seen. These children usually have fair complexrons,eyes, and a peculiar malar flush. Generalized osteoporosis, ecially of the spine, is the marn roentgenographic finding, Thrboembolic episodes involving both large and small vesespecially those of the brain, are common and may occur at

age. Optic acrophS paralysis, cor pulmonale, and severe hytension (due to renal infarcts) are among the serious consequeof thromboemboli sm, whrch is caused by changes n the valar walls and increased plarelet adhesivenesssecondary to vated homocl'stine levels.The risk of thromboembolism rncreafter sr-rrgical rocedures. Sponraneouspneumothorax and apancreatitis are rare comphcadons.

Elevations of both merhionine and homocystine (or homoreine) in body fluids are rhe diagnosric laboratory findiFreshly voided urine should be cested or homocystine, sincecompound is unstable and may disappear as che urine is stoCystrne rs low or absent in plasma. The diagnosis may be elished by assay of the enzyme in liver bropsy specimens, cultufibroblasts, or phytohemagglutinin-strmulated lymphocytes oDNA analysis.

Tieatmentwith high dosesof vitamin Bs (200-1,000 mg/2causesdramatic improvement in most patients who are ressrve to this therapy. The degree of response to vrtamin 86 trment may be different in different families. Some patrents

not respond becauseof folate depletion; a patient should noconsidered unresponsive to vitamin Bo until folc acid (1-5

24 hr) has been added to the ffealment regimen. Resrrictiomethionine ntake n conyunctionwith cysteine upplementis recommended for parients who are unlesponsive to vitaminThe need for dietary restrictrcn and its extenc remains conversial in patients with vitarmn 86 responsive form. ln sparients wrth this form, addition of betaine may obviate the nfor any dietary restncrion. Betaine (trimethylglycioe, 6-9 yJ2

for adults or 200-250 mg/kg/dav for children) lowers homoteine levels in body flurds b1' remethylatrng homocysteine

methionine (seeFig. 85-3); this may resuk in further elevadoplasma methronloe levels. This treatment has produced clinimprovement (preventrng vascular events) ln patients who unresponsive o vitamin 86 therapy. Cerebral edema has occLin a patient with vitamin 86 nonresponsive homocysrinuria dietary noncomphance dunng betaine rherapy. Administracionlarge doses of vitarnin C (1 giday) has improved rhe endothfunction; lonB-term clinical efficacy is not known.

More than 100 pregnancies n women wich the classic formhomocystinuria have been reported with favorable outcomesboch mothers and infants, The majoricy of infants were full tand normal. Postpartum thromboembolic events occurred few morhers. All but one of the 38 affected male patients hasnormal offsprrng.

The screening of newborn infants for classrc homocystinu

has been performed worldrvrde and a prevalence of:t/200,0001/350,000 has been estimared, The condition seems mcommon in Neu.South Wales,Australia {1/60,000)and IrelEarly trearment of patients idencified by the screening processproduced favorable results. The mean IQ of 16 patients wvitamrn Bu unresponsive form treated in early infancy lvas 94. Dislocation of the lens seemed to be prevented in spaflents.

Homocvstinuria is inherited as an autosomal recessive The gene for cystathionine p-synthase s located on chromoso21q22.3. Prenaral diagnosis is feasible by performing an enz

assav of cultured amnrotrc cells or chorionic villi or by D

analysrs. Many disease-causingmucations have been identifie

different famihes. The majorrty oF affected paciencs re compo



Chapter 5 r oelects n Metabolisml AminoAcids r

NH'

IcH3-s-(cHr)2 cH-cooH

'Methionine-\| M"thi",fi;A

o \,

-----* oilgiflt s-Adenosyrmethronrne/ glycrne \

c , l

t'/

I

ioS-Adenosylhomocysteine

- Homoserine Cysteine

/ J \\

/ l \I Glutathione

Sultite

Sulfate

cblc,D, E,F, Gvit B'rz ------- ll-- MethylCbl

Cyslathronrne

Cystathioninemiat ^

T \l/

d-Ketobutyricacid

iPropionic ci d

III

Succinic cidIt

co2 + H2o

Figurt 85 3- parhways in rhe metabolLsm f sulfur containing arnrno acids. Enzymesr 1) methronine adenosyttraDsferase,2) adenos-vlhomoc),steineydro

(i)cysrarhion svnrhase, 4) cyrrathionase, 5) sulfite oxrdase, 5) betainchomocysreinenethvltransferase, 7) merhylene er.ahydrofolare eductase.

hererozyg,' teror tw o ditfercnt allele' ' .Heterozygoutcarriersar e

u .ua l l . a ' tm p t< rm ar i . ; h rom bocm ho l i ceven tsand c , ' r ona r '

he.rrt disease r" rno." aoarrrrn rn rhere rndrvrduals han in rh e

Methylcobalamin is rhe cofaccor for the enzyme methioninc syn-

thase, which catalyzes remethylation of homocysteine to methio-

nrne. There are at least iive distincr defects in the inlracellular

metabolismof cobalamin ha r may interferewirh the formation

of methylcobalamin.To better understand he merabolism of

cobalamrn,se emerhylmalonicacidemia (seeChapler 85.6 an d

amjn is impaired (s e ChaPter85.6).

Patients *.rrh cblE nd rblG defeccsare unable to form methyl-

cobalamin and develophomocysrinuria virhout methl' lmalonic

laurine

acidemia {seeFig. 85-4); fewer than 40 patients are known *

each of thesediseases.

The clinical manifestations are similar in patients wich al

rhese defects. Vomrting, poor feeding, letharg,v, hypotooia,

developmental delay may occur in the 1st fer,..months of life. O

patient \r.ith rhe cblG defect was not symptomatic (exceptmild developmental elay)until shewas 21 yr old, horvever,

she developed difficuJty in walking and numbness of the han

Laboratory findings include megaloblastic anemra, homocys

uria, and hypomethioninemia.Th e presenceof megalobl

anemia differenciates these defects from homocysrinuria du

merlvlenetetrahydrofolate reductase deicjency {see later).

presenceof hvpomethioninemia differentiates borh of these c

dirions from cystachionine -synthase eEciency se eearlier)

Diagnosis is establishedby complementacion studiesperform

in cuhured ibroblasts.Prenataldiagnosis as beenaccompli

by studies rn amniotic cell cukures. The gene for c6lE (MTR

is mapped to chromosome 5p15.3-p15.2 and that for c

(MTR) is mapped lo chromosome1q43; severaldisease-ca



538 PAnTX Motatolic iseases

(Dielaryom)Biolin-C N Prolein

o

Acetoac€lc acid + Acelyl CoA

I

(;

cbro cbrcI

oHcbr+3

,Proteinsynthesrs

\

i" ..t f", I \ cHscH3-cH cH cooH cHr-cH,-cH

?HCOOH CHI-CH-CH' CH COOH

-NHz NHz ,ln

cYt*ol

V.lin. lsolsuclne Lsuclne

2-Keto-3-n€lhylval€riccid 2-Ketoisoca proic cid

l$lf -*'*' ir'i".."e'f l#;:?:Hf"l I rr'a'i"ee

lsobutyryl-CoA 2-Methylbutyryl{.A lsovaleryl4oA

1 f r"*a.l"-lI I T I acidsmia I

Melhacrylyl-CoA Tiglyl.CoA

i |3-Melhylcrolony-coA

r i co, -.l \ g-gvo,o*rl"-"r.rc""io-fryfioryisobulyrrl-CoA 2-Merly-3-fydroxybutyryLcoe l

Tr----ffi;6;-] N\--oddchan I| -^ , : ^_, - | | \ ' \ r r8$yac |os t-I acid€mra

|-\)i;;"",";

Il3-Hld,.']+l"9ihvrffii|l'

\ 'Mehon,ne

Methytcttncacd'cBestercl

l\

fTiil;Gii"d,-l

-+ -,-.1F- Melhyl cbl

Fffi;Hcu-l

Figur€ 85-4. Pachwaysn the metabolismofthe branched-chain mino acids,biorin, and vrramin BD (cobalamin).MMA, methylmalonicacidemE; HCU,c1'stinuria;CbJ,cobalamin; OHCbl, hvdroxycobalamin; cbl, defect n merabohsmof cobalamin; TC, rranscobalamine.

vary from apnea, seizure, microcephaly, coma, and deatdevelopmental delan ataxia, and motor abnormalities or psychiatric manifestations, Premarure vascular diseaseor per

eral neuroparhyhas been reporred as che only manitestairthis enzyme deficiency in some patients. Adults with seenzyme defrciency may even be completely asymptomatic. Esure to the anesthetic nitrous oxide (which inhibrts methiosynthase) n patients wirh MTHFR deficiency may result in rologic deterioration and dearh.

Laboratory fndings include moderate homocl'stinemiahomocystinuria. The methionine concentration is low or normal. This findine differertiates this condition from cla

mutations, ncludrnga common missensemufation (P1173L) nthe MTR gene,havebeendescribed.

Tlearmentwith vitamin 812 n the form of hydroxycobalamin(1-2 m9l24 hrl is used ro coffect the clinical and biochemicallindings.Results ary among both diseases nd sibships.

Homocystinuria ue o Deficiency t MethylsnetotrahydrololateBeductaseMTHFBI.his enzyme educes -10 methylenecetrahy-drofolate o form S-methyltetrahydrofolate, hich provides hemethyl group needed or remethylation of homorysteineromerhioninese e ig .85-3).

The severir,v f the enzymedefectand of the clinicalmanifes,tationsvariesconsiderablyn different amilies.Clinical findings



homocystinuria caused by cvstathionine synrhase defrciency.

Absence of megaloblasric anemra distingurshes chis condition

from homocysdnuria caused by merh,vlcobalamin formation (see

earlier). Thromboembolism of vesselshas also been observed in

tion in the MTHR gene.

A number ofpolymorphisms have beendescribed n the MTHR

sene.T'"!o of these 677C > T and 1298A > C) may affecr evels

ofplasma toral homocystein€ and have been studied as possible

risk factors for a wide variety of medical conditions, ranging from

birrh defects to vasculal diseaseand even risk for cancer, ProS-nosrs for survival in leukemia, and risk for Alzheimer disease.To

po l lm o rph i .m i . w ide lu ava i lab le , t s p red rc r i re a lue n ny

g iven nd iv idua l as er to be de re rm ined .-Treatment of severeMTHFR deEcrencywitb a combinatio of

folic acid, itamin 85, vrtamin Br2, methionine supplementanon,

and betain has been ried. Of rhese,early treacment with betaine

seems o have the mosr beneficial eftecr.

The condition is inherited as an autosomal recessive raiti tfie

gene or rhe enzlme has been ocatedon chromosume pl 6 J and

iranu drsease-causrng utarion\ have been reported Prenalal

diagnosis can be offered by measuring N{THFR enzyme activrty

in cultured chorionrc villi cells or amnioc],tes, by linkage anal,v-

sis in informative families, or by DNA analysis of the muration

HYPERMETHI0NINEMIA.econdary hypermethioninemia occurs in

liver disease, qvrosinemia type I, and classic homoc,vstinurra.

Hypermethionrnemia has also been ound in premarure and some

full-term infanrs receiving high protein drets, n whorn it ma,v ep-

resent delayed maruration of the enzyme methionine adenosyl-

rransferase. Lorvering the protein inrake usually resolves rhe

abnormaliry Primary hypermethioninemia caused by the de6-

ciency of hepatic metbionine adenosyltransferase (seeFig. 85-3)

has been reported in a few patients. The majority of thesepatrencs

have beendiagnosed in the neonaral period rhrough screening or

homoc,vstinuria. Affected individuals wrth residual enzyme acliv-

rr).remain asymptomatrc throughour life despirepersistent hypermethroninemia. Some complain of unusual odor to cheir breath

(boiLedcabbage),A few patients with complete enzyme deficiency

have had neurologic abnormaliries related to demyelination

( ntal retardarion, dystonia, dvspraxia). The gene for merhion-

i adenosyltransferases on chtomosome 10q22 and several

hypermethroninemia,

CYSTATHI0NIt{EMIACVSTATHI0NINUBIA). econdary cystathion

inuria occurs in pahents with viramin Br or Brz deficiency, liver

drsease partrcularlv damage caused bv Balactosemia), thvrotox

icosis, hepatoblastoma, neuroblastoma, ganglioblasroma, or

defecrr n remethtlatronoF homocysfeine.

Cystathionase defciency results in massive cystathionlnuria

and mild to moderare cystathroninemia; cysrarhionine is not nor-

mally detectable in blood. Deficiency of this enzyrne s inherited

as an autosomal recessive ralt and rts prevalence is estrmated co

be about l/14,000 live births. Affecred subjectswith a wide

variery oF clinical manifestations have been reported. Lack of a

consiscentclinical picture and the Presenceof cystathionrnuria in

a number of normal persons suggesr hat cystathionase denciency

thionase is located on chromosome 16.

Ghapter 5 r Doloctsn Metabolism l AminoAcids |

85.4.CysrElNVCvstNtlrajRezvani

Cysreine is a sulfur-containing nonesseDtial amino acid tha

synrhesized from methronine (seeFig. 85-3). ln rhe presenc

oxygen! two molecules of cysteine are oxidized to f orm cys

The mosc common disorders of cysteindcystine metaboli

cyscinuria seeChapter J47) and cystinosis se eChapter 529

are discussedelsewhere.

SUI.TITE XIDASEDEFICIENCYMOIYBOEI{UMCOFACTORClEltlCY). t the lasr srep n cysteinemetabolism, sul6te is oxidi

to sulf ate bv sul6te oxidase. and the sulfate is excreted n the u(see Fig. 85-3). This enzyme requires a molybdenum-p

comDlex named molvbdenun cofactor, This cofactor is also

essaiy for the function of rwo other enzymesrn humans: xanth

dehydrogenase (which oxidizes xanthine and hypoxanthine

uric acrd) and aldehyde oxrdase. Three enzymes, encodedbv th

drfferent genes,are involved rn the synthes is of the cofactor

genesar e mapped to chromosornesL4924,6p21.3, and 5q

Deficiency of any of the rhree enzymes causescofactor deflci

wirl jdentrcal phenotype. Most patrents who were origrn

diagnosed as having sullire oxidase deficrency have been pro

to have molybdenum cofactor deficrency. Both conditions

ioherited as autosomal recessive raits.

The enzyme and the cofactor deficiencies produce idenclinical manifestations. Refusal !o feed, vomiting, se

intractable seizures (ronic, cLonic, myoclonic), and severe de

opnental delay may develop wirhrn a few weeks after birth. B

eral dislocation of ocular lenses s a common finding in pati

\4ho survive the neonaral period.

These children excre!e large amounrs of sullire, thiosulfate

sulfocysterne,xanthine, and hl,poxanthrne in their urine. Urin

and serum levels of uric acid and unnarv concentratio[ of su

are dimrnished. Fresh r-rrine hould be used or screeningpurpo

and for quantitative measurements of sulfite, because oxida

at room temperature may produce false-negative results,

Diagnosis is confrrmed by measuremenr of sulfite oxidase

molybdenum cofactor in fibtoblasrs and liver biopsies, res

rively- Prenaral diagnosis is possible by performing an assa

sul6re oxidase activi ty in cultured amniotic cells or in samplechorionic villi.

No effective treatnent is available, and most children di

the 1st 2,vr of hfe. The prevalence of neither of the deficien

ls known.

85.5.TRYPToPHAN.raiRezvani

Tryptophan is an essential amino acid and a precursor for n

tinic acid and serotonin (Fig. 85-5). Presumeddeicienciesvariecy of different enzymes involved in tryptophan cacabo

have been epor ted, but no distinct clinical entity has yet emer

Hartnup disorder causes disturbance in trvptophan absorpti

HARTNUP IS0RDER.n this autosomal ecessive isorder, a

after che 1st reporced famill there is a defect in rhe transpor

monoamlno monocarboxylic amino aclds (neutral amino a

by the intestinal mucosa and renal tubules. Mosc children

Hartnup defecr remain asymptomatic. The major clinical m

festation in the rare symptomatic paoenr is cutaneous photo

sitivit,v.The skin becomes ough and red afrer moderate expo

to the sun! and with greater exposure, a pellagra-like rash

develop. The rash may be pruritic, and a chronic eczema

appear The skrn changes have been reponed in affected inf

as young as 10 days of age. Some patients ma,vhave inrermit

acaxia manifested as an unsceady,u'ide-based gair. The at

may last a few days and usually recovers spontaneously. Me



540 PABTX Metabolic iserses

Protein ynthesis

Figure 85 5. Pathwa)-sn rhe merabolismof tryprophan. PKU. indicareshyperphenvlatanemia ue co tecrahydrobiopterindeficiency see 'ig. 85 ll. Enzt(1) tr-vptophanhvdroxylase,{2) aromadc L-amino add decarboxylase A-qDC), (3) monoamineoxidase (MAO).

ln vitro

development is usually normal. Two indrviduals in the originalkindred were menlally retarded, however Episodic psychologic

changes,such as irritabilit)', emotional instability , depression, andsuicidal tendencies,have been observed; thesechangesare usuallyassociated r,r.ithbouts of ataxia. Short starure and atrophic glos-

sitls are seen rn some pallents.

Mosr chrldren diagnosed with Hartnup disorder by neonatalscreening have remained asymptomatic. Thrs indicates thac otherfacrors are also involved in parhogenesrsof the clinical conditron.

The marn laboratory finding is aminoacrduria, which isrestricted to neutral arnino acids (alanine, serine, threonine,valine, leucine, isoleucine, phenylalanine, tyrosine, rryprophan,histidine).Urinary excretionof proline,hvdroxyproline,and argi-nine remains normal. This findrng differentiates Hannup disor-

der from other causes of Eeneralized amrnoacrduria, such asFanconi syndrome, Plasma concentrations of neutral amino acldsare usuaLlynormal. This seemingly unexpecred flndrng is becausethese amino acids are absorbed as dipeptides and rhe transportsvstem for small pepcides s ntact in Hartnup disorder. The mdolederivarives (especially ndican) may be found in large amounts rn

some patients, owing to bacterial breakdown oi unabsorbed rryp-topnan ln the lntestrnes.

Diagnosis is established by the striking intermiment nature ofsymptoms and the yust described urinary findings.

Treatment rvich nicotinic acid or nicorinamide (50-300 me/24 hrr and a hrgh prorcrn dier resulrs n a tavorable espon.. ins).[lptomatic patients. Becauseof rhe mtefmitlenr nature of theclinical manifestations, the efficacy of thes€ treatmeols is drfnculr!o evaluate. The orevalence of the disorder ls estimated to be

1/30,000.Normaloutcome both Ior mother and fetus s reportedin affected pregnant lvomen. The gene for rhis condition has notvel been rdentified.

85.6oVATINE,EUGINE,SOTEUCINE,NDRELATEDORcnrtc clDEMlAslrai Rezvani ndDavid$. Eosenhlatt*

The early steps n the degradation of these three essentralaminoactds, the branched-chain amino adds, are similar (see Fig. 85

*DavidS.Rosenbla|tontributedo rhesection n merhvlmaloniccidemia.

5-OH-indoleacetic cid(5 H|AA)

4). The intermediate metabolites are all organic ac rds, and ciency of any of the degradative elzymes, except tbr the transinases,causesacidosis; n such instances, he organic acids bethe enzymatic block accurnulate in bod;r fluids and are excrin the urine. These disorders commonly cause metabolic acsis, which usualll/ occurs rn the 1st few days of life, Althomost of the clinical lindings are nonspecific, some manifestatrnay provide imporrant clues to the nature of the enzyme dciencv. An approach to infants suspected of having an orgacrdemia is presented in Figure 85-6, Delinirive diagnosr:sually established by identifying and measuring specilic orgaacids in body fluids (blood, urine), by the enzyme assal andrdenrification of the mutant gene.

Organic acrdemras are not limited co defecrs in the catab

pachways of branched-chain amino acids. Disorders cauaccumulalion of olher organrc acids include chose derived flysme (seeChapter 85,13), those associatedwith Iactic acidChapter 87), and dicarboxylic acidernias associated with detive fany acid degradation (seeChapter 86.1).

MAPTE SYBUP URI E DISEASE (MSUD). Decarboxylationleucine, isoleucrne, and valine is accomplshed by a compenzyme system (branched-charn c-kecoacid dehydrogenase)uthiamine pyrophosphate (vitamin 81) as a coenzyme. This mchondrral enzyme consists of four subunits: E1", E'p, E., ndThe E3 subunit is shared wrth two other dehydrogenase inbodl namelv p;rruvare dehydrogenase and or-ketoglutarate dedrogenase. Deficiency of this enzyme system causes MSUDFig, 85-4), named after rhe sweet odor of maple syrup found

body fluids, especially urine. Based on clinical findings response to rhramine administration, five phenotypes of MShave been denri6ed.

Classic MSUD. This form has the most severe clinical manitations. Affected infants who are normal at bir th develoD Dfeeding nd vomrting n rhe lst wk ot l ite; ethargyand coma mensue wrthin a felr, days, Physical examinarion reveals hytonicity' and muscular rigidity with severeopisrhoronos. Perof hypertonicity may alternate with bouts of flaccidity. Neulogic findings are often mistaken for generalized sepsis meningitis, Cerebral edema may be present; convulsions occumost infants, and hypoglycemia is common. In contrast to mhypoglycemic states, correction of the blood glucose concenrion does not improve the clinical condition. Rouline laborat

Formylkynurenine

III

Nicotinic cid



Chsplor 5 r oelocts [ Motabolisnol AminoAcids I

Common eatureg

Flelusalo eedVomitingAcidosis

DehydrationNeutropenaa

Hypoglycemia

Ketosis

r___-_-r

Fisu.e 85-6. Ctinical approach o infancswith organic acidemia Asrerils indicare

2). MSUD, mapte syrup urine dis€ase.

findingsare usuallyunrernarkable, xcept or metabolicacidosis.

Death usuallyoccurs n untreatedpatients n the 1st {ew weeks

or monrhsof life.

hrgher han thoseof the orher hreeamino acids Urine containshigh levelsof leucine, soleucine, nd valineand their respective

keioacids. Theseketoacids may be detectedqualitatively by

addinga few drops of 2,4-dinitrophenylhydrazineeagent.(0.17"

in 0.aN HCI) to the urine; a yellow precipitateof 2,4-dinitro-

measuredn leukocytes nd cuhured ibroblasts.Treatmentof the acutestate s aimed at hydrarionand quick

removalof thebranched-chain mino acidsand theirmetabolites

lasix, or hypertonicsaline.Trearmentafter recovery rom the acutestate equiresa dier

low in branched-chainminoacids.Syntheticormulasdevoidof

leucine, isoleucine, and valine are available commercially.Becauseheseamrnoacidscannot be synthesized ndogenously,

disard€rs n which patients ha"e a characterisric dor (se€ ext and Table

small amountsof rhem shouldbe added o the diet; he amoshould be ticratedcarefully by performing requentanalysethe plasmaamino acids,A clinical condition resemblingadermatitisenteropathica ccurs n affected ofantswhosepla

isoleucine oncentration ecomes ery ow; additionof isoleuto the diet causes rapid and complete ecovery.PatientswMSUD should emainon the diet for the rest of their lives.Lrransplantatron as beenperformed n a smallnumberof pati

with classicMSUD with promising esults.Thesechildrenhbeenable o roleratea normal diet.The long-termprognosis f affected hildren emainsguar

Severe etoacidosis,erebral dema, nd deathmay occurduany stressful ituation suchas infectionor surgeryr speciamid-childhood, Mental and neurologic deficits are com

sequelae.Intemitt€nt rlSUD. n this form of MSUD, seemingly or

chrldrendevelop omiring,odor of maplesyrup,ataxia, ethaand coma during any stressor catabolicstate such as infecor surgery.During theseattacks, aboratory findings are inringuishablerom thoseof the classicorm, and deathmay ocTreannenr f the acuteattack of intermitrentMSUD is srmrlthat of the classic orm. After recovery, lthougha normal ditolerated,a diet low rn branched-chain mino acids s rec

mended.Activity of dehydrogenasen patientswrth the ntertent form is higher han n che lassicorm and mayreach5-2of the normal activity.

Mild lhtennediate)MSUD. n this form, affected childdevelopmilder disease fter the neonatalperiod. Clinical mfestations re nsidiousand imited o the centralnervous ys

Patients avemild to rnoderatemental etardarion usuallya5 mo of age) with or without seizures. hey have he odo

maple syrup and exctetemoderateamounts of the branccharn amino acids and rheir ketoacidderrvarivesn the uPlasma oncentrations f leucine, soleucine, nd valinearem

erately increasedwhereas rhose of lactate and pyruvatenormal. These hrldrenare commonlydiagnosed uringan ncurrent llnesswhen signsand symptomsof classicMSUD

No ketosis r mildketosis

1.3-Hydroxy-3-melhylglularicaciduria

2.AcylCoAdehydrogenasedaficiency

3. HMGCoAsynthetasedeficiency

No skinmanifestations

1. rethylmaloniccidemia2. Propionic cidemia3. Ketolhiolaseefciency



542 PARTX MotabolicDiseases

occur The dehydrogenase activiry is 3-30% of normal. Sincepatients wirh rhiamine-responsive MSUD usually have manifes-tatrons similar to those seen n the mild tbrm. a trial of thiaminetherapy is recommended. Diet therapr., similar ro that of classiclvISUD, is needed.

Thianine-Sesponsiye MSUD. Some children wrth mild or inter-mediate forms of MSUD who are ueated with hish dosesof thi-am ine havc d ram ar icc l in i ca l and b iochem rca lm o rovem enr .AJthough some rerpond ro rrealmenr with rhiamine ar l0mg/24 hr, others rnay require as much as 200 mg/24 hr for at least 3

wk before a favorable response s observed- These patienrs alsorequire drets deficient in branched-chain amino acids. The enzy-matic activity in these oatie[ts is 2-407o of normal.

MSUD Due o a 0efici;ncy ot ErSubunit (Dihydrolipoyl Dehydroge-nasel. This is a very rare drsorder Patients develop lactic acido-sis in addition to signs and symptoms simrlar ro those ofintermedrate MSUD because he E1 subunit is also a componentof pyruvate dehydrogenase and o-ketoglutarate dehydrogenase.Progressrve neurologic impairment manifested by hypotoniaand developmental delay occurs aIrcr 2mo of age. Abnormdmovements progress to atax ia. Death ma,v occur in earlychildhood.

Laboratory findings include persistent actic acidosis wirh highlevels of plasma lactate, pyruvate, and alanine. Plasma concen-trations of branched-chain amino acids are moderatelv increased.

Patienls excrete large amounfs of lacrate, pvruvate, cr-glutarate,and the three branched-charn ketoacids in rheir urme.No effeccive treatment is available. Dietary resrtrction of

b ranched -cha inm ino rc rds and r reaLm enr. r r rh i eh doses frh iam ine . io t in .and ipo icac rdhasbeen ne f fec t i re .

Geneticsand Preyalenceof MSUD.All forms of MSUD are nher-ited as an autosomal recessivecrait. The gene for each subunitresides n dil lerenr chromosomes.The E1, gene s on chromo

different disease-causine mutations have been idenrified inpatrents with different forms of MSUD. A given phenocl,pe iscar:sed by a variety of genotypes; patients from different pedigrees u'ith the classic forrn of MSUD have been shown co havemLllations rn 64enesor E1", Ern, or E2. Most paciencsare com-

pound hererozygotes nheriting tlvo different mr.rtant alleles-The prevalences estimatedat 1/185,000.The classic orm ofMSUD is more prevalent in the Old Order of Mennonires in theUnrted States, with estimated prevalence of 1/358, Affectedpatients rn this population are homozygous for a specific muta-tion (Y394N) in the Ero subunit gene.

Early detection of NISUD is feasible by mass screening ofnewborn infants. Prenatal diagnosis has been accomplished byenzyme assayof the cultured amniocytes, cultured chorionic villitissue, or direct assay of the chorionic vrlli samples and by identrfication of che mutant eene-

Several successful pregnatr.re" have occurred in women wirhdifferent forms of MSUD. No ill effects have been observed inthe offspring of rhesepatients. Episodes of metabolic decompen-sations have occurred rn rhe mothers during pregnancy and the

postpartum perlod.

IS0VALEBIC Cl0EMlA. This rare condrtion i s due to the delicrencyo f r sova lc ry l oenzym e lCoAt deh ld rogenasesee ig . 8s -51 .

Clinical manifestations rn the acute form include vomiting andsevereacidosis in che 1st few days of life. Lethargy, convulsions,and coma may ensuer and death may occur if proper therapy rsnor rnitiated. The vomiting may be severe enough to suggestpyloric stenosis. The characterisric odor of "sweaty feet" may' bepresent (seeFig. 85-6). Infants who survive rhis acure episode wrllgo on to have the chronic ntermitten! form later on in life. Amilder form of the disease (chronic intefinittent form) also exists;rn rhis, the 1st climcal manifescation (vomicing, lechargy, acido-sis or coma) may not appear unrrl the child is a few monrhs o. a

few;lears old. lo both forms, acute episodesof metabolic depensacionsmay occur during a catabolic state such as an intion. Sen rive methods for newborn screenng have identifieda m i lde r nd po ten f ial l ) ' a \ ym p tom ar ichenotvpe f rhe cotion; a few older siblings of these affecred newborns were foto have identical genotype and biochemical abnormawithout any clinical mamfescations.

Laboratory findings during the acute attacks include ketodosis, neucropenia, thrombocytopenia, and occasionally patopenia. HypocaLcemia, hyperglycemia, and moderace to se

hyperammonerma may be present in some parients. Increasplasma ammonia may suggest a defect in the urea cycle. Incycle defects the infant is noc acidotic (seeFig. 85-6).

Diagnosis is esrablished by demonstrating marked elevaof isovaleric acid and its metabolites (isovalerylgft.crne

hydro:':aisovaleric acid) in body fluids, especiallyurine. The mcompound in plasma is isovalerylcarnitine, which can be msured even in a few drops of dried blood on a filter paper. lvsuring the enzyme in cultured skin fibroblasts confirmsdiagnosis.

Treatment of the acute attack is aimed at hydrarion. reveof the catabolic state (bv providrng adequare caloties orallyintravenously), corre ion of metabolic acrdosis (by intusodium bicarbonate). nd removal of the excess rsovaleric aBecause sovalerylglycinehas a high urinary clearance, adm

rradon of glycine \250 mglkg/24 hr) is recommended ro enhformation of rsovalerylglycine. L-carnicine (100 mg/kg/2orally) also increases emoval of isovaler acid by formrng valerylcarnirine, which is excreted in the rine, In patients

s ign i f i can t ype ram m onem iab loodam m on ia 200 ; rM r . msures thar reduce blood arnmonia should be employedLhap re r 85 ,1 l ) . Exchange rans l : us ionnd pe r i t onea l iama,v be needed if the just described measures fail to induceni6canr clinical and biochcmical imDrovemcnr.Alrer reco

tine supplemenrs. Pancreatitjs (acute or recurrent forms) has breported in survivors. Normal development can be achieved r€arly ano proper rreatment,

Prenatal diagnosis may be accomplished by measuring

valerylglycine in amniorrc fluid, by enzyme assay in cuhuamniocytes, or by Ldentification of the mutanr gene. Succepregnancy wich favorable outcomes both for the mother andinfanr has been reported. Mass screening of newborn infanrrn use in the United Srates and othet counrfles. lsova

disease-causingmutations have been dentilied. The prevalencrhe condirion is estimated from 1/52,500 (io parts of Germato 1/250,000 (in the United States).

MUtTtPtECARBoXYIASEEFtCIE'{CIESDEFECTSN UTIUZA0F BlOTlt{1.Biotin is a water-soluble vitamjo that is a cofactorall four carboxylase enzymes rn humans: pyruvate carbox_vacetyl CoA carboxylase, propionyl CoA carboxylase, and

methylcrotonyl CoA carboxylase. The latter two are involvethe metabolic pathways of leucine, isoleucine, and valine (see

85-4).

Dietary biotin is bound co proteins; free biotrn is geoeratethe intestine by the action of digestiveenzymes, by intestinal bteria, and perhaps by biotinidase. The latter enzyme, v.hicfound in serum and most tissues n the bodr', is also essentiathe recvcling of biotin in the body by releasing rt from the apozymes (carboxylases, seeFig. 85-4). Free biorin must form a colent peptide bond *'ith the apoprotein of the four carboxylato activate them (holocarboxylase). Thrs binding is catalyzedholocarboxylase svnthetase.Deficiencies n thrs enzyme or intinidase result in malfunction of all the carboxvlases andorganic acidemia.



of biotin.Treatment rvich biotin (10 mg/day orally) usually results in an

imDrovement n clrnical manifestatton\an d ma y normalize thebiochemical abnormalit ies. Early diagnosis and treatment ar e

related to cheourcome lemains unclear.

ciency. Infants q'ith this defictency may de lop. clinical

maniiestations similat to those seen in infants lth holocar-

ChaDter6 r Defsctsn ltle{abolism f AminoAcids r

The orevalenceof this aucosomal recessivecrait is estimated

1/60,000. The gene for brotinidase is located on chromoso

3p25 and manv disease-causingmutations have been dentif ied

different families. Prenatal diagnosis is possible by the measu

ment of rhe enzyme actrvity in the amniotic cells or by ident

cation of the mutant gene.

Mult iple Carboxyl6s;DeficiencyDue o DietaryBiotin Delicie

Acquired de6ciency oI biotin may occur in infants receir.ing lo

parenreralnurrit ion without added biorin, in parienrs ecei

prolonged antrconvulsant drugs (phenycoin, prirnidone, car

mazepine) or in children wrth short bowel s1'ndrome or chrodrarrhea who are recervrng formulas low in biotin. Exces

ingestion of raw eggs may also cause biotin defictency beca

the protein avidin in egg white binds biotin and makes it unav

able for absorption, Infants with biotin deficiencv develop d

matitis, alopecia, and candidal skin infections.

ISOTATED.METHYTCROTONYTOACARBOXYTASEEFICIThisenzymes oneof fourcarboxylasenzymesn the bodyrequire iotinasa cofacrorsee ig.85-4).An solated eliciof this enzvme musc be differentiaced from disorders of bio

metabolism (multiple carboxylase deficiency), which causedrm

ished actrvity of all four carboxylases, 3-Methylerotonyl CoA c

bo:'ralase is a heteromeric enzyme consisting of cr (bio

containing) and p subunirs.Clinical manifestations are highly variable, ranging from fa

neonatal onset wrth acidosis, severe hypotonra, and seizure

asympromatic adults. In the severe form of the condition,

affected in{ant who has been seemingly normal de.'elops an ac

episode of vomiting, hypotonia, lethargy, and convulsions afte

ninor infection. Death may occur during the acute episode.

Laboratory findings during acute episodes nclude mild to m

erate acidosis, ketosis, severe hypoglycemia, hyperammonem

and elevaredserum levels of liver transaminases. Large amou

of 3-hydroxyisovaleric acid and 3-methylcroconylglycine

found in the urine. Urinary excretion of 3 mechylcrotonic aci

not usualh' increased n this condition because he accumula

3-merhylcrotonyl CoA is converted to 3-hydroxvisovaleric a

Severesecondarv carnrtrne deficiency is common. The condit

should be differenciated biochemically from multiple carboxyldefcrency (seeearlier) in which lactic acid and metabolites of p

pionic acid are present in body fluids in addition to 3-hydro

isovaleric acid. Diagnosis rnay be confirmed by measuremen

the enzyme activity in cultured fibroblast s, Documentation

normal activities of other carboxylases is necessary or delim

diagnosis.Aggressive treatment of acute episodes with hydration, in

venous infusion of glucose, and alkali is recommended. Th

parienrs are unresponsive to biorin therapy. Parients who

earlier reporrs were found to be t' iotin fe\ponsrve were mprobably suffelng from muftiple carboxylase deliciency due

biotinidase defrciency (seeearher). Long-term treatm€nt inclu

a dier rescricced n leucine in conjuncrion with the oral admi

tration of L-carnitrre (7 5-100 m{k{24 hr) and the preven

of catabolic states.Normal growrh and development are expecin thesepatlents.

The condition is inherited as an autosomal recessive rait.

gene for cr subunit (MCCI ) is located on chromosome 3q25-

and rhar for the p subunir \MCC2) is mapped to chromoso

5q12-13. Mutation in either of these enesmay resulc n the d

ciency of rhe enzyme activity. Srmilar phenoqvpe may be cau

by different genotype. Severaldrsease-causrng utations rn ei

gene have been idennfied in different families. Newborn scr

ing programs using tandem mass specrrometry have identifred

unexpectedl;r high number of infants with 3-methylcrotonyl C

carboxylase deficiency (1:50,000), suggesting hat this condit

may be one of the most common organic acidemias in cer

ooDulatl()l1s.



544 PARTX MetabolicDiseases

546 PART r Metabolic isrosas

during acure artacks.Diagnosismay be confirmedby enzymeassayn cuftured ibroblasts, eukocytes, r liverspecimens r byidentificationof the mutant gene.Prenacal iagnosrss possibleby the assay f the enzyme n culturedamniocytes r a chorionicvilli biopsy or by DNA analvsis.

Treatmentof acute episodes ncludes hydratron, nfusion ofglucoseo control hypoglycemia, rovisiono{ adequate alories,

and adminisuationof bicarbonareo correct acidosis.Hyperam-monemia hou ldbe r reared rompt ly seeChaprer 5.11) .Exchange ransfusionand peritonealdialysismay be required npati€ntswirh severe yperamrnonemia, estrictionofprotein andfat intake is recommended or long-term management.Oraladministrationof L-carnitine 50-100mg/kg/24hr) prevents ec-ondarycarnitinedeficiency. rolonged astingshouldbe avoided.One child died after routine immunizarion. The condition isinheritedasan autosomal ecessiverait. Theeeneor HMG-CoAlyare resides n chromosome prer-p33and several rsease-causingmutationshavebeen denrified n different amilies.Thegenedefectappears o be more common n the Arabic popula-tion, especiallyn SaudiArabia.

SUCCINYt 0A:$KETOACID0ATRAiISFERASESc0T)DEFICIENCY

This enzyme s necessaryor the metabolismof ketone bodies(acetoacetarend 3-hydro:r1'butyrate)n peripheral issue (seeFig. 85-7). A deficiency f this enzyme esults n the underuti-lization and accumulationof ketone bodies and ketoacidosis,Only a few patientswirh SCOT deficiency ave been eportedto date; he condirion may not be rare becausemany cases reundiagnosed.

The presentation s an acute episodeof unexplainedsevereketoacidosisn an infant who had beengrowing and developingnormalh'.About half of rhepatientspresent n the 1st wk of lifeand all before2 yr. The acureepisode s oftenprecipitated y anintercurrent infection or a catabolic state. Death may occurduring hese pisodes. chronrc uhclinical erosis sually er -sis!sbetrveen heattacks,Developments usually normal.

Laboratory findingsduring the acute episodeare nonspecific

and includemetabolicacidosis nd ketonuria with hieh evelsofaceroacetatend J-hydroxyburyraren bloodand urini. No orherorganicacidsare ound n the blood or in the urine.Bloodglucoselevels reusuall) ormal,bur hvpoglycemiaar been eponedntwo newborn infants rvirh severeketoacidosis,Plasmaaminoacidsareusuallynormal. Diagnosis an be established y demon-stratinga deliciency f enzymeactivity n cultured ibroblastsorbv DNA analvsis.

Treatmentof acuteepisodes onsists f hydration,correctionof acidosis, nd theprovisronof a d iet adequaten calones. ong-term treatment vith a high-carbohydrare iet and avoidance fcarabolicstates s recommended. his condition sbould be con-sideredn any nfant tuith wnexplamed oatsof hetoacidosis.hecondition is inherited as an autosomal ecessiverair, The eenefor rhis enzlme s locared n chromosome plJ, and .eieral

drsease-causingutationshavebeen ound in different amrles.

MEVAL0NICCIDUBIA. levalonicacid, an incermediatemetabo-lite of cbolesterol ynthesrs,s converted o 5-phosphomevalonicacid by tbe action of the enzymemevalonate inase seeFig. 85-7). Based n clinical manifestations,wo formso{ this condirionhavebeen ecognized.

Mevalonic Aciduria, Seyere Form. Clinical manifesrarionsincludemencal erardation, ailure to thrive,growth rerardation,hypotonia,ataxia,hepatosplenomegalnataracts, nd acialdys-morphrsm dolichocephaln ronral bossing,ow-setears,down-ward slanringof the eyes,aod long eyelashes). ecurrenc rises,characterizedby fever, vomiting, diarrhea, arthralgia, edema,lymphadenopathy',urther enlargement f liver and spleen,andmorbrlliform rash have been observed n all patients. These

eprsodesast 4-5 days and recff up to 25 times/yr Deathmayoccur durine these rises.

Laboratory findings include marked elevation of mevaacid n urme; he concentrationmay be as high as 56,000pmmole of creatinine(normal <0.3). Plasma evelsof mevaacid are alsogreatly ncreasedashigh as 54 pmole/dl; nor<0.004).This is the only abnormal organic acid found in tpatients,The levelo[ mevalonicacid tends o correlarewithseverityof the condition and increasesuring crises.Serum

Iesterol oncentrations normal or mildlv decreased. erumcentrarionof crearinekinare 1CK1 s markedly increSedimentationate and serum eukotriene-4 re ncreased uthe crises, erial xamination f rhe brain by MRI revealsgressjverrophv f the cerebellum,

Diagnosismay be confirmed b,v assayof mevalonate inactivity in lymphocytesor in cultured fibroblasrs.No effetherapy s available,Tieatment with high dosesof predm

12mg/kEl24 r) causesmprovement f the acute rises. he cdition is inheritedas an autosomal ecessiveuait. Prenataldnosis s posribleby measuremenrf mevalonic cid inamniotic luid, by assay f theenzyme crivity n culturedamcytesor chorionicvilli samples r by demonstration f lhe mugene.The gene or mevalonate inase MVK) is on chromos1,2924.

Pe odic Fever with Hyperimnunoglobulinemia {MevaAciduria,Mild Form).Somemutarionsof mevalonickinaseetMVKt causemild deficienciesf rhe enzyme nd producclinicalpicture of periodic everwith hyperimmunogobulinD. Thesepatientshaveperiodic bouts of fever associatedabdominal pain, vomiting, diarrhea, arthralgiaj arthrhepatosplenomegaly,ymphadenopathy, nd morbiliform r(evenpetechiaand purpura) which usually start before 1]'rage. heanacks an beproduced v vaccinarion, inor rauor stress;usually occur every 1-2 months and last 2-7 dPatientsare free of symptomsberween cute attacks.The dnostic aboratory inding is elevationof serum rmrnunoglogammaD (lgD); IgA is also elevatedn 8070 of patients.Duacute attacks, Ieukocvtosis, ncreasedC-reactjveprotein,mild mevalonicaciduria may be present,High concentratio

serum IgD differentrateshis condition from familial \4edranean ever.

Tieatment of acuteartacks emainssymptomaric.The cotion s nherited san aurosomalecessirerairrmostoafienwhirean dar e rom western uropean ountries60'i, ar eeiDutch or French).The enzymeactivity is usuallyabout 5-1of normal. The parhogenesis f the condition remainsuncSeveral isease-causng utationsof the gene locatedon cmosome12q24) havebeen dentifred, ut one mutation (V3is present n 807o of pacrents. ong-term prognosis s usugood,bu t amyloidosir asoccurredn a teu parienrs.

PBOPIOI{IG CIDEMIA PROPIONYT OA CABBOXYTASECIENCY).Propronic acid is an intermediate merabolite

isoleucine, ahne, hreonine,methionine,odd-chain ary acand cholesterol atabohsm.t is normallvcarboxvlatedo metma lon ic c idby rhemr rochondr ia lnz lme rop ionv l oA boxylase,which requiresbiotin as a cofactor(see ig. 85-4).enzymes composed f rwo nonidentical ubunits, and p. Biis bound o the cr subunic.

Clinical indingsarenonspecific.n the sel'ere orm of the cditior, patientsdevelopsymptoms n the 1st few days or weof life. Poor feeding, omiting,hypotonia, etharg,r', ehydraand clinicalsignsof severe ecoacidosisrogress apidlv to coand deach. eizures ccur n =307oof affectednfancs.f an rnsurvives he 1st attack, similar eprsodesma,yoccur duringintercurrent nfecrionor colstipation or afrerrngestion f a hprotein diet, Moderate o severemental retardattonand nelogicabnormaliries uchasdystonia, horeoathetosis,emor,

pyramidalsignsare common sequelaen the older survivorthe milder forms, the older rnfant nay havemental retarda



without acute attacks of ketosis. Some affected chrldren mav hat'e

episodesof unexplained se,'erekeroacidosis separated by periods

oi seemingly noimal health. Mass screening of newborns- has

identified milder forms of rhe condition; a few of theses nfants

were complerely asl/mptomatic at diagnosis. The seleriry of cln-

ical manifestartons may also be variable wirhin a familv; io one

kindred, a brother was diagnosed at 5 yr of age whereas his

13 yr old sister, wirh the same level of enzyme deficiency, was

and oreviouslymenrionedorganic acids usualll persisL erueen

the acureanaik,. ( T rcan and MRI oF he brain mar revealer

Chapter 5 r oefucls [ Mdtabolisn l AminoAcids r

tered (10 mg/24 hr orally) to all infants during the 1st attack a

until the diagnosis is established.

Long-rerm treatment consists of a low-protein diec (1

1.5 dkg/24 hr) and admrnisrradon of L'carnicine (50-100 mg/

24 hr orallyr. Synrheticproteins deficienr n propionare prec

sors (isoleucine, aline, methionine,an d threonine)may be u

to increase he amount of dietary protein (ro 1.5-2.0 g/kg/24

rvhile causing minimal change in propronate productron. Exc

sive supplementarion wich these proteins may cause a defrcie

of the essenrialamino acids. To avoid rhis problem, natural p

reins should comprise most of che diecary protein (50-75%Some patienrs may require chronic alkaline therapy to corr

chronic acidosis. The concentration of ammonia in the blo

usually normalizes between attacks, and chronic trearmen

hyperammonemia is not usually needed. Carabolic srates t

may trigger acute attacks (rnfections, constipation) should

treared promptly and aggressively.Close monitoring of blood p

amino acids, urinary content of propionate and its metaboh

and growth parameters is necessary o ensure the proper bala

of the dret and lhe successof therapy.

Long-term prognosis is guarded. Deach may occur during

acute altack. Normal psychomotor developmenr is possible, es

cially in the mild forms identrfied through screening program

mosr children identified clini cally manifest some degree of p

manent neurodevelopmental deficit such as dystonia, chorea, a

pyramidal signs despite adequate therapy. These neurologic liings may be sequelae of a metabolic stroke occunng duringacute decomoe[sadon seeearlier).

Prenatal diagnosis is achieved bv measuring the enzyme ac

ity in c uhured amniotic cells or in samplesof unculturedch

onic villi, by measurement of methylnitrate in amniotic fluid,

by identi6cation of the murant gene.

The condition is inherited as an autosomal recessive rait a

can be identified by mass screeningof newborns. Ic is more pre

lenr n S audi Arabia (1 :2,000 co 1 :5,000). The gene or th

subunit (PCCA gene) s located on chromosome13q32 and c

of rhe p subunit (PCCB gene) rs mapped to the chromoso

3921-q22. Many mutations in either genehave been dentified

differenr patients. Pregnancy with normal ourcome has b

reporred in affected females.

METHYIMAI0I{|C ACIDEMIA. Methylmalonic acid, a structuisomerof succinicacid, s normally derived rom propionic aas part oI the catabolicparhwaysof isoleucine, aline, hreonmethionine,cholesterol, nd odd-chain att) 'acids. Two enzy

are involved in the conversion of D-methvlmalonrc acid to s

crnjc acid: methylmalonfl CoA racema'e, rthich iorms rheisomer; and melhylmalonyl CoA mutase, rvhich converts L-methylmalonicacid to succinicacid (seeFig. 85-4). The la

enzyme equiresadenosylcobalamin, metaboliteof vitaminas a coenzyme. Deficiency of either the mutase or its coenzycauses he accumularion of methylmalonic acid and its prec

sors-in body fluids. A defrciency of rhe racemase has not bconnrmeo.

At least tr.o forms of mutase apoenzyrne deliciencieshave b

identified. These are designared muttt, meaning no detectenzyme actrvrty, and muf, indicating residual, alrhough abnmal, mucaseactivity. The majority of reporred patients.rmethylmalonrc acidemla have a deficiency of the mutase apozyme mult or m / ). The\e patienrs re nor respon\ive o vitaB12 herapr'. In the remarning patients with methylmalonrc aemia, the defecr resides n che formarion of adenosylcobalam

Defectsn Metabolism lVilaminBu (Cobalaminl. ietar_v ita812 equires rntrinsrc factor, a glycoprotein secreted by the gasparietalcells. for absorption in the terminal i leum, It is traported n the blood by 6apcocorrin TCI) and transcobalam(TCII). The complex of rranscobalamin l-cobalamrn(TCII-C

is recognized by a specific receptor on the cell membrane enters the cell by endocytosis. The TCll-Cbl complex



550 PARTX Metaholiciseases

l{eonatalHypelglycemia. his is the most common form ofNKH. Clinical manifestations evelop n the lst few daysof life(between6hr and 8 daysafter birth), Poor feeding, ailure tosuck, ethargy,and profound h1'potoniamay progress apidly toa deep coma, apnea, and death. Convulsions, especiallymyoclonicseizures nd hiccups,are common,

Laboratory indings evealmoderate o severe yperglycinemia(as high as eight rimes normal) and hyperglycrnuria.Theunequivocal levationof glycineconcentrationn the spinal luid(15 to 30 timesnormal) and the high ratio of glycineconcentra-tion in spinal fluid to that in plasma (a value >0.08) are diag-nostrc of NKH, SerumpH is normal; plasmaserine evelsareusually ow

About 30% of affected nfantsdie despite upportive herapy,Thoservho sun' ive developprofound psychomotor etardationand lntractable seizuredisorders myoclonicand/or grand malseizures).Hydrocephalus, equiring shunring, and pulmonaryhypertension avebeennoted [ somesurvlvors.

Inlatttile lKH. Thesepreviouslynormal infants developsignsand symptomsof neonaralNKH (seeearlier) after 6 mo of age.Seizures re he commonpresenting igns.Thiscondition appearsto be a milder form, infantsusuallysurvive,and mental etarda-tion is not asprofound as n the neonatal orm.

laboratory findings n these atientsare rdentical o he neona-tal lorm.

Late-OnsetlKH,Mild Episodic orm. rogressivepastic iplegia,optic atroph]'.and choreoathetoticmovemenls re he main clin-ical manifestations, ge of onserhas beenbetween2 and 33 yr.Symptoms f delirium,chorea,and verticalgazepalsymay occurepisodically n somepatients during an intercurrent nfection.Mental developments usuallynormal, but mild retardationhasbeen eported n somepatienrs.Seizures ave occurred n onlyone parieqt.

Laboratory indingsaresimilar o but rtot aspronouncedas nthe neonatal orm.

TransientNKH. Most clinical and laboracory manifestationsof thrs form are indistineuishablerom those of the neonaralform. By 2 to 8 wk of age,however,he elevated lycine evels nplasmaand cerebrospinalluid (CSF)normalizeand a complereclinical recoverymay occur.Most of thesepatientsdevelopnor-mally with no neurologicsequelae, ut mental retardationhasbeen noted in some. The etiology of this condition is notknown, but it is believed o be due ro immaturity of the enz:/mesvstem.

Atl formso{ NKH shouldbe differentiatedrom ketotichvoer-glycinemia, -glyceric ciduria se e arert,and ingestion f val-proic acrd.The latter compound causes moderate ncreasenblood and urinary concentrations f glycine.Repeatassays fterdiscontinuation f the drug shouldestablishhe diagnosis.

Diagnosis an be established y assay f theenzymen liver orbrain specimens r by idenrifcation of the mutation. Enzymeactivity n the neonacalorm is close o zero,whereasn the otherforms,some esidualactivitv s present. n mostpatientswrth theneonatal orm, the enzymedefect residesn the P protein; thedefect n the T protein accounts or rhe rest. The enzymeassayin three patients with rhe infantile and late-onset orms hasrevealedwo patientswith the defect n the T protein and one nthe H protein.

No effectivereatment s knorm, Exchangeransfusion, ietaryrestrictionof glycine,and administrationof sodium benzoate rfolate havenot altered he neurologicoutcome.Drugs hat coun-teract he effectof glvcineon neuronalcells,suchas strychnine,diazepam,and dexuomethorphan,have shown some beneficialeffeccs nly in patrentswith the mild formsof the condition.

NKH is inherited as an autosomal ecessiverait. The oreva-lences nor known.bur high requency f the disorder ai beennoted n northern Finland (1/12,000).The gene or P protein slocaredon chromosome p22. The gene or H protein s mapped

to chromosome 6p24and that for T protein s mapped o chro-

mosome3p21-p21,1.Several isease-causingutarionshbeen dentified.Prenatal iagnosis asbeenaccomplished yIorming an assay f the enzymeactivity in chorionic villi biospecimens r by identifrcation f the murantgene.

SARC0SIIEMlA.ncreased oncentrations f sarcosineN-meglycrne) reobservedn borhbloodand urine.but no consi

clinicalpicture

hasbeenattribuced o this melabolicdefect.Tis a recessivelynherited nborn error involving sarcosine drogenase,he enzyme hat converts arcosineo glycine see85-8).The gene or this enzymes ocaredon chromosome qq34.

D-GIYCEF]CCl0UBIA. -glycericacid s an incermediate etalite of serine nd fructosemetabolism see ig. 85-8).At leastforms of this rare condition have been dentrfied, n one foclinical manifestationsof severeencephalopathy hypotoseizures, nd mentaland motor deficits)and the laborarory irngsof hyperglycinemia nd hyperglycinuriawere suggestinonketotichyperglycinemia. hesepatientsexcreted arge qutitiesof o-glycericacid(thiscornpounds not normallv detecin urine). Enzyrne studies ndicated a deficiencyof glyce

kinase n one pacienrand decreased ctivity of o-glycericdedrogenasen another.In the other form, the major findrngsare persistentmetab

acidosis and developmentaldelay, This infant excreted aamountsof p glycericacidwithout hvperglycinemia. he enzdefect n this patient s not known.

No effectrve rherapy is available. Resrncrion of frucimprovedseizuresn one pacient.

TBlMEttlYLAMlNUBlA.rimetiylamine is normally producethe ntestine rom the breakdo*'nof dietarycholineand trimelamine oxide by bacceria. ggsand liver are the main sourcecholine, and fish is che major sourceof trimethylamrne xTrimethylamines absorbed ndoxidized n the iver bv uimetlamine oxidase flavin-containingmonooxygenases)o trime

lamineoxide,which s odorless nd excreted n the urine (see85-8). Deficrency f rhis enzyme esults n massive xcretiotrimethylamine in urine. Severalasymptomaticpatients wtrirnethylaminuria ave been eponed; here rsa foul body othar resemblesha! of a rottefl lish, which may have signifisocial and psychosocialamifications.Restrictionof fish, eIiver,and other sources f choline suchas nutsand grarns) ndiet significantly educe he odor The gene or trimethylamoridase asbeenmapped o chromosomeq23-q25,

HYPEROXURIAAND XAt0SlS.Normally, oxalic acid s dermostly from oxidation of glyoxylic acid and, to a lesser egfrom oxidation of ascorbicacid (seeFig. 85-8). Glyoxylic acformed from the oxidation of glycolic acid in the preoxisoThe source of glycolic acid remainsunclear.Foods containoxalic acid, such as spinachand rhubarb, are the main exonous sourcesof this compound, Oxalic acid canlor be furtmetabolized n humansand is excreted n the urine as oxalaCalcium oxalate s relatively nsoluble n water and precipitin tissueskidneysand oints) f its concenuation ncreasesnDOOy,

Secondary yperoxaluriahasbeenobservedn pvridoxinedciency cofactor or alanine-glyoxylareminotransferase,ee85-8) after ingestionof ethyleneglycol or high dosesof vitaC, after administrationof cheanesthetic gent methoxyflur(u'hrch oxidizes directly to oxalic acid), and in patients winflammaroryborveldisease r extensive esection f the bo(entetichyperoxaLarlal. cute, fatal hyperoxaluriamay deveafter ngestionof plantswith a high oxalic acid conten! sucsorrel.Precipitationof calciumoxalate n tissues auses l?oc

cemia, iver neclosis, enal arlure,cardiacarrhythmia,and de



The lethal dose of oxalic acid is esrimated to be berween .5 and

3 o gPrimary hlperoxaluria is a rare genetic drsorder in wbich large

amounts of oxalates accumulate in the body. Two tvpes of

peroxrsomes se eFig. 85 8).

There is a wide variation rn rhe age of presentarion. The major-

ity of patientsbecomesymptomaticbefore5 yr of age. n =10%

of cases, s,vmptoms de"elop before 1vr of age (neonatal

oxaluria). The inicial clinical mariifestations are related to renal

as gout becauseuric acid is usually elevared n patients wirh rype

I hyperoxaluria. Late forms of the disease presenting during

adulihood have also been reported. Crystalline retinopathy and

optic neuropath,v causing visual loss have occurred in a fe*

patlenrs.

A marked rncrease in urinary excretion of oxalate {normalexcrerion 10-50mg/24 hr) is the most important laboratory

fiading. The presence of oxalate crystals in urinary sedimenr rs

rarely helpful for diagnosis becausesuch crystals are often seen

in normal indivrduals. Urinary excretion of glycolic acid and gly-

oxylic id is rncreased.Diagnosis can be confirmed by petform-

ing an say of the enzyme in hver specimensor by identification

of the mulant 8ene.Medical trearment has been largely unsuccessful. In some

patrents, administration of large doses of pyridoxine redu s

urinary excretion of oxalate. Renal transplantation in patie s

with renal failure has not improved rhe outcome in most cases,

because oxalosrs has recurred in rhe transplanted kidney. Com-

bined liver and kidnev transplanrs have resulted in a sLgnificant

decrease n plasma and urinary oxalate in a few patients, and this

this condit ion. The most common muracion esults n the mis-

targeting of the enzyme to the mitochondria instead of the per-

oxiiomes. The in vicro enzyme activi!y in thesepatients may reach

the level found in obligate heterozygotes. n vivo function remains

defectrve, owever About 30% of parientswith hvperoxaluria

type 1 are estimaled to have this defect.

Prenatal diagnosishas been achievedby the measurementof

fetal hepatic enzyme activiry obtained by needle biopsy or by

dition is due to a deficiency of D-glycerate dehydrogenase

(hydroxypyruvate reductase)/glvoxylate reductase enzyme

complex (see rg .85-8).A deficiencyn the activrtyof rhis enzyme

resu[|s in an accumulation of two intermedrate metabolites,

hydroxypyruvate (the ketoacid of serine) and glyoxylic acrd. Both

these compounds are further metabolized by lactate dehydroge-

nase(LDH) to L-glyceric acid and oxalic acid, respectrvely.About

307' of reporced patients are from the Saultear-rx-Oiibway

Indians of Manicoba.

Clinically, chesepariencs are rndisc inguishable rom those with

hyperoxaluria type I. Renal stonespresenringwith renal colic and

hemarr.rria may develop before age 2 yr. Renal failure rs less

Ch60ter 5 . 0elects n Motabolism l AminoAcids r

comrnon in this condition than rn hyperoxalurra type [; the ur

concains large amounts of L-glyceric acid in addition to h

levels of oxalate (L-glyceric acid is not normally present n urin

Urinary excretion of glycolic acid and glyoxylic acid is

increased.The presenceof L-glvceric acid without increased e

of glycolic and glyoxylic acids in urine differentiates this ty

from type I hyperoxaluria. The gene is mapped to chromoso

No effective therapy is available.

CREATINEEFICIENCYreacine s synthesized n th e liver, p

creas, and kidneys from arginrne and glvcrne (Fig. 85-9) and

rransported to muscles and the brain, in lr'hich there is high c

atine kinase activitl'. Phosphorylation and dephosphorylation

creatine by this enzyme in conjunction with adenosine diph

phate and triphosphate (ADP/ATP) provide high-energv ph

phare reactions in rhese organs. Creatine is nonenzymatrc

metabolized to crearinine ar a constanr daily rate and is excre

rn the urine. Three eenetic conditions are known !o cause cr

tine defciency in rissues,Two are due to deficiency of the enzym

involved in the biosynthesrs of creatine. The enzymes

arginrneglycineaminotransferaseAGAT) an d quanidinoace

methyltransferase (GAIIT) (see Frg. 85-9). Borh conditio

respond well to creatine supplementation. The third condition

caused by the defect in the creatinine transporter(CRTR)

annot resoonsir ro crearinineadminisuation.

Cliniial mani{estations of the three defects are similar, re

to the brain and muscles, and rnay appear in the 1sr few we

or months of hfe. Developmental delan mental retardati

speech delal and serzures are common. Dystonic hyperkine

movements are seen n severe GAMT deficiencv.

Laborarory f indings nclude decreased rearineand crearn

in blood and urine in patients with AGAT and GAMT defe

Marked elevations of guanidinoacetare in blood, urine, and es

cially in CSF are diagnostic of GAMT defects,Low level

suanidinoacetate are found wirh rhe AGAT defect. Absence

ireatine and creatine phosphate (in all three defects) and h

levels of guanidinoacetare (with GAMT defects) can be dem

strated in the brarn by MRS. MRI shows signal hyperintensiry

the globus pallidus. Diagnosis of AGAT or GAMT defects m

be confirmed by measurement of th€ enzyme n the livert cuftu

Gbroblascs,or srimulated lymphoblasts or by DNA analysis

rhe gene. Diagnosis of CRTR is confirmed by genetic analysis

creatrne uptake b;i libroblasrs.

Treatment with creatine monohydrare (350 mg-z g/kg/d

orally has resulted in a dramatic improvement in muscle tone

overall mental develooment and has normalized MRI and e

rroencephalographic 6ndings in pacients wich AGAT and GAM

defects. It is believed that early treatment may assure norm

development. No therapy rs available for the CRTR defect.

AGAT and GAMT defects are inherired as aulosomal reces

traics. CRTR rs an X-hnked rrait. The orevalence of the enzvdeficrencys nor known: lour patientswrrh CA\lT derecr,,rh

from one family) were identified among 180 insticutronal

patients with severe mencal handicap. This condition must

considered in any patienc with brain and muscle disorders, s

treatment calr produce a dramatic response.

85.8.SrRttr raiRezvani

Senne rs a nonessenrial amino acid synthesized rom glucose

glycine (seeFig. 85'9).

3-PH0SPH0GLYCEBATEEHYDR0GENASEEFICIENCY elicie

of this enzyme causes deficiencies of serine and glycine in

body. Clinical manifestations, which are developed in the 1st

months of life, include microcephaly, severepsychomotor re



552 PAFIT I Met6bolicDiseases

3-Phosphoglyceraledeficiency

Glucose

II

3-Phosphoglycerate

l Î "

Sarcosine

clyoxvlate I

\ l\:ryutrre -

Arginine ------|

\ /-:\Ornithine --4 \9/

IGuanidinoacetate

3-Phosphopyruvate

Serine - 3-Phosphoserine

Figure 85 9. Pathways or the svnthesisof serin

cre3tine.Enzymes:1) 3-phosphoglycerateehydr

as€,(2) guanidinoacetaremethyltransferdseGA

(3) arginine:glycineaminorransleraseACAT).

hydroxyproline (dipeptides nd tripeptidescontaininghydroproli[e) reflectscollagen u.nover and is iflcreasedn drsoof accelerated ollagen turnover, such as rickets or hypa!alhyroidism.

HYPERPR0IINEMIA.wo types oI this rare autosomaLececondition have beendescribed. ype hypetprolinemia s dra deficiency f proline dehydrogenase,nd type II is duedefect n A'-pyrroline-5-carboxylrc cid dehydrogenasenz

(Fig.85"10).Neither type causes ny specific linical manifetion attributable o hyperprolinemia.ncreased lood concetions of proline (morepronounced n rype I) and prolinuriafound in both types. Hydroxyproline and glycine areexcreted n abnormal amounts n the urine because f the sratjon of the commofl nrbular reabsorprionmechanismbymassiveprolinuria. The presenceof ALpyrroline-S-carboacid in plasmaand urine d ifferentiates ype II from rype L treatment s recommendedor the affecred ndividuals.

The gene or prolinedehydrogenases mapped o chromos22q11.2 and several isease-causrngutationshavebeen de6ed;somemutationshavebeenassociated ith an ncreasedof schizophrenia.vlicrodelerion f chromosome 2q11.2cavelocardiofacial DiGeorge,Shpritzen) syndrome. n a steightout of 15 patientswith this syndrome lso had type hy

prolinemia. It has been suggested hat patienrs wirh hyprolinemia be screened (by FISH analysis) for presof rnicrodeletronof chromosome22q11.2. The gene forpyrroline-5-carbor.1.liccid dehydrogenases mapped ro cmosome:1p36,

PR0IIDASEDEFICIENCY uring collagen degradation,dodipeptidessuchasglycylproline) re eleased nd arenorrncleaved y tissueprolidase.This enzyme equiresmanganesits proper activity. Deficiency f prohdase, vhich s inherirean autosomal ecesslvetait. results n the accumulationofdodipepridesn body fluids.

The clinical rnanifestations f lhrs rare condirion and rheat onsetar e quitevariable 19mo to 19yr) and nclude e

S-noenosVlmethionine6{

S-AdenosylhomocysteineJ

Creatine+ + CreatinineI

IUrine

darion, and intractable eizures. ther findingssuchas ailure othrive, spastic etraplegia, ystagmus, ataracts, ypogonadism,and megaloblastic nemiamay also bepresent.

Laboratory indings nclude ow lel'elsof serineand glycine nplasma and very low levelsof serineand glycine n CSF Noabnormalorganicacid s found in the urine. Magnetic esonanceimaging of the brain shows significant attenuation of whitematter and incompletemyehnation.

Diagnosiscan be confrrmedby measurement f the enzyme

activity in cultured ibroblastsand by DNA analysis.Tieatmentwith serine 200-600mg/kg/24hr, orally) alone or

in conjunctionwith glycine (200-300mg/kg/24hr) normalizesthe serine evels n the blood and CSF.This rreatmen!producessignificantmprovement n all clinical rndings xcept or thepsy-chomotor etardation;seizure ctivity subsides ithin a few daysof therapyand may be haltedcompletely.Microcephaly mprovesin young affectednfants. There s evidenceo indrcate hat psy-chomoror etardationmay bepreventedf rhe rearment tarrs nthe 1st few daysof hfe.

The condition s inheritedasan autosomal ecessiverait. Thegene for 3-phosphoglycerateehydrogenase nzyme has beenmapped o chromosome q12 and a few disease-producinguta-tions have been dentified n different amilies,Prenataldiaeno-si sha sbeen chievedy DNA analysisna familywith previously

affectedoffspring; administrationof serine o the mother cor-rectedmicrocephalyn the affected etusas evidenced y ultra-sound imagrng.The favorable response f this condition to asimple reatmentmakes his dragnosis n important considera-tion in any child with microcephaly nd neurologicdefects uchaspsychomotordelayor a seizure isorder

85.9 PR0LINElrai Rezvani

Prolineand hydroxyprolineare found in high concentrarionsncollagen.Neitherof theseaminoacids s normally found in urinein the free form except n early infancy. Excretionof "bound"



Chaoter 5 . Doloctsn l{otabolism l Amim Acids .

\.)A'-Pyrroline- Glutami

acrd

!-igure 85-10. Pathways n rhe mecabohsmof pro

line. Enzymes: 1) proline oxidase, (2) ^lpyrroline

l-carboxylic acid dehydrcgenase,3) hydroxyproline

5-carboxylicacrd

i+

Ornithine

A'-Pyrroline-+ Pyruvic ++hydroxy-s- acid

carlgoxyliccid

19Glyo

acHydroxyproline

Hyd.oxyprolinemia

rent, parnful skin ulcers, which are rypically o hands and legs.

Other skin lesrons hat may precede ulcers by veral years may

include scaly erythematous maculopapular rash, purpura, and

telangiectasia. Mosr ulcers become nfected Healing of the ulcers

mav iake 4 to 7 mo. Mild to severe mental and motor deficits

an d suscepribil ity o infecrionsar e also present n morr patients

(recurrent otitis media, sinusitis, respiratory infection,

splenomegaly). Infection is rhe cause of death.Some patients may

have some craniofacial abnormalities such as ptosis, ocular prop-

cosis, and prominent cranial sutures. Asymptomatic cases have

also been reponed. Development of systemrc upus erythernato-

sus {SLE) has been nored in affected children of one family; young

patients wrth SLE should be screened for prolidase defrciency.

iligb leuels of urinary excretion of imidodipepcides are dragnos-

tic. Enzyme assaymay be performed in eryrhrocytes or cultured

skin 6broblasts,

Oral supplementation wrth proline, ascorbic acid, and man-

ganese and the topical use of proline and glycine result in an

improvement in leg ulcers. These reatments have not been found

consisrently effective in all patients.

The gene for prolidase enzym has been mapped to chtomo-

some 19cen-q13,11and several isease-causing utations have

been identified in drfferent families,

85.10. turAMtcclD lraiRezvani

Glutarhione (y-glutamylcysternylglycine) is the major product of

glutamic acid in rhe body. This ubiquitous tripepcide is synthe-

sizedand degraded through a complex cycle called the y-glutamyl

cycle (Frg.85'11). Because f irs free sulfhydryl (-SH) group an d

its abundance in the cell, glutathione protects other sulfhydryl-

containing compounds (such as enzymesand coenzyme A) from

oxidation. It rs also involved in rhe detoxification of peroxides,

including hydrogen peroxide, and tn keeprng the cell content in

a reduced stare. The common consequence of glurathione defi-

ciency is hemolytic anemia. Glutathione also partrctpates in

amino acid traflsport across the cell membrane through the 1-glutamyl cycle.

GIUTATHI0NEYNTI|EIASEEFICIENCYFlG.85-11).hree orms of

this condition have been reported. In the severe form, whrch is

due to generalzed deficiency of the enzyme' severeacidosis and

massive S-oxoprolinuria are the rule. ln rhe mild forrn, in which

the enzyme deficiency causesglutathione deficiency only in ery-

throc;tes, neither 5-oxoprolinuria nor acidosis has been

observed. A moderate form has also been observed rn which the

hemolytic anemia is associaredwith variable degrees of acidosis

and 5-oxoprolinuna. In all forms, patients have hemolpic anemia

secondary to glutathione defictency.All forms are rare (a coral of

55 patients have been reponed).

Gldathione Synthetase Deficiency, Severe Form (Pyiogluta

Acidernia, Severe 5-oxoFrolinuria) and Modelate Form, Clin

manifestations of thrs rare condition occur in rhe 1st few day

life and include metabolic acidosis, jaundrce, and mild to m

erate hemolytrc anemra. Chronic acidosis continues after rec

ery. Similar episodesof li fe-threatening acidosis may occur dugascroenteritis or an infection or after a surgical procedure.

gressive neurologic damage manifested by mental retardat

spastic tetraparesrs, ataxla, tremor, dysarthria, and seiz

develops with age. Susceptibrlir y ro infection, presumably dL

granulocyte dysfunction, is observed in some patients. Pati

wirh rhe moderate form have milder acidosis and less 5-oxop

linuria than with the severe orm; neurologic manifestations

atso aDsenc.Laboratory frndings rnclude metabolic acidosis, mild ro m

erate degreesof hemolytic anemia, and 5-oxoprolinuna. H

concenrations of 5-oxoproline are also found in blood. The

tathione content of erythrocytes is markedly decreased. ncrea

svnrhesis f S-oxooroline n this disorder is believed o be

!o the conversiol of 1-glutamylcysteine to 5-oxoprolne

the enzyme lglutamyl cyclotransferase see Frg. 85-11)

Glutamylcysteine production Increases greatly because

normal inhibitory effect of glutathione on thelglutamylcysresynthetase enzyme is removed. A deficiency of glutathione

rhetase has been demonstrated in a variety of cells includ

erythrocytes.

teatment of acute attack includes hydration, corr€ctionacrdosrs (by infusron of sodiurn brcarbonate), and measure

correct anemia and hvoerbilirr-rbinemia. Chronic adminisrra

of alkali is usually needed indeGnitely. Administration of l

doses of viramins C and E has been recommended. Drues

oxidants thar are known to causehemolvsir and stressfulbolic srares hould be avoided,Oral adminisrrationof elutarhanalogshas been ried wirh variablesuccess.

Prenatal diagnosis can be achieved by the measurement o

oxoprohne in amniotic flurd, by enzyme analysis in culru

amnrocytes or chronic villi samples, or by DNA analysis of

gene,Successfulpregnancy rn an affecred female (moderate fo

with favorable outcomes for both mother and rnfant has b

reported.

GlutathioneSyniheiaseoeficiency, Mild Form.This form has b

reported in only a few patrents. Mild to moderate hemo

anemia has been rhe only clinical finding in these patie

Splenomegaly has been reported in some patrents. Mental de

oDment is normal: metabol ic acidosis and increased concen

tions of S-oxooroline do not occur Thrs condrtion is due

mulations in tle gene chat encodes for glutathione synthe

enzyme, These mutations, however, presumably render

enzyme unstable but wirh normal catalyti c function. The e

dited rate of enzyme turnover caused by these mutations is o

consequence or all tissues with normal protein synthesis ex

for erythrocltes rn which the absenceof protein synthesis re



554 PABTX MotabolicDiseasss

Glutathioneynth€la6€deficiency

Vitamin 86 dependency

_.--Glutathione(GSH\

. //,,''\\ -Glulafi]'ylcysteinylglycine

,' Aminoacidoutsidethecell

"y-Glutamyl mino acid

Succinicacid

@

LysrneHistidineProline-Histidine*-Prcline.' tOrnithine/

mylcysteine

Glutamica(

Glutamyl

,? 61 ,nz' r

Figure85-11. The glutamylcycle. De

of the glutarhione slnthesis and degr

rj<,n are nored. Enzymes: (11 ysluca

transpeptidase, 2) rglutaDryl cyclotr

ferase, J) s-oxoprolinase,(4) lslutamcvsteine svnthetase,(J) glutathione

thetase,(6) gluramjc acid decarboxy(7) G,{BA transaminase,8) suc.inic s

aLdehyde ehydrogenase.

5-Oxoproline(pyroglutamiccid)

@

@GABA Succinicci d

semialdehyde

III

t-Hydroxybutyricacid

in a serious deficiency of glutathione. Treatment is that of

hemoll.ric anemia and avoidance of drugs and oxidants rhat can

trigger the hemolytic process.

All forms of the condition are inherited as an aulosomal reces

sive trait. The gene for rhis enzyme ls located on chromosome

20q11.2. Several disease-causingmutations have been identifed

in different familiess-0xoprolinase 0eficiency {s-0xoplolinurial. The main cause of

massive 5-oxoprolnuria is glutathione synthetase deficiency lseeearlier). Moderate 5-oxoprohnuria has been found in a variety of

metabolic and acquired conditions, such as n patients with severe

burns, Srevens-Johnsonsyndrome, homocystinuria, urea cycle

defects, and tyrosi lemia type I.

A few individuals with moderate 5-oxoprolinuria (4-10 g/day)

due to 5-oxoprolinase deficiency have been denti6ed. No specific

clinical picture has yet emerged. Modera!e !o severemental retar-

darion has been reported in two patients. Asymptomatic individ-

uals with the enz-vme deficiency have also been identifed,

holvever. It is, therefore, not clear r-herher S-oxoprolinase de6-

ciency is of any clinical consequence. No treatment has been

recommenoeo.

T-Glutamylcysteine Synthase Defciency. Onl)' a few patients

with this enzyme deficiency have been reported. The most con-

sistent clinical manifestation has been rnild chronic hemolytic

anemia.Acureart.rck,, f hemolysishaveoccurredafter expoiure

to sulfonamides. Peripheral neuropathy and progressive spin-

ocerebellar egenerarionavebeennoted n tlvo siblings n adhood. Laboratory findings of chronic hemolytic anemia wpresentn all patients.Generalized rninoacidurias alsoprebecausehey-glutamylcycle s involved n amino acid transpin cells(seeFig. 85-11). Treatmmt is that of hemolvtic aneand avoidance of drugs and oxidants that may triggerhemolytic process.The condition rs rnheritedas an autosorecesslvetatt.

GIUTAIHI0NEMIAT-GTUTAMYI BANSPEPTIDASEGGTjDClEl\lCYl,his enzyme spresentn any cell chathas secretorabsorptive irnctions. t is especiallyabundant n the kidnepancreas,ntestines, nd liver. The enzyme s alsopresent nbile. Measurement f thisenzymen the blood is commonlypformed to evaluate iver and bile duct diseases.

Deficiency f this enzyme auses levation n glurathionecentrations n bodv fluids. but the cellular evels emain normOnly a few patieniswrth enzymedeficiency avebeen eportherefore, he scopeof clinical manifestations as not yet bdelined.Mild to moderatemental retardationatrdsevere ehioral problemswere observed n threepatients.One of the tsisterswith this condition had normal intelligence s an adhowever, nd the other had Prader-Willisyndrome.

Laboratory indings ncludemarked elevationsn urinary ccentrations f glutathione up o 1 g/day),lglutamylcysteine,acysteine.None of rhe reported patients has had genera



aminoaciduria,a 6ndrng hat would have beenexpeccedo occur

in this enzyrnedeficiency seeFig. 85-11).

Diagnosis can be confirmed by measuremenc of rhe enzyme

activirr- in leukocytes or cultured skin fibroblasts No effective

tr€atment is available.

The condicion s nhetited as an autosomal ecessiverair' Th e

enzyme GG T is a complex prorein an d is encoded by at least

sevengenes.

INBoRN8[0BS t METABoLISMt

IAMINoBUTYFICClo

(GABA).Decarboxylation of glutamic acid by glutamic acid decar-

boxylase (GAD) the main biosynthetrc pathway for GABA pro-

duction in the b n and other organs, especially the kidneys and

th e p cells oi the pancreas.Thrs enzyme requires pyridoxine

to chromosome2q31. Knockour of rhe gene or CAD"' in mice

causes left palare; he associarion f mutacions n GAD6' gene

rvhich rs presumably caused by decreasedactivitv of GAD The

maio clinical manifestation of thrs condition is seizures, which

usually occur in rhe 1sc ew hours of life and are unresponsive to

conventional anticonvulsanr cherapy. Adminlsrratioo of vltamin

86 in large doses (10-100 mg/kg) usuallv results in a dramatic

improvementof both serzures nd electoencephalographicbnor

malities. Late onset forrns of checonditton (as ate as 5 yr of age)

have been reported. A trial wirh vitamin 86 therapy has, there-

fore- been recommended n anv infant with intracrableseizures-

The dependency is usually hfelong. Other neurologic findings

such as delayed speechhave been noted in some parients.

Laboratory studies bave revealed increased gluramate and

decreasedGABA levels in the brain and in rhe spinal fluid.

Th e parhogenesis f this condirion remains unclear Alrhough

an increase in che Km of the GAD enzyme for its cofacror

(viramin 86) in the brain seemsa logical explanation, no abnor-

mality in the GAD activicf in the bram has been documented.

DNA studres of rhe gene for GAD* and GADer have likewrse

revealed no mutations. Linkage studies have mapped che condi-

t ion ro rhe long arm of chromosome5q31,2, a locus completely

different from loci of GAD genes.

Treatment wich high daily doses of vitamin 85 is necessary

indelinitell'.

GABA Transarninase eficiency, This is a very rare autosomal

recessivecondition that has been reported rn three infants from

tu,'o different families, Clinical manifestarions include severepsy-

chomotor retardation, hypotonia, hyperreflexia, lerhargl, and

refractory seizures. Increased linear growth was present in the

ofiginal report of two siblings but not in the third patien

Increased concentrations of GABA and B-alanine are found i

the spinal fluid. Evidence of ler.rkodystrophy u'as noled in thepostmortem examination of the brain. GABA transaminase deli-

ciency is demonsrated in the brain and lymphocytes. No effec-

tive treatment is available. Treatment rvith vitamin B; has been

ineffective. The gene for this enzyme is located on chromosome

deficiency (see Frg. 85-11) have been reported. Clinical

manifestarions, which r:sually begin in early infancl rnclude mild

to moderate mental retardation, delaved speech. marked hypo

tonia, ataxra,and seizures-Other associacedindrngsare oculo-

moror apraxia, choreoarhetosis, utist ic €aluresr nd aggressrve

behavior.Ataxia may improve with advancemenc f age,

ChaDter5 | oelects n Metabolism l AminoAcids .

Laboratory studies reveal marked elevarions in 1-hydroxvbtyrrc acrd concenrrations n the blood (u p co 200-fold), sp

fluid (u p to 1,200-fold),and urine (u p to 800-fold). There is

acidosis. Urinary excretion of y-hydroxyburyric acrd decrea

wirh age. ncreased oncentrations f glycinemay also bepres

in pJasma, rine, and spinal f lLrid.

Diagnosis can be confirmed by measuremenr of the enzy

activi!]' in lymphocvtes. Prenatal diagnosis has been achieved

measurement of 1-hydroxybutyric acid in the amniotic fluid

assayof the enzyme activity in lhe amniocytes of in biopsy sp

imens of chorionic vil l i,Treatment has been largely ineffective; vigabatrine has p

duced some improvement !n ataxia end mental status n so

Patlents.The condicion s inheritedas an autosomal ecessiverait, T

gene for succinic semraldehydedehydrogenase has been map

to chromosome 6p22; several disease'causingmutatrons h

been identilled in drfferent families.

The role of 1-hydroxyburvric acid in the pathogenesis of

condit ion remains unclear and somewhat confusing beca

admrnistration f this compound to humansand animalsha sp

ducedsomeopposireeffects,1-Hydroxy-bur,vrateGHB) has b

used ll i cit ly as a recreationaldrug with anesthetic ffecr an

on e of th e dare-rape rugs (seealso Chaprer 113).

Congenital Glutanine Deficiency. This uncommon disorde

du e to a deliciency f glutaminesynthase.Glutamine s absenplasma, urine, and CSF but plasma levels of glutamate rem

normal. Manifesracions nclude cerebralmalformations (abn

ma l gyration, u.hire matter esions),multrorgan arlure ncltrd

respiratory ailure, and neonataldeath. t may be nhericedas

autosomal rart; the gene s mapped o chromosome 1q31.

85,11 UREAvclrro Hvprnamnirolrtsr(Anetrne, ITRULUNE,nlrutrurl lrai Rezva

Catabolism of amino acids resulrs rn the production of

ammonia, u'hicb is highly toxic to the central nervous s,vs

Ammonia is deroxif ied to urea lhroueh a seriesof reactkno rvn as rhe Krehs-Hen .e le i tr u rea cyc le F ig .E5 -12 t .

enzymes are required for the synchesisof urea: carbam,vl ph

phate synthetase (CPS), ornirhine transcarbamylase(OT

argininosuccinate ynchetaseAS), argininosuccinateyase (A

and arginase, A sixth enzyme, N-acetylglutamate s,vnthetas

also required for synthesis of N-acetylglutamate, which is an a

vator of the CPS enzyme. Individual deficienciesof theseenzy

have been observed and, r'ith an overall estimated prevalenc

1/30,000 live births, they are the most common genetic cause

hyperammonemia n infants,

GENETICCAUSES0t HYPEBAMMONEMIA.n addrtron to sen

defectsof rhe urea cycle enzymes.a marked increa.e n pla

level of ammonia is observed in other inborn errors of meta

lism (Table85-2).

Ctll{l0At MANIFESTATI0t{S F HYPERAMMONEMIA.n the neo

tal period, symptoms and signs are rnostly related to brain d

function and are simrlar regardless of the cause of

hvoerammonemia. The affected infant is normal at birth

beco-es sympromatic within a few days of protein feed

Refusal to eat, vomrtinB, rachypnea, and lethargy quic

progress o a deep coma. Convulsions are common. Phy

examination may reveal hepatomegaly in addition to rhe ne

logic signs of deep coma. In infanrs and older children ac

hyperammonemia is rnanifested by vomiting and neurolo

abnormalicies uch as ataxia, mental confusion, agrtation,

tabilit l, and combativeness. hese manifescationsmay alcer



556 PABT I MetabolicDiseases

Benzoate

I

Glycine+ BenzoylCoA

.. Glutamate' . +

A m m o n i a + c o 2 + A T P Phenylacetate

Acetyl CoA+

Glutamicacid

Putrescine

oTc

Citrulline

Citrulline

.. OrnithineU ea+--__\

I\ ^

r--------------- l(5)I A ' s i n i n e m i a | { v- \

Cylosol

Arginine

,,.*".-\q"i:?#;;.

\JnthetaseI I ,

del lLiency | 1_

I f - N-Acetyl-glutamiccid NAG) *^+ | cps oeficiency | -- IA (1)l

_J phenytacetyl

V, \, I glutaminephosphale

l-cl,----;".t'.phy-l- Glutamic acid

'y-semialdehyde

Argininosuccinicaciduria

f isrrcgi- l l . t t reacycle:larhways tr ammonrrdisposal ndorni thinemerabol ism. eact ions ccurringn rhemitochondria redepictcdn rwPl" Rea.

shown whh i,,crruptud anoars are rhe afternarepathways or rhe disposal of ammouia. Enzyncs:(l

) carbamll phosphatesynthetaseCPSi,

2) onrthine trc a r b a m y l a s e ( O T C ) , l ] ) . . g i n i n o s u c c i n j c a c i d s V n t h e t a s e ( A s ) ' i 4 ) a r g i n i n o s u c c n l i c a c i d 1 y a s e l A L ) , i j ) a I g i n a s e , ( 6 ) o r n i t h i n e 5 - a m l n o r agluranletc NA(;) synthctasc. 'HHH syndrome. yperammonrnra-hvperorni thinemiaomocrrrul l inemia.

u.rth periodsoi lechargvand somnolence bar may progres

coma.Routine laboratory studies sholv no spec ifrc findings u'

hyperamrnonemia rs due to defects of rhe urea cycle enzymBLoodurea nirrogen s usually ow SerumpH is usuall-v or

or mrldly elevated. In infants with organic acidemiirs, hvper

monemia is commonlv associated vith severe acidosis. NewbinFants vichhyperammonemia re ofren misdiagnosed s ha

sepsis; hev may succumb vr.ithouta correct diagnosis.CT m

reveal cerebral edema iFig, 85 13). Autopsy is usually umarkable, t is imperative o measure lasma ammonia leve

any il l infant q.hoseclinical manifestations annot be expla

by an obvious infection.

DlAGtloSlS. The main cflterion for diagnosis is hvperammo

mia. The plasma ammonia concentration in the ill infan

usuallv >200 ptmole/I. (normal values <35 pmole/L).

approach to the differeotial diagnosis of hyperanmonemia rn

newborn nfant is l lustrated n Figurc 85-14-Patienrswith a d

crency of CPS or OTC have no specific abnormalities of plas

amino acids except for increased levels of glutamine, aspa

acid, and alaninc secondary o hyperammoncmia. A mar

incrcase n urinary orotic acid in patients with OTC defici



Figure 8-s 11. Compurer axiat tomographic scansof rhe head oI hyperamnonemic encephalopathy n the composite case of ornirhine transcarbamylascjency.A, Imagedone on admissioD o the community hospital. B, Image done 24 hours larer denonstrates bilateral hemispheric€dem, with eff.cemenr of

brospinal fluid spaces. From Brusiloe SV/: HyperammonemicencePhalopathv.Medicine 2002;81:240 )

NoacidosisIIt

Obtain

Transienihyperammonemi

of henewborn

Figure 85-14. Cljnical approach to a newborn infant lvirh symptonatic hyperammonemia.CPS, carbamyl phosphate synthelaseiHHH syndrom€, hyp

monemra-hvperornithinemia'homocrtrullinernia;AG, N acetvlSluramateiOTC' ornrrhin€ uansarbamvlase

Specificaminoacid elevation

Chrpler 5 r Delocls [ Motabolism l AminoAci& r

Nospecilic minoacidelevation

IObtain

urine oroticacid

Normal r elevated

I

High

I oic--lI oeticiency



55t r PAR|IX MerEboliciseasos

differentiateshis defect rom CPSdeficiencv, atientswith a deli-ciency of AS, AL, or arginasehave a marked increase n theplasma level of citrulline, argininosuccinicacid, or arginine,respectively. ifferentiation between he CPSdeficiency nd theN-acetylglutamateNAG) synthetase eficiencymay requireanassay f the respective nzymes.Clinical mprovementoccurringafter oral administration of carbamylglutamate, oweveqmaysuggest AG synrhetase eficiency.

TREATMENTt ACUTEYPERAMM0T{EMlA.cure

hyperammone-mia should be treatedpromptly ard vigorously.The goal oftherapy s !o removeammonia rom chebodyand o provideade-quate caloriesand essential mino acids ro halt further break-down of endogenous roteins (Table85-3). Adequatecalories,fluid, and electrolytes hould be provided intravenously. ntra-venous ipids (1 ElkglL4ht providean effectivesourceof calo-ries.Minrmal amountsof protein (O.25gkgl24 hr), prefetably nthe form of essential mino acids,should be added o the intra-venous luid to preventa catabolic tate.Oral feedingwith a low-protein forrnula \0-5-7.0glk9lz4 fu) rhrougha nasogastricubeshould be srartedas soon as sufficient mprovement n lhe clinical condition s seen.

Because he kidneysclear ammoniapoorly, its removal fromthe body must be expeditedby formation of compoundswirh ahigh renal clearance. odium benzoateorms hippuric acid withendogenous lycine (seeFig. 85-12). Each mole of berzoareremoves1 mole of ammoniaasglycine,Phenylacetateonjugareswith glutamine o form phenylacetylglutamine, hich is readilyexcreled n the urine.One mole ofphenylacetateemoves molesof ammoniaasglutamne from the body (seeFig. 85-12).

Arginine adminisrration s effective n the rreatmentof hyper-ammonemia hat is due to defectsof the urea cycle (except npatients&'ith arginasedeficiency)because r supplies he ureacyclewith ornrrhrneand NAG (seeFig. 85-12). n patientswithcitrullinemia,1 mole of arginine eactswith 1 mole of ammonia(as carbamyl phosphate) o form citrulline. In patients wirhargininosuccinic cidemia,2 moles of ammonia (as carbamylphosphareand aspartate) eact with arginine to form argini-nosuccinicacid. Crrrullineand areininosuccinic cid are far less

roxicand more readily excreted

6y the kidneyshan ammonia.

In patientswith CPSor OTC deficiency , rginineadministrationis indicatedbecause rginrnebecomes n esseotial mino acid nrhesedisorders,Patientswith OTC deficiencybenefit rom crt-rulline supplementarton200ng/kEl24 hr) because moleof crt-rulline can accept1 moleof ammonia asasparticacid) ro formarginine.Adminrsrratronof arginine or ci trulline is contraindi-cated n patiencswith arginase eficiency. rginasedeficiency sa rare condition n which acutehyperammonemiaarely occurs

as a presenting ign, n patienrswhosehyperamrnonemias sondary o organicacidemias,reatmenrwirh arginine s not incated becauseno beneficialeffect from such theraov canexpected.n a newborn nfant with a lsr artackoi'hyp.rnmonemia, arginine should be used until the diagnosisestabhshed.

Benzoare,phenylacetate, nd arginine may be administetogether or maximal therapeutic ffect.A priming doseof rhcompounds s followed by continuous nfusion until recovfrom the acutestateoccurs seeTable85-3). Both benzoatephenylacetate re usuallysuppliedas concentrated olut ronsashould beproperly dlluted(l-2yo solution) or intravenousThe recommendedherapeutic osesof bochcompounds elia substantial mountoI sodium o the patient hat shouldbe cculated s parrof the daily sodium equirement. commepreparationof sodium benzoateplus sodium phenylacetaavailable or intravenous se(MedicisPharmaceutical orpocion,wwwmedicis.com),Benzoare nd phenylacetacehouldused wirh caution in newborn infants with hyperbilirubinebecausehey may displacebilirubin from albumin (seeChap102,4). n infants at risk, it is advisableo reducebilirubin tosafe evel beforeadministering enzoate r phenylacetate,

If the foregoing therapies ail to produce any appreciachange n heblood ammonia evelwithin a few hours,hemodysisor peritonealdialysisshould be used.Exchangeransfushas little effecton reducing otal body ammonia. t shouldusedonly if dialysiscannot be employedpromptly or when tpatient s a newborn nfant wrth hyperbilirubinemia see arliHemodialysis, lthough the most effectivemeasure or remoof ammonia, s technicallydifficr:lt to perform and may notreadil;' available.Peritonealdialysis s the most practical aexpeditiousmethod or treatmentof patients vith severe ypammonemia; here s usually a dramaticdecreasen the plasammonia level withrn a few hours of dialysis, and in mparients, he plasmaammonia eturns o normal within 48 hrinitiarion of peritoneal dialysis. n a patrent whose hyperamonemia s due ro an organicacrdemia, eritonealdialysiseffttvely removesboth the offending orgamc acid and ammofrom the bodv.

To curtail the possibleproduction of ammonia by rntestbacteria,oral adminisrrationof neomycinand lactulosehroua nasogastricube shouldbe nitiatedvery early n the coursetherapy.There may be considerableag betrveenhe normalition of ammoniaand an mprovementn the neurologic tatusthe patient.Several aysmay beneeded efore he nfant becomfully alert.

Long-Tern horspy.Once rhe nfant is alert, therapy shouldtailored to the underlyingcause of the hyperammonemiageneral,all patienls require some degreeof protein restrict(1-2 glkg/24hi) regardless f the enzymaticdefect. n pariewith defectsn the wea cycle. hronic administrarion f benzo(250-500rng/kg/2a r), phenylacetate 250-500mgikgl2ahand arginine 200-400mglkg/24hr) or citrulline(in patientswOTC deficiency, 00a00 ngfl<g124 r) is effective n maintaing blood ammonia evelswithin the normal range. Phenyl

tyrate may be used n placeof phenvlacetate,ecausehe patiand the family may not accept he latter owing to its offensodor.A commercial reparation f thecompound s availableoral use(Buphenyl,Medicis Pharmaceutical orporation).Cnitine supplementations recommended ecause enzoateaphenylacetate ay cause arnitinedepletion; he clinical beneof this compound emain o be proved.Skin lesrons esembacrodermatitisentropathicahave been noted in a few patiewith differenr ypesof ureacycledefects, resumably ue o deciency of essentral mino acids, especiallyarginine, causedoverzealous ietary protein restliction. Carabolicstacesrigging hyperammonemia hould be avoided. n patientswith CPOTC, and AS deficiencies, cute hvperamrnonemicttacksmbe precipiraredy vaLporatedministration.



CARBAMYLPHOSPHATE YNTHETASECPS)AND fl.ACEIYI.GI.UTA-

MATE NAGISYNTHETASEEFICIENCIESSEE lG.85-12}Deficien-

cies of these two enzymes Produce slmilar clinical and

biochemical manifestations. There is a wide varianon in severit,v

of symptomsa in the ageof presenta!ion.Most commonl), rh e

affected rnfant comes symPtomatic durrng rhe 1st few days of

byperammonemia intelspersed wirh bouts of acute h-vperam

molemia have also been observed.

term therapy of rhe condicion s oullined earlier (see able 85-3).

ParientsvvrthNAG synthetasede6ciency benelir from oral admin-

istratron of carbamylglutamate. It is therefore important to dif

ferentiate betrveenCPS and NAG synrhetasedelicienciesby assay

dicion is not known.

OBI{ITHINE TBANSCAREAMYIASE OTC) DEFICIENCY SEE FIG.

85-12). n tbis XJrnked partially dominant disorder, lhe hemrzl'

gote males are rno severelyaffected than heterozygote females-

The heterozygous males may have a mrld form of the disease,

but the majonty 757o) are asymptomatrc.This is the most

common form of all rhe urea cycle disorders

Clinicalmanifesrations in a male newborn infant are usuallv

rhose of severehyperammonemia (seeearlier) occurring in rhe 1st

ferv days of life. Milder forms of che condirion are commonl)

seen n heterozygous females and in some affected males. Mild

forms characterrsrically have episodic mamfesrations, t'hich may

occur at any age (usually after infancy). Episodes of hvperam

monemia (manifested by' vomiting and neurologic abnormalities

survivors; the mechanism remains unclear

The maj laboratory finding during rhe acuceatrack is hvper-

ammonem without an increase n any specificamino acid rn the

blood. Elevatronof cheplasma concenlrationsof glutamine and

alanine are secondary to hyperammonemia A marked iocrease

tare in urine as gravel or stones. n the mild form, these boratory

abnormalities may revert to normal between artacks. hrs form

should be differenriated from all the episodic conditions of child-

hood, ln parcicular, lysinr:ric prorein inrolerance (see Chapter

85,13) mimics the clinical and biochemical characterist ics f

OTC deficiencl', ncreased urinary excretions of lysrne, ornithine,

and rginine and elevated blood concentrations of citrulline,'w'hic are salient features of lysinuric protein intolerance, are not

seen n patrents with OTC deEciency.

Chalter85 r Delectsn Metabolism t AminoAcids .

The diagnosisma,v be confir med b1-performing an assa

enzyme aclivity that is nonnally presentonly in che iver or

identif ication of tbe murant gene. Prenatal dragnosishas b

achieved by means of fetal hver biopsl' or by DNA studie

chorionic r.illi samples. An oral protein load, u'hich incte

plasma ammonia and urinary orotic acid levels , may iden

asympromatic heterozygous female car'riers. A marked incre

rn urinary excrecion of orotidine after an allopurinol loading

also detects obligate female carriers. Mild cerebral dysfunc

may be present n asymptomacic emalecarriers.

Treatment of acute hyperammonemic atracks and the lo

term therapy of the condirion is outlined in earler pages of

chapcer. Citrulline is used in place of arginine in patients w

OTC deficrency.Lrver transplantarion is a successfuland def

treatmenr for patients with OTC delicrency who have been

conrrolledand have avoided mult ipte hyperammonemrc ris

The gene for otnithine transcarboxllase has been mappe

X chromosome (Xp21.1). N' lany disease-causingmutac(>200) have been identified in different patients. The degre

enzyme deficiency and rhe genotype dictate the severitv of

phenorype in most cases,Mothers of affected nfants are expe

ro be carriers of the mutant gene, A rnother rvho gave birth

rwo affecred male offspring vas found to have normal genot

suggestinggonadal mosaicism in the mother.

ARGININOSUCGINATEYNTHETASEAS) DEIICIENCYCITRUt

MlAl [SEEFlG.85-12]. wo clinically and genetically distinct fo

of citrulUnemiahave been dencif ied. he classic orm (type

due to the deflciency of rhe AS enzyme, The adult form (typ

is due to deficiency of a mitochondrial transport plotein na

crttrn,

Citrull inemia ype (ClassicCitrull inemia, TLN'l). his cond

is causedby the deliciencyof AS (seeFig. 85-12) and has v

able clinical manifestation depending on the degree of the enz

deficiencv. Two maior forms of che condition have been ide

fied. The severe or neonatal form, which ls the most comm

form of rhe condition, appears in the lst few days of life w

sign and synptoms of hyperammonemra (seeearlier). In rhe

acute or mild form, clinical findings such as failure to thri"e,

quent vomiting, developmental delay, and dr1 brittle hai r ap

gradually after 1 yr of age. Acute hyperammonemia, triggere

an inrercurrentcatabolic stace,may bring the diagnosis o li

Laboratory findings are similar to those found in patients w

OTC deficrency except thar the plasma cicrulline concentratro

markedly elevared (50-100 rrmes normal) in patients with

rull inemia ype I (seeFig. 85-14).Urinary excretionof orotic

rs moderarely increased; crystalluria drLe o precipitation of

rates may also occur The diagnosis is confirmed by perform

an assayof the enz-vme ctii,it,v n cuhu.ed fibroblasts or by D

analysrs. renaraldiagnosis s accomplishedby th e assayof

enzyme activit], in cultured amniotic cells or by DNA analys

cells obtained from chorionic vilh bropsv.

Treatment of acute h,vperammone[lic attacks and the lo

term rherapy of the condition are outlned in rhe earlier pag

rhis chapter Plasma concentration of citrulline remains elev

at all times and may increase urther afrer administration ofnine. Although prognosis is poor for symptomatic neon

patients with the mild disease usually do rvell on a prot

restricted diet in conyuncdon with sodium benzoare and argi

therapy. Mild to moderate mental deGcrenc,v s a com

sequela, ven n a rvell-treared acient.

Citrullinemia is inheflted as an autosomal recessive rait.

gene rs located on chromosome 9q34. Several disease-ca

mulations have been identi{ied in differenr families. The ma

icy of patients are compound hererozygotes for two diffe

alleles. The prevalence of rhe condrtiol is not known,

Cilrurullinemia ue o CitrinDeficiencyCitrull inemia ype l. C

2), Citrin is a mitochondrial transport protein ercoded by a

(SLC25A13) located on chromosome7q21.3. One of the f



560 PARTX. MGtaboliciseas6r

tions of this protein s ro transport aspartaterom mitochondriato cytoplasm;aspartate s requrred or convertingcitrr:llne toargrninosucciniccid see ig. 85-12).Citrin deficiency auses is-ruption of the urea cycle.AS activity is deficient n the liver ofthese atients,but no mutatron n thegene or AS hasbeen ound,It ispostularedhar crtrin deficiency r its mutatedgenenterfereswith translationof nRNA for AS enzymen the liver.Mutatronin the gene or citrin produces wo distinct clinical entities,Thecondition s reportedalmost exclusivelyn Japan.

NeonatalntrahepaticholestasisCitrullinemia

yp el-Neon8talFotm).Clinical and laboratory manifestations,which usuallystarts at 3 mo of age, nclude cholestatic aundrcewith mild tomoderate direct (conjugared) hyperbilirubinemia, markedhypoproteinemia, lottrng dysfunction (increased rothrombintrme and partial thromboplastin times), and increasedserum

lglutamyltranspepridase (GGTP) and alkaline phosphataseactiviues; llver transaminasesare usually normal. Plasmacorcentrationsof ammoniaand crtrullineare usuallynormal, butmoderateelevations re reporled.Theremay be also ncreasesnplasmaconcentrations f merhionine, yrosine,alanine,and thre-onine,Elevation n serumgalactoseevelshasbeen ound n somepatlents; all enzymes nvolved in galactosemetabolism arenormal. The reason or hypergalactosemias not known. Markedelevation n serurn evelof c-fetoprotein s also present.Thesefindings esemblehoseof tyrosinemia ype , but unlike he attercondition, uilnary excretion of succinylacetones not elevated(seeChapter85.2), Liver biopsyshows arty nfiltration, cholesta-srswith dilatedcanaliculi,and a moderatedegree f 6brosrs.Thecondition is usually selfJimicing and the majority of infantsrecoverspontaneously y 1yr of age with only supportiveandsymptomatic reatment.Hyperammonemra nd hvpercitrullinemia, f present, houldbe treatedwith low-proreindiet and otherappropriatemeasuressee arlier).Hepatic ailure requiring ivertransplantation as occurred n a few cases. lthough the condi-tion is almost exclusively een n Japan,chediagnosis hould beconsideredn any neonatalhepatirissyndromewrth cholestasis.Data on the long-termprognosrs nd the natural history of thecondition are imrted:develoomentnto theadult orm of thecon-drtion (see ater) after seueril yearsof seemingly symptomatichiatus has beenobserved.

CitrullineniaType l, Adult Fo n {Adult-onselCilrullinemia, it-rullinemia ype l-Mild Form). his form stans suddenly n a pre-vrouslynormal individual and manifestswith neuropsychiatricsympromssuch as disorienration,delirium, delusion,aberrantbehavior, remors, and frank psychosis.Moderate degreesofhyperammonemia nd hypercitrullinemia represent. he ageofonsets usually etween 0 and40 yr (range 1 o 79 yr).Patientswho recover rom the 1st episodewill have ecurrentattacksandmost will die within a few yearsof diagnosismarnly from cere-bral edema. Pancrearitis,hyperlipidemia, and hepatoma aremajor complicatrons mong he survivors.Medical reannenthasbeen mostlv ineffective or oreventionof future attacks.Livertransplantation s the most eifective herapy.

Several isease-causingutationsof the genehave been den-tified in affected amilies in

Japan.The pathogenesis f cit-

rullinemia rype I (neonaral nd adult forms) remarns nigmatic.Although the frequencyof abnormalgene s quitehigh in Japan(1;20,000homozygosity),he clinical condition has a frequencyof onlv 1:100.000. his rndicateshat a substantial umberofhomozygous ndivrduals emainasymptomattc.Only a few non-

Japanese atientshave been dentified.

ARGININOSUCCINATEYASEATIDEFICIENCYARGININOSUCCINIC

ACIDURIAISEEFlG. 5-12]. he severityo{ rhe clinical and bio-chemical manifestationsvaries considerably, n the neonatalform, signs and symptoms of severe hyperammonemia seeearlier)develop n the lst few daysof lile andmortaliry s usuallyhigh. Infantswho survive he lst acuteepisode ollow the ctini-cal courseof chesubacuteorm. In the subacute r lare orm. the

major finding is mental retardation,which is associatedwfailure to thrive and hepatomegaly. bnormahtiesof rhe hcharacrerizedy dryness nd britdeness re of specialdiagnovalue.Gallstones avebeenseen n someof the survivors.Acattacks.. f severehyperammonemia ommonly occur durincatabollcsrate.

Laboratory findings ncludehyperammonemia,moderatevations n liver enzymes, onspecilicncreasesn plasma evegluramineand alanine,moderate ncreasen plasma evelsof rulline (less han that seenn citnllinemra), and marked ncrein plasma evelsof argininosuccinic cid (see ig. 85-14). n mamino acid analyzers, rgininosuccintc cid appearswithrn isoleucine r methionine egion,which may cause onfusiothe diagnosis,Argininosuccinic cid can also be found in laamounts n urine and sprnal luid. The levels n the spinal flare usuallyhigher han those n plasma.The enzyme s normpresentn erythrocytes,he iver,and cultured ibroblasts,Pretal diagnosis s possibleby measurernent f the enzymeactiin culturedamnioticcellsor by identificationof the mutanr geArgininosuccinicacid is also elevated n rhe amniotic fluidaffected etuses.

Tieatrnentof acute hyperammonemic ttacks and the loterm thelapy of the conditionare outlmed n the earlierpagethis chapter Mental retardation,persistenthepatomegalywmild increasesn liver enzymes, nd bleeding endencies ueabnormalclotting factorsare common sequelae f rhe diseThis def iciency s rnheritedas an autosomal ecessiverait witprevalence f =1/70,000 ive binhs. The gene s locatedon chmosome cen-q11.2

ARGTNASEEFTCTET{CYHYPEBARGTNtNEM|A)SEEFrG. 5r2]. Tdefect s inhentedas an autosomal ecessiverait. There are tgenetically istinctarginasesn humans.One scytosolic A1) ais expressedn the liver and er;throcytes,and rhe other (A2found in rhe renaland brainmitochondria.The gene or cytolic enzyme,which is the one deficient n patientswith argindeliciency,s mapped o chromosome q23, The role of the mchondnal enzyme s not well understood;ts activity ncreaspatienls with argininemiabut has no protec ve effect.Sevdisease-causing utations have been identified in differmm tes.

The clinical manifestatiomof this rare condition areouire ferent rom rhore ol: other urea cycleenzymedetects. he onis insidious; he infant usuallyremainsasymptomatrcn thefew months orr sometimes, earsof life. A progressive padiplegiawith scissoring f the ower extremities, horeoarhernovernenrs,nd ossof developmentalmilestonesn a previonormal infant may suggest degerierative isease f the cennervoussystem.Two children were fteated for several earcerebral alsybefore he diagnosis f arginase eficiencywascfirmed. Mental retardation s progressrve;eizures re commbur episodes I severe yperammonemia re nor usuallyseethis disorder Hepatomegalymay be present.The acuteneonform with intractable eizures,erebral dema, nd deathhasabeen eported.

Laboratory findings nc ludernarkedelevationsof argininplasma nd CSF se e ig. 85-14).Urinaryoroticacid s modately ncreased. lasma mmonia evelsmay be normal or milelevared.Urinary excretionsof arginine, lysine, cystrne,aornithine are usually ncreased, ut normal levelshavealso bnoted. Therefore,determrnationof amino acids in plasma cri tical step in rhe diagnosisof argininemia,The guanidcompourids {a-keto-guanidinovalenc cid, argininic acid) markedly ncreasedn urine.The diagnosiss confirmedby aslng arSrnasechvrtym erytnrocytes,

Treatmentconsisrsof a low-prorein diet devoid of arginAdministration of a synthericprotein made of essential macids usually resulls n a dramatic decreasen plasmaarginconcentralionand an improvement n neurologicabnormali



gooo conlrol.

TBANSIENTHYPERAMMONEMIAF THE NEWBOBN.Althoughplasma levels of ammonia in normal full-cerm infants are within

normal limits, very low birthweight rnfants may have a mild ran-

sient hyperammonemia (40-50 pmole/L), which lasts for about

5-B wk. These infants are asymptomatic! and follow-up studies

up to 18 mo of age have not revealed any signifrcancneurologrc

delicirs.

Severe transient hg>erammonemia has been observed in

newborn infants. The maioriry of affected infants are premaLure

and have mild respratory drstress syndrome HyPerammonemic

coma may develop within 2-3 da1'sof life, and the infanr may

succumb to the drsease f treatment rs not started immediately.

Treatment of hyperammonemia sbould be initiated promptly and

contrnued vigorously (seeearlier). Recovery without sequelae s

common, and hyperammonemia does nor recur even wirh a

normal protein diet.

oRNITHINE,Ornithine is one of the intetmediate metabolites of

and converts ornithtne to Putrescine (seeFig. 85-12) Two genetic

disorders result in hyperornithinemia: gyrate arrophy of the re

rina and hyperammonemia-hyperornithinemia-homocirrulline-

loss of peripheral vision, and postelror subcapsulal cataracts.

These eyi changes start betweel 5 and 10 yr of age and Progress

to complete blindness by the 4rh decade of life. Atrophrc lesions

rn the retina resemble cerebral gyri. These patients usually have

normal inrelligence.There is a 10- co 20-fold increase rn plasma

levels of ornithine (400-1,400;rrnole/L). There is no occurrence

of hyDerammonemia nd no increasesn any other amino acids;

pla"ma levelsof gluramare.glutamine. ysine,crearine. nd crea-

iinine are moderarelydecreased. om epaLients e*pond partially

to hieh dose' uf pyridoxine 1 00 - I 00 0 mg/24 hr). Argrnine-

res r r i ; t ed ie r n cun iunc r ion i t h .upp lem en ra lys rne . ro l ine .

and creatine has been successful tn leducing plasma ornithlne

concentration and has produced some clinical imProvemen s The

gene for ornithine 5-aminotransferase is mapped !o chromosome

10q26.M"ny (a t least 60) drsease- ausrngmutations have been

identifred in drfferent famrlies

HYPERAMMONEMIA.HYPEBORNITHINEMIA-HOMOCITRUTLINEMIA{HHH}SYNDR0ME,n hts are utosomalecessivelynheritedrs -

Chaoler 5 r oelecL in Motobolisn l AminoAcids r

order, the defect is in the transport sysrem of ornirhine from

cytosol into rhe mitochondria, which causesan accumulatio

ornithrne in rhe cytosol and a defciency of ornithine inside

mitochondria. The former causes hyperormthinemia and

latter resuks n disruprrono{ the urea ycle and h} peramm

mi a (seeFig. 85-12). Homocirrull ine s presumably ormed f

the reacrion of mitochondrial carbamyl phosphate with lys

which occurs because of the intramitochondrial deficienc

ornithine. Clinical nanifestarions of hyperammonemra

develop shortly afrer birch or may be delayed until adultho

Acute episodes of hyperammonemia manrfesr as refr.rsal o f

vomiring, and lethargy; coma may occut during infancy.

gressiveneurologic signs, such as lower limb weakness, ncre

deep cendon reflexes, spasticitn clonus, seizutes, and var

degreesof psychomotor retardalion may develop if the condi

remains undiagnosed. No clinical ocular f indings have b

observed in rheseDatients.Laboratory findings reveal marked increases n plasma le

of ornirhine and homocirrull ine n addrtion o hyperammone

Rescricrion of protern inrake improves hyperammone

Ornrthrne supplementation may produce clinical improvemen

somepatients.The gene or rhis disorder(SLC25,415) s loc

on chromosome 13q14.

85,12. rsrtDtNEraiBezvani

Histidine is an essentral arnino acid only during infancy

biosynthetic palhway in older children and adults is po

understood. Hrstidine is degraded through the urocanic

pathway ro glutamic acid. Severalgenetic ondit ions invo

rhe degradative parhway of histidine hav been reported,

none has any clinical consequence.

85.13.vstt ' tt raiRezvani

The major pathway n the catabolismof lysine nvolves ts

densarionwirh ct-ketoglutaric cid to form saccharoprnecharopine s then degraded o o-aminoadipicacid semialdand glutaric acid. These lst two steps are catalyzed baminoadipic semialdehyde ynthase,which has two activlysine-ketoglutarateeductase; nd saccharopine ehydrog(Fig.85-15). n a mrnorparhway or ysine egradation,ysrransaminated6rst and rhen condensed o the cyclc fpipecolicacid.This s the maior pathwa), or Dlysine in rheban d or the L-lysinen the brain se e ig .85-15).

Hyper$sinemia, a-aminoadipic acidemta and a-ketoaacidemia arethree condicions har are due to rnborn erromembolsm of lysine. Individuals wirh these conditionsusuallyasymptomatic.

GIUTAEICCIDURIAYPE Gluraric acid s an intermediatendegradation f lysrne see ig. 85-15), ydroxllysine, ndtophan.Glutaric aciduria ype , a disordercaused y adefrcof glutaryl CoA dehydrogenase,hould be drfterentiatedglutaric aciduria ype Il, a distinc t clinical and biochemicaorder causedby defects n the electron transport systemChaocer5 ,1 ) .

ClinicatManifestations, ffected nfants with gJuraricacrrvpe may developnormally up to 2 yr of hfe; macrocepha common6nding n these nfancs.Symptoms f hypotoniaof head control, choreoathetosis, eizures, eneralized igopisthotonos,and dystoniamay occur suddenly n a seemnormal infant after a minor infection. Recover-vrom th

anack usuallyoccurs lowly,but some esidualneurologic bmalicies, specrally ystoniaand extrapyramidalmovements



562 PABT r MetabolicDisoases

Protein ynthesis

o-N-acelyl-lysine

NH2-(CH2)4 CH-COOH

Pipecolicacrd

........- Piperidine-6-carboxylic cid

persist.Addidonal acuteepisodesesembling he 1st one usuallyoccur during an intercurrent nfecrion. n other patients, hesesignsand symptomsmay developgradually n rhe 1st feu,'yearsof life andhypotoniaand choreoathetosis aygraduallyprogressinto rigid iry and dystonia.Acuceepisodes f metabolc decom-pensarionwith vomiting, ketosis,seizures, nd coma also com-monly occur in thesepauentsafter infectionor other catabohcstates.Death usually occurs n the 1st decade f life during oneof theseepisodes. he intellectualabilities usually remain rela-tir..el) 'normaln mostpatienrs.

Laboratory indings. uring acute episodes,mild to moderatemetabolicacidosis nd ketosismay occur Hypoglycemia, yper-ammnnemia ,nde leva t ionsl se rumransamrna lesreseennsomepatients.High concentrations f glutaric acid are usuallyfound n urine, blood, and CSF, -Hydroxyglutaricacid may alsobe present rn the urine. This frnding drfferentiatesglutaricaciduria ype from rype I. In glutaricaciduria ype I, 2-hydrox-yglutaric rather han 3-hydroxyglutaricacid s elevated.lasmaamino acrdconcentrations re usuallvwithin normal hmrts,Lab-oratory findirrgsmay be unremarkable etween t tacks.Severelyaffected children wrthout elutaric aciduria have also beenreported. n someof thesepiriencs, he glutaric acid s elevatedonly in tbe spinal fluid. In any child with progressive ystoniaand dyskinesia, ctivity of the enzymeglutaryl CoA dehydroge-nase houldbemeasuredn leukocytes r cultured ibroblasts.CTand MRI of che brain revealmacrocephaiy, ilated lateral ven-rricles, cortical atrophy', fibrosis, and atrophy of striatum(putamenand caudate).

Treatnent.A lou-protein diet (especially diet restricted nlysine and trvptophan) and high doses 200-300mg/24hr) ofriboflavin (che oenzymeor glutaryl CoA dehydrogenase)nd L-carnitine (50-100mg/kgl24 u orally) produce a dramatic

1 r-N-acetvFlvsine

I s "I ln,/

o

Glutamicacrc

cr-Aminoadipicactd

6-Semialdehyde

Pipecolicacidemialx-Aminoadipic

acro

t'igurc 8s-1s- Parhwavs n che netabolismo{ lysrne ErzFnes: (1) lysine keroslutarate eductase, 2) sacchrropinedehvdrogenase,3) d-aminoad,pic acjd rraftrase, (4) a-ketoadipic acid dehydrogenase,s) glutaryl CoA dehvdrogenase,6) o-anlnoadipic semialdehyde xjdase.

decrease n the levels of giutaric acid in body fluids, but the clical effect has been variable. The addrtion of a GABA anathaclofen)and valproic acid to the therapeuric egimenprodu

improvement in some affected children,

The condition is inherited as an autosomal recessive rait. Tprevalence is not known. The condrtion is more prevalentSweden and among the Old Order Amish population in

United States. The gene rs located on chromosome 19p13.2 amany disease-causiflgmutations have been reported in drfferfamilres, A single mutat:on (A421V) accounts for all the patie

from Lancaster County Old Order Amish.Prenacal diagnosis may be accomplished by demonstrat

rncreasedconcentrations of glucaric acid in amniotic fluid, by assay of the enzyme activit], in amniocytes or chorionic vsamples, or by idencification of the mutant gene.

tYslNURtc RoTEINNTotEBANGEtAMtUAtPR0TE|NNTotAITCE).his rare autosomal ecessive isorder s due to a defin the transportof the cationicamino acids ysrne, rnirhine,aarginine in both kidneys and intestine.Unlike patients rvcystinuria,urinarl. excrelion of cystine s not increasedn lhpatients.About half ofthe reported ases avebeen rom Finlawhererheprevalence as beenestimatedo be 1/60,000.

Clinical manifestationsonsistof refusal o feed.nausea. vs ion upro te in ,omi r ing .ndmi ldd ia r rhea .h ichmay esufailure to thrive, wastrng, and hypotonra. Breasr-fed nfausually remain asymptomaticuntil shonly after u,'eaning.may be due to the low protein contentof breastmrlk. Episoof hyperammonemia ay occur after ngestionof a high-protdiet. Mild to moderate epatosplenomegaly',steoporosis, pabrirtle hair, thin extremicies ith moderate entripetaladiposand growth tetardationare commonphysical rndings n patie



whose condition has remained undiagnosed. Mental development

patients and may cause death-Laboratory findings may reveal hyperammonemi and an ele-

vated concentration of urinary orotic acid, rrvhich evelop only

afcer protein feeding- Fasting blood ammonia and urinary olotic

acid excretion ar e usually normal. Plasma concentlations of

l ys ine . rg in rne , nd o rn i t h ineare ucua l l vm r ld lydec reased .ur

urinary lerels oi rheseamino 66i615.specralll vsine,ar e S,reatlrincreased. The mechanism producing hvperammonemia rs not

clear All enzymes of the urea cycle are normal. Hyperammone

mia ma-v be related co a disturbance of the urea cycle secondary

to a deEciency of arginine and ornithrne. In patjents rvitb c1'strn-

uria rvho also have defects in the transporc of l,vsine,arginine,

and ornirhine in both intestine and kidneys hyperammonemia is

not observed. Piasma concentrations of alanine, gJutomine,

serine, glycine, proline, and citrulLne are usually increased.These

abnormaliciesmay be secondary o hyperammonemia nd areno t

specific to thrs disorder.

N{ild anemia and increasedserum levelsof ferritin, laccic deh,v-

ated from hyperammonemia due to urea cvcle defects (see

Chapcer 85,11), especrally n heteroz,vgousemaleswith OTC

de6ciency'. ncreased unnary excretion of l,vsrne,ornithrne, and

arginine and elevated blood levels of cicrulline are not seen in

mented with citrulline (3-8 g/day) has produced biochernrcal and

the management of acute pulmonary conplications

The gene for l,vsinuricprotein incolerance SLCTAT) is mapped

to chromosome 14q11.2 and severaldisease-causing utations

have been identified in different families, Pregnancies n affected

morhers har.e been complicared by anemia, thrombocytopenia,

toxemia, and bleeding, but offspring have been normal.

85,14. ASPABTICgD (CAI,IAVANTSEASE}

Reuhen .Matalon

N-acet,vlasparricacid, a derivacive of aspartic acrd, is synthesized

tn the brain ard is found In a high concentrarion, similar to that

of glulamic acid. Its function is unknown, but excessiveamounts

of N-acetylaspartic acid rn urine and deficiency of the enzyme

aspartoacylase !hat cleaves he N-acetyl group from N-acetylas-

partic acid are associaled rvith Canavan drsease.

Chroler95 . Doloctsn Mctabolism l AminoAcids r

CANAVANDISEASE.Canavan drsease,an autosomal recessrv

order characterized by spongy degeneration of the whire ma

of the brain, leads to a severe orm of leukodystroph;'. lt rs m

prevalent in individuals ofAshkenazi Jewish descent han in o

ethnlc groups.

Etiology snd Palhology,The deficrency of the enzyme aspar

cylase leads to the accumulation of N-acety lasparric acid in

brain, especially in white marter, and massive urinary excre

of this compound. Excessiveamounts of N-acetvlaspartic acid

also present n the blood and CSF.There is striking vacuoliza

and astrocytic srvelling in white matter. Electron microscreveals distorted mitochondria. As the diseaseprogresses! he

tricles enlarge, ow'ing to cerebral acrophy.ClinicalManiteslations. he severityof Canavandisease o

a $'ide spectrum. Infants Lrsuallyappear normal at birth and

not manifest symptoms of the drseaseuntil 3-6 mo of age, u

they develop progressive macrocephaly, severe hypolonia)

persistenr head lag. As rhe infant grows older, dela)'ed mil€sto

become evrdent. These children become hyperreflexic and hy

tonrc; joinr sriffness mav be encountered. As they grow o

seizures and opric atrophy develop, t-eeding difficulti es, p

weighc gain, and gastroesophageal eflux may occur in the 1

of life; swallowing deteriorates in the 2nd and 3rd yr of life,

nasogastric feeding or permanen! gastrostomy may be requi

lVIost parrents die i[ the lst decade of life; rvith irnproved nur

care, they may survive through the 2nd decade.AtypicalCanavan isease.Somepaoenrswith Canavandis

ma!,have a mild allele (Y288C), a substitution of ryrosine

cysteine or (R71H) substitution, or arginrne u'ith histidine. S

patienrs have very mild delays and are no! suspected of ha

Canavan disease.Th e excretion of N-acecvlasparticaci

increa.ed moderately in urine, whrch rarses hi que.rru

Canavan disease and the MRI of the brain shorvs a diffe

image,no r globalwhite matter drsease, ut increased rgnal n

sities with che basal ganglia, rvhich may be confused with rn

chondnal drsease.Diagnosis. CT scans and MRI reveal diffuse white ma

degeneratron, primarily in the cerebral hemispheres, with

involvement in the cerebellum and brainstem (Frg. 85-

Repeated evaluations may be required. N1RS performed at

time N1RI is done can show the hrgh peak of N acetylaspacid, suggesting Canavan disease. The differential diagnosi

Canavan disease should include Alexander disease, rvhic

anorher leukodystrophy wirh macrocephal,v. Progressio

usua)ly slorv ra Alerarder disease; hypotonia is not as

nounced as it is in Canavan disease.Brain biopsy shows spo

degeneration of the myelin livers, astrocytic swelling, and e

gared mirochondria. Defi^rtrve diagnosis can be establshed

6nding elevacedamounrs of N-acetylaspartic acid in the unn

blood. A deliciency of aspartoacyclasecan be found in cultu

skin flbroblasts. The biochemrcal method is the preferred ch

for diagnosis. Levels of N-acetylasparcic acid in normal urine

only trace amounts (24 i 16 pmol/mmol crealinine), r,|.here

patients with Canavan disease hey are in the range of 1,44

873 pmol/mmol creatinin€. High levels of N-acetylaspartic

in plasma,CSF,and brain lissuecan also be derected. he airy of aspartoacylase n the libroblasrs of obligate carriers is a

half or lessof the acrivitv found rn normal individuals,The gene for asparroacvlase s cloned, and mutations lea

ro Lana\an disease re idenrrf ied. here are tu.o mutarion\

dominant in che Ashkenazi Jewish population. The 1st is

amino acid substituoon (E285A) in which glutamrc acid is

sriruted to alanine, This muration i s che most frequenr

eflcompasses 3% of 10 0 mutanr allelesexamined n Ashke

.lewish parients. The second common murarion is a change f

tyrosine ro a nonsensemutation, ieadi[g to a srop in the co

sequence Y231X). This mutatron accounts or 13% of the

mutant alleles, n the non-Jewish population, more diverse m

cions have been observed; the two mutarions common in Je



564 PART r M€tabolic iseares

Fieure 85-16. Axial T werghted MRI of a 2 yr old patienr with Canavan

disease. xrensivehicl iening f the uhi te maner s seen.

peopleare rare. A different mutation (A305E), substitution ofalanine or glutamicacid,accounts or 40/ of 62 mutant allelesin non-Jewish atients.Wirh the diagnosis f Canavandisease,tis mportant o obraina molecular iagnosis ecausehiswill leadto accurate ounseling nd prenatal or the family, f the muta-

tions are not known,prenatal

diagnosis elieson the evelof N-

acetylaspartic cid in the amniotic fluid. In AshkenaziJewishpatients, he carrier frequency an be as high as 1:36, which isclose o that of Tay-Sachs isease. shkenazi ewish ndividualsmay need o be screenedor Canavandisease,

Treatment nd Prevention. o specific reatment s available.Feedingproblemsand seizures hould be fieated on an individ-ual basis.Geneticcounseling, arrier testing!and prenataldiag-nosisare the only methodsof prevention. njection of liposomeswith the human aspartoacyclase enewas introduced to the ven-tdcles of two children with Canavandisease, he resultsof thisgen€ herapy haveno! beenencouragrng.

General

Crombez E, Koch R, Cederbaum S: Pitfalls in newborn screeniq. I Pediatr

2005;147:r19-120.

Holtzman NA: Expanding newborn screenng. /A MA 2003;290:26O6-2608.

McKusick VA: Online Mendelian lnhentance in Man (OMIM), Available ar

www.ncbi.nlm.nih,gov/entrez/qu€ryfcg?db-omim

Morioka D, KasaharaM, Takada Y, et al: Living donor liver transplantation

for pediacricpadentswjth inheritablemerabolic disodlrs. Am I Tlansplant

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Na|owicz M: Newborn screening-Setting evidence-basedolrcy for prorec-

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SchulzA, Lindner M, Kohlmuller D, et al: Expanded newborn screening or

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Scriver CR, BeaudecAI. Valle D, et al (eds): The Metabolic and Molec

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Phenylalanine

Blau N, Koch R, Matrlon R, et al: New de"etopment in phenylkero

and tetrahydrobiopr€rin rescarch.Mol Genzt Mektb (S"ppl 1) 2C)01-156.

Blau N, SeriverCr N€r,r' pproaches o trearPKUt l{ow I arc wel Mol G

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and macrocephaly:Diagnosricprobtem./ Clld N2nol 2003;18B09-812

Tacke U, Olbrich H, Sass O, et at: possibtegeneotype-phenotypeorrelatrons

in children wirh mild clinical course of Canavan dlte^se Neurcpedidtl'cs

2005;36:252-25i .

Topcu M, Erdem G, Saatsi , ec al: Clinical and masnericresonance masins

featuresof L 2 hydroxygluraric aciduria: Report of threecases n compari-

son with Canavan disease. Chil,1Neurol 1.996;11:373-377

Yalcinkaya 1,Benb; G, SalomonsGS,et al: Atypical MRI findinss tn Canavan

disease:A parienr wirh a mtld colrse. Neuropediarl;rr 2005;36:316-339

86.1 DTSoBDERSFMtrocHoNDRtALATTYclD

B-0xlomono Charles . Stanley ndMichael . Bennett

lvlitochondrial l-oxidationof faay acids s an essential nergy-producingpathrvay, t is a particularly mportanrpathwayduring

Chapt€r6 Defectsn MotobolismfLipids

prolongedperiodsof starvalron,and during periodsof reducaloric ntake due to gastrointestinalllnessor increased nexpenditureduring febrile illness.Under these conditronsbody switches rom using predominantlycarbohydrate odominanrlyacas csmajor uel.Facry cidsar ealso mporfuels or exercising keletalmuscle nd are he preferred ubsfor the heart. n these issues,actl' acidsare completelyoxidro carbon dioxide and water The end products of hepfatry acid oxidarion are the ketone bodiesp-hydroxybuc

an d These cannot be oxidized by che liver

serv€ as important fuels in peripheral tissues, particularlybrarn.

Genetic defects have been identified in nearly all of the kno

steps n the fatry acid oxidation pathway; all are recessively nh

ited (Table86-1).

Clinical manifestatiozs characterisncally involve lhe tiss

with a high p-oxidation flux including Iiver, skeletal, and card

mr:scle. The most common presentation is an acute episode

life+hreatening coma and hypoglycemia induced by a period

fasting due to defecrivehepatic ketogenesis.Other manifestat

include chronic cardiomyopathy and muscle weakness or e

cise-induced acute rhabdomyolysis. The fatty acid oxidat

defects can be asymptomatic during periods when rhere is

fasring scress.Acutely presenrrng drseasemay be misdiagnose

Reve syndrome or, if fatal, as sudden unexpected infant de

Facty acid oxrdation disorders are easily overlooked becauseonly specific clue ro the diagnosis may be the frnding of in

propriately low concentrations of urinary ketones in an in

who has hypoglycemia. Genetic defects in ketone body util

uon may be overlooked because kecosis s an expected find

with fasting hypoglycemia, ln some circumstances, clinrcal m

rfestations appear to ar ise from toxic effects of fatty acid rneta

lites rather than simply rnadequate energy production. Th

include disorders (LCHAD, CPT-IA, SCAD, TFP; see larer

which the presence of an af fected fetus (homozygous) incre

rhe risk of a life-threatening rllness n che helerozygote mot

resultrng in acute fatty liver of pregnancy or preeclampsia rHELLP (hemolysis, elevated liver enzymes, low platelets)

drome. Malformations of the brain and kidne;rs have b

described in severe electron rransfer flavoprotein (ETF),

dehydrogenase (ETF-DH), and carnitine palmitoyltransferas(CPT-ll) deficiencres har might reflect ir utero toxiciry of f

acid metabolites. Progressive retinal degeneration arrd chrprogressive liver drseasehave been identifred in LCHAD

ciency. Newborn screening programs using ta[dem mass s

rromerry (MS/MS) detect characterisric acylcarnicines seemany of these disorders and permir presymptomatic diagnScreeningprograms have provided evidence thar all the fatry

oxidation disorders combined are among the mos! comminborn errors of metabolism.

Figures 85 1 and 86 2 outline the steps nvolved in the ox

tion of a rypical long-charn fatty acrd. In the carnitine cycle,Iaclds are transported across the barrier of the rnner mitochon

ial membrane as acylcarnrtine esters. !(Iithin che mitochond

successive urns of the four-srep p oxidation cycle convert

coenzr,nteA (CoA)-activated fatty acid to acety'lCoA units. to three different chain length specific soenzymes are neede

each of these p-oxidation steps to accommodate the differ

sized farty acyl CoA species. The electron r ransfer path

carrres electrons generated in the 1st P-oxrdation step (

CoA dehydrogenase) to the ele.trorl ttufispol t .hdin for ad

sine triphosphare (ATP) produccion,while electronsgene

from che third step (3-hvdroxyacyl CoA dehvdrogenase) e

the respitatetry chain ac the level of complex 1. Most of

aceryl CoA generated from hepatic p-oxidation flows throthe pathway of ketogenesis to form p-hvdroxybutyrare

acetoacelale.



568 PAnTX Melabolic iseases

EI{IYMETFIOTNfl GINE

airllinelnnsporter AJM

Longlra ar,vcioanrpofrer {Irl6lam r?p,]lroylttilil.rase GL-i

ftIIII(ATPHENOTYPT

[a-iion)'op,rtlry,kr ehl i '0pdth]r,ver ease,udceneafiendo(adiaFbr0easl l ]5s, ln1; t ,ndl lB(r ren inqdiaqn05rrepnted

Fare,aru '€, /erfaluainrhldhoodrequrrngveri ran5platal icI

Lverf i re.slclpiavopalhIrenaubulopathy.andsuddeldedthenatalandNBsoeenlqCraqn05se|orted,rnaterndlre?tampsa,H[iLP5ynd'0me;llocalon

des(nbedn fuhpatcnlJ

[rrcni( o-cr55r./everrr,9,p€r5sreft'lfr, iipertrophcrd myopathy

idfyafd;te rnsalpes ,r?r ure, i(epta paihrrdi0noparhit

al l( riharqes,NErceflg aEnoi53oled

funEn o eyer€rese1tdtr0n,0 nc de n(ephaiopdthic5€aierpr0qftsslve

my0pdthy.Brpenrnqragnt!po5se,male'narl]ecampsa,HL:LPsyncrofie

a5so03:1 8ftb,od fgwrdt,ent5

Hypo!i,Gnia,ep,rtencephaE h,; rddeneathBscftninqaqnosircr5€matara reeCimpria,IEL5ynlmme550ridt0nesc,ibedarely

D dleda icmy0patrrt,rd)thnrs. ypogefiia,ano ppau.erlogrs

Ldte-on5et,5tr5sduapd'habdomyoy5i5,eps0dirn]yopaihy.Prena:rndNB5CreeqlqdBqno!i ril5 ie

Nonctot(;st 9hlprq/(enr ,conqeFalanomas,m erorm5f verd ase,GdiornpFthlanck. t, nvopdtlly

\onkeloti(altr.aypoql)rem, on-cenrultonal 5. erdisea5e,(;rdmyopath\1afdsiprtaly0oethi lso eic,ibed

fu n! ypog.,/(em, orgeniralrunas. vEdiseasqard myopatl.y,ndkelera

myopallry6o es(red|]/Dq emia,yper5, nenidadomyopathtllyopaihy.BsftenlqC cnol

po55ibhl{B ftrnin! driqncirs5rbh,maternalrelanF6 ,HEL[)indfo1le,dnc,\F.P

arso(iirn de5dbedrcquen'

9eve.erard,r(andlkeeta.n)opafry,hypoglycema,a(d05s,hype.N|1, ,suddendeaih,

eelrtediveren4,me5,relcpatliy.l\,1dterftree(ldmpj, ]ELLPyrdrome,ard

neuroFlhyrdeary edtiaE0nserre5enrsirhm/opath/iatemalpredampsia,HIii-Plfdr0me5s0c],rtonLrent

lr yone 6tent6cxbed,ypolon4 de newbom,may ererekeetalmyotathl

dfd:e5pctorya ur€ ]/poqi)tefirL]re

:lypcket0sirnd ftr-a iem , ;re r)€pithl

i yprket05i5nd ypoqrem, ardv y0p,rthl

TTBORATORYINOI}IGS

J irrrl ndiee 'nit e, offnaay;mitineiclqltr e,3ndqa a(d

lcrraior lreecdnLlinr,elelateiir et\tlrdhniiid,ncoi5ttefabnoma(ll(arneprcle

Normalortreern ,re,fpasmar.r,ir clcrD he

fpa5Fra,-:r

Ireediy ( j

acikam,t,nesNo |](ea5edat0ofacyo .ecm n,,,1rceaq

0N arnitine5

\ 0 1 a 0 + h F e r i r f e l d y l ] l r p " n t t . a t o 0 ' f J L r ' e o r q d

a(csdno ryql0ne5

itl)blani may E ogno5li.

irrr nrerabolrc leconlpensaflol f cxposcclo suf6ciert peli()d

iesring.

Lahoratory indin(Js.)uring acutc cpisocles, ypogl-vcc'mnsualll prcscnt. Plesma enrl urirrary <etone onceorrati()l linappropri:rrclv or.r {hyp6ks161ic ypoglycemia),Bccausc l

rclati\ .ch\ pokct{)nemii, here s l i t r le or no metaLrolic crde

Tcsrs of lircr iLrnctiou ruc atrnorrnal, widr cle\rt i(nrs oi l

enzymes AI l. , \S' l), eLcvatecl lood ernnronia,an d prolon

prothrombin 1Pf) arrl pertiei t lxornhoplastin i rcs LPTT).hiopsl, at f inles of rcufe il lness shows rnicrovcsjculr

mecrovcsicular cearosisLr eo trigl,vcerlde ccurnulatjon. )ur

fastingstrcss r dt t iurcsoi:rcLlte lltess,uriLrarv rganrcacid p6lcs by gl s chromirrogr.lphy/rnasspectronctlv shorv indp

priateLy rrv concenrrationsof keroncs an d clcvaccd cvel

rlrcdiuDr-chain licarLrrxl. l ic ci t ls ladipic, suberic. lr)d seb

ecicls)har dcri!e ironr microson.rl an.1perorrsonrrl onrcgl r

danon o{ iarrl acids l)Lasma nd rissuccorceDtfationsol t

. irr it inc ;rrc rcduced ) l j .50lzu l normal. and the liaction

total esrerif ierl irnrf ine is increased This pattcrn () t lccond

carnit ine dcficicncy s secn n alrnostall thc frtty acjd oxrdrt

clcfccts nd fcflccfscl)rr)peflt ion .crnrcn incrcascddcvlcrrni

lcvcls end frcc c ^rnirinc rlensport lt the plesrnanrenrbr:rrre

r i ic l l l r te\ccpfr(ns to fhis r-Lrle re rhe llesmd rncmbrlnc cr

Iinc rrdnsporfer (IPTIA .lrd p h-vdrox-v-13-urcthyLglur,r

iH\. iC C.oAl svrrth:rsc cficrencies.

(drftfl: fari oca5e(dmimea

itcy ran5feraje

5hcfr hin a!! aoA

dehlcroqera5e

lvhdiunrha dd l-!A

celyorogl:ndje

VerIofq ha aril[1rA

d?hydroqena5e

:Tfdehld'cEeidie'

flecttofranspcrt

I e(tftnrdn5port

fia,Jopr,iredShrri-(hdint'ltdrcrfdr)

ao,qeh)'d'casna!eLonq{hjir I qrror)"aql

[oAdehydrogefa5e

MitochondiianfuNrcnapr0le

-I)llg-(hdin-ketorcloA

rhicdse

2,4Di..noylol rect(raie

Hl\,161-oAsyntietise

Hlil6uA \tse

'A50lniu,nrq Fr. :dtnr;ne

G(i(Pt

!

'[AD

[)t(R1

HM6l5)iI16t

MU!

t/'i(AD

tLt-'tt1

tEli

SGID

(HAA

LIOI

|]Lttlh?mr!,ie.ukd jvfl$zimc5,0w,rte trNB, ewl}r|n

DEFECTSNTHE -0Xr0ATr0NYCTE

MEDIUM HAIN CYICOA EHYDBOGINASTMCAD)DETICIENCYM(lAD clcficicncrs hc rnostconrmon f fhe eftv acido\i( l,r-tiorr lisorclers.

lhe Jisorderhor,r 'sstrone,()un(ler ffecri nost

patieDf havc il l()rrl l\ ,vcsrcrn uropei] lr lncestrv. nd rhe major

irv of paricnrs are homozvgous krr a sing,le ()mrlon orisscrrsc

nutariol! en,,\-(i trensirion rt cDNA posirion 9il-5 har chalges

d lvs ine o g u taLn i r c r ( l r r r s rduc 29 iK l29 t - ) .

ClinicalManilestahDIs {f iecred pafrenr\usuall-v rcscnr n rhe

lsr 3 nro I rr of l i ic rlith episodes I acure rllness rrggcrcdby

prolong,c.l ,rsring asring onger rhan 12-16 hr. SigLrs nd slmprorns in.ludc vonlit i lrg end lerhargv,u'hrch rapicLlv rog,rcsso

co]rra or seizulesand cardiorcspirarorycollapsc.SuddcLt rex

pected ntaDf deathmal occur. I 'hc ivcr mav bc slightly enJlrged

rvirh far rleposit ion.Affacks are rare until rhc infant is beyorrcl

rhe st few monthsoi l i ic, presurnablyJue o nrore requenr ced-

irrgsar a younger:rge.Affeoed oider intinrs are ar higher risk of

il lnessas rhc,vbcgin nr iast thlough th e rright or ale erpose.l cr

iasting strrss rllrring an rntercurrenr hrlJhood iLlness. rcscLrra-

t ion in rhe irt clrvs of l ifc has bccn rcporrcd irr rrcq.borns hat

r,vcrc astcd lradrerrentlybelirre successhrl least ieerfil lg.Dieg-

nosisol Nl(-AD hls occasjonall-vccn r](rcrrrncnrcclrr prrcvir;LrsJv

hcllrhl tcerage antl acLulr ndivirluals. indrcirt ing t lrrr even

prrt icnrs vho h.rvcbeenasymptomatic u inaency rc strll .r t r isk



Chapter 6 . Delectsn Metabolism t Lipidsr

Carnitine

Plasmamemb

Lcaclrctrl:le

Outermitochondrialmembrane

brane bv carnitine/acylcarnitine randocase(TRANS). and rhen reconvcned nro , ton8 chain fany acvl CoA bv carnitine palmrtoyltransferase"Il CP

undergop-oxidarion. r;ery long chaln acvLCoA dehydrogenaseVLCAD/LCADi leads o tbe prodLrctionof (C15-l0i 2,3 eDoylCoA. Trifunctional protein

conrains rhe acriviries of enoyl CoA h,vdrarasehvdrataset,3 OH-hvdrox,vacyl CoA deh;rdrogenase3'OH-ACD), a|d P ketorhiolase(thiolase) Acervl

FADH. and N,iiDH are produced.Medium, and shorr-chain aay acrds C8-.+lcan enrer he Inrrochondnal matri\ independenrof rhe carnitine c-vcle.{ed

chain acyl Q,A dehvdrogenaseMCAD), short-chaiuacyl CoA dehydrosenrsc SC,{D). and shorr chain h,vdrcrv ac-vlCoA dehydrogenaseSCHAD) are req

Acecyl CoA can rhen enrer rhe Krebi tl CAI cycle. Electronsare rranspoir.d fro'1 FADti ro rhe respirak).y chain via the eJecrron rnnsfer lavoprore,n h-T

rhe eledron ugnsfer 0avoprorein dehydrogenaseET}--DH). NAI)H mrers rhe electron ra'rspo( chain through compLexL Acervl CoA can be converre

h_vdroxymerhylsltrrar_vlHMCI) CoA bv 0 hvdrcx,'-0 merhvlglutaryl CoA svnthase HNl(; GiA svnthase)and rhen r,be erone body acetoacerate -v hc a

of p hydrory'p-merhl lgluraryl CoA lvrse (HMG CoA lyase)

Dtagnoscicmarkers include increasedplasma Cro, Crl,o,an d

C101 acylcarnit ine specresan d increased urinary ylglycines

including hexanovl-, suberyl- an d 3-phenylpropio glvcines.Newborn screening programs using tandem mass spectrometry

can diagnosepresymptomatic nfants basedor the detectionoi

the abnormal acylcarnit ines n 6lter paper blood spots. n many

cases, he diagnosiscan be confirmed by f inding the common

A985G mutacion.A second ommon mutalion. T199C, has been

detecred n infants with characterisric cylcarnitrnesn nervborn

screening esrs. nterestingll, this allele has not been seen to

date in symptomatic N{CAD patients; ic may represent a miLd

mutatron.Treatrenl. Acure i llnesses should be promptl]' treated \r'ith

inrravenous luids containing 107" dexrrose o treat or prevent

hypoglycemra nd !o suppress ipolysisas rapidly as possible se eChapter 92). Chronic therapv consistsof avoiding fashng. This

usually equrres imply adjusting he dier to ensure hat over

fascingperiodsare limiced o <10-12 hr Restncting dietar

or treatment wilh carnit ine is controversial.The necessiactive theraDeutic ntervention for individuals u.ith the T1

murarion has not yet beenesrablished.

Prognosis. p to 257. of unrecognized atienrsmay die du

rheir ls r attack of i l lness.There is frequendv a histor,v f a

vious sihhngdearh due ro unrecognizedMC,{D deficrency.patienrsmay developpermanenrbrain injurv during an attaprofound hypoglvcemia.Th e prognosis for survivors rvit

brarn darnage is excellenr becausemuscle weakness or

diomyopathy does nor occur in MCAD deficiency, asting

ance mproveswith ageand the risksof rl lness ecreases.s m

as 509. of affected patienrs have never had an episode; there

testing of siblings of affected patienrs is imporrant to d

asvmDtomatrc familv members.

Long-charnree atty acid (C16'palmilate)

\



Palnitate

Iv

Cr5 CO-CoAI

l c P r - 1Y

C15-CO carnit ineInnerm i tochond r ia l I __^ .

; ; ;b ; ;__- . -__ _____I_TBANS_____

Cj5 CO-carnit ine

Jcer.,

CanitineCycle

ElecironTransfer

Electronransponcharn

C1s CO-CoA

ErF-DHrF rno .1 ^^^*- -- rao14

^""

R CH2-CH:CH-CO-CoA

I uyorataseV

R CH2-CHOH-CH-CO-CoA

NA D.js_oFt_nco

NADH+

R CH2-CHO-CH2-CO Co AncetvtCoA--y' Thiolaset

C1s-CO-CoA,J

AcetylCoA<--1

C11-CO-CoA

nceVrcoe --{

Ca-CO-CoAA

AcetylCoA<--1

C7-CO CoA

AcervlCoA<-4- v

Cs-CO CoAAcet/ Con+{

Ca-CO-CoA

Acetvl on.-{

AcetylCoA

13-OxidalionCycle

KetoneSynthesis

I HM G oA synthasef

Leucine->' -+ HydroxymethylglutaryloA

Iuuccooy"""i

Acetoacetate

i{

13-Hydroxybutyrate

570 I PABT r MetabolicDiscases

f igurc l t6-l Pnthwarof ni tochondriaL xrdarxrn f palmrratc, rvpical16

carkrn Longchain firly alid. Fnz)'lne sleps rt{rt1r tarnitinc palmrtorltr:ns

f t rase CPT] I anJ 2, carri tmc/ecl lce rninne. rnsbcase TRANSI. electron

trans{er lavop<,re (FTt ) , ETF deh}drogrnascET}-DHt. rcv l t :bA dehy

drcscDaseA(lD), enovl CoA hydratast hvdrarasc) .l -hydn)\-v cyJ Co A

clehvdrogenasei OH ACD), p-kctorhiolasethLolase),P h_vdrox l methl l '

glutarrl CoA iH\4c CoA) syntlase, and lvase.

VEFY IONG CHAIN ACYI. COA DEHYDROGENASEVI"CAD)OCIENCYVLCAD deficiencyu'as olginally termed LCAD dciency be{ore rhe existence of the inncl mirochondmembranebound VLCAD lvas knorvn.,A.ll paticnts prevro

d i . rgnoseJ. hav ing ( \D , l r6 . ien . ' hav . \ ' L t \D enzvmccienc,v.No patient s with isolated LCAD dcliciency have bdescribed nd the rolc o1 LCAD i human fattv acid oxidariou rknown . P i t re r r t ' , t r rh r l LAD r lehc ienc t r r u .uc l l r rnseverely afiecced than rhose with MCAD dcficiencl', prcsenearlier n infanc]'- nd having more chromc problems virh mu

,,r;caknessr episodes f musclepain and rhabdomyolysis.Cdromyoparhymay'bepresentdurmg acuteattacksassociatedfasting. The left vencricle may bc hypertrophic or dilatedshow poor contractility on echocardiograph,v.Suddenunexpecdeath has occurred in severalpatients, b$r most lvho surviledinitial eprsodeshorved improvement, including normalizatroncardiac unctjon. Other ph1'srcal nd routine laboratory learare similar to those of -\.ICAD deficiency, ncluding secondary cnirine deliciency'- The urinary' organic acid pro6le shownonkctotic dicarboxylic aciduria. Increased levels of (

dicarboxylic acrdsmay be noted in the urine. Diagnosisma,suggested ,v an abnormal acylcarnit ineprofile n' ith plasma

blood spor C1111a6ac-vlcarnicinepecies, ut chespecif icdiag

sis requires assay of enz,vmeactivities of VLCAD in culrufrbroblastsor direct mutarional analysis of thc VLCAD ge

Treatment is based primarily on avoidance of fasts for >112 hr. ContinuousrntrallastrLceeding s usefu) n somepatie

SHORT_CHAINCY TCO AOEHYDSOGENASESCAD} EFICIEN

small number of paticncs vith tu.o clear null mutaoons in

SCAD gene have been described u.ith variable phenor,vpe.Mpaticnts classifredas being SCAD deficienr have been shor,vhave polymorphic DNA changes rn the SCAD gene and hresidual activity. he ru<r common polymorphisms are Gl8and R147Vi Currenth, i t is believed hat rhcs eare susceptibchanges, rvhich require a 2nd, as vet unknor-r.rt,genetic mutat

!o express a clinical phenotype. These indrviduals do nor pres

rvith hvpoketoric hypoglycemia. Skeleral myoparh,v secms o p

dominate. br:r a consistent clinical ghenot,vpe has not hccn id

ri6ed. Somepatientshave severemetabolic acidosis.Ncurolo

signs are present in most patientsr although mildly aftccted in

vidualsma v be asympcomatic. iagnosis s indicatedby eleva

levelsof butyr,vlcarnirine n blood spotsor plasma and increa

excrerioi of urinary erh,vlmalonic cid and butvrvlglycine.Thmetabolic abnormalit iesare most pronounced in paoents w

null murationsan d variably presenrn parrenrs 'ho are homogous or th e polymorphisns. Confirmacionof dragnosis equ

mutacion analysls.Some of the clinical featuressuggesc toxity s,vndrome. erhapsowing to accumulationof short chain fa

acid merabolites.One reported pariencha d nornal ketogcn

irnplving chat there is no irnpairmenrof longer chain farrv a

oxidation.Treatment is lirnitarion of fastrng strcss and dierary far.

IONG_CHAIN -HYDROXYACYTOA OEHYDROGENASETCHMITOCHONDRIATRIFUNCTIONAT ROTEIN TTP} DEFICIE

LCHAD deficienc,v s the second most common of the fatty a

oxidanon disorders.The LCHAD enzyme s part of a mitoch

drial crifuncrionalprorein (TlP), which also contains two ot

stcps n B oxidation, long chain enoyl CoA hvdrataseand lo

chain p-kerorhiolase.r rs a hetero-occameric rotein compo

of 4o and 4J3 hains hat dcrive iron disnncr contiguousgc

wirh a common promoter region. In somc paricnrs,onlv

LCHAD acivity of the TFP is affected (LCHAD dedcienrvhereas chershavedeficiencies f all three acriviries TF P d

cienc,v).Clinical manilestations include rtracks of acute hypo

toric hvpoglycemia similar ro MCAD deficiencv;patientsof

shou' e1'161s...1 m.rc severedisease, nclucling cardiomyopat



mav also be associared l'ith malernal lllness.'ireatmenr

is similar to that for MCAD or LCAD/VLCAD defi-

ciencn thac is, avoiding fasring stress. Sorne invescigators have

suggested hac dietary suPplements wirh medium-chain trrglyc-

eride oil and docosahexaenoic cid (DHA) may be useful Liver

tlansplantariondoesnor ameLorate hemetabolicabnormalicies.

SHORT_CHAINHYDROXYACYI._COAEHYDBOGENASESCHADI

DEFICIENC y few patrents with rhis inborn error have been

described. frvepatientswith proven mutatronsof SCHADhave been reported. Four cas in three families wirh recessive

mutarions of SCHAD presen d with episodesof hypoketotrc

hypoglycemra that was shown to be due lo hyperinsulinism ln

contrast !o patients wlrh other forms of fatty acid oxidation dis-

orders, these cases equired specific therapv for hyperinsulinism

to avoid recurrent hypoglycemia. A Sth child presencedwith ful-

minant hepatic failure at age 10mo and was compound her-

erozygous for two different SCHAD mutations. Orher reports

include a child wrrh attacks of fascing h,vpoglycemia and myo-

globinr,rria associated wrth deficiency of SCHAD in muscle but

not in cultured fibroblasrs, three children with fatal liver disease,

and an rnfant wbo died suddenly and unexpectedly.Thrs variable

phenotvpe may be due lo genetic heterogeneitv.Specificme bolic

markers for SCHAD deficiencv have not yet been ide i6ed,

making this a particularly dif6cult diagnosisco establish.

DEIECTSNTHE ABNITINEYCLE

PTASMA MEMBRANE CARNITINETBANSPOBTDEFECTPEIMARYCABNInNEOEFICIENCY).rimary carnit ine deficrencys the only

gene c defecr in rvhich carnirine de6ciency is the cause, rather

than he consequence,of imparred fatcl' acid oxidation. The mosr

colrlrlron presentalio is progressive cardtomyopathy wirh or

w i rhou t ske le ra l u ' e weakness eg inn ing t l - 4 ' r o f age.A

smaller number of patients may present rvith fasring hypoketotic

hypoglvcemra in the lsr yr of life before the cardromyopachl'

becomessymptomatic. The underlying defect involves the plasma

membrane sodium gradient-dependent carnitlne uansporter that

is present n heart, muscle, and kidney. Th:s transporter rs respon-sible botb for maintainioe ntracellular carnit ine concenrratrons

20- to 50-fold trigher than plasma concentracions and for renal

conservallon or carnlrlne.

Diagnosis of the carnirine cransporter defect is aided by rhe fac

that patients have extremely reduced carnitine levels in plasma

and muscle (1-27o of normal). Hereroz,vgoteparents have plasma

carnitine levels =50% of normal. Fasting kerogenesis may be

normal because iver carnitine transport is normal, but ir may be

irnpaired if dietary carnirine intake is interrupced. The fascing

unnary organic acid profle may show a hypokecocicdicar-

box,vlicaciduria pattern if heparic fatty acid oxidation is impaired,

but it is orherwise unremarkable. The defect in carnitine trans-

porl can be dem,rnstrated linicallr by severe eduction n renal

Chapter 6 r oefecls n Metabolism f Lipids

carnitine threshold or in vilro by assav of carnitine uptake u

cultured 6broblascs or lvmphoblasts. Mutations in the orga

carion/carnitine transporler (OCTN2) underlie this disor

Treatment of chis disorder with pharmacologic doses of oral

nitine (100-200 mg/kg/day) is highlv effective in correcting

cardiomyoparhy and mlrsc le weakness as well as any impairm

in fascing ketogenesis. Muscle total carnitrne concentrati

remarn 5ozo l no rm a l on l rea lm en t

CAEI!ITINE PAIMITOYLTRANSFERASE_IACPT_IA} DEFICIE

Several dozen infancs and children have been described wrtdeliciency of the liver and kidney isozyme of CPTIA. Clin

manifestations include fasting hypoketotic hypoglycemia, o

sionally ';r'ithmarkedly abnormal Iiver funcrion rests and, rar

rvith renaltubular acidosis- he heart arld skeletalmusc]eare

involved because the muscle isozyme is unaffected. Fas

urinary organic acid profile shows a hypoketotrc Cr-Cr: di

box;rlicaciduria but may be normal. Plasma acylcarnione an

sis demonstrates mostly free carritine with r.ery littLe acyla

carnitine. This observarion has been used to esrablish CPT

diagnosis on newborn screening by tandem mass spectrome

CPT-IA deliciency is the only fatty acid oxidation disorde

rvhrchplasma otal carnit ine evelsar e elevated o 150-200%

normal. This may be explained by the fact rhat rhe inhibit

effects of long-chain acylcarni tines on the renal rubular carnr

rransporter are absel! in CPT-L{ deficiency. The enzyme decan be demonstrated in cukured fibroblasts or lvmohobla

LPT.IA deficiencyn th e fe tus has beenas'ociaredwrth icute f

liver of pregnancy rn the mother in a single case report. Tr

ment is similar to rhat for N{CAD defc iencl' with avoidanc

situatrons where fasting ketogenesrs s necessary.

CARNITINE_ACYTCABNITINERANSTOCASE CACI) DEFICIE

This defect of tie rnner mitochondrial membrane carrier pro

for fatcy acylcarnirines blocks the entry of long-chain fatqv a

inco che mitochondna for oxidation. The clinical phenotyp

this disorder rs charactenzed by a severeand generalized imp

ment of farty acid oxidation. Most neu'born patrenrs present *

acracksof fasting-rnduced hypoglycemia, hyperammonemia,

cardrorespiratory ollapse.All symptomatic newborns have

evidence of cardiomyopathy and muscle $eakness. Sepacienrs with a partial rranslocase deficiency and milder dis

wirhout cardrac involvemenc have also beeo idenrified. No

cincciveurinary or plasma organic acids are noted, althoincreased evels of plasma long-chain acylcarnitines are reporDiagnosis can be made using cultured fibroblasts orphobLasts. he human genehas beencloned,and mutarions h

been identilied in affected parienrs. Treatment is similar toof other farty acid oxidacion disorders-

CARITIITINEATMITOYTTRANSFERASE_IICPT_II)DEFICIEIIIGYh

forms of CPT-II defrciencv have been described. The antenpresenlation of this drsorder rs associatedwirh a profo

enzyme deficiencl and neonatal death has been reported

several newborns with dysplastic kidneys, cerebral malfortions, and mild facial anomalies- A severedeficienq' of enz

activity is assocrated w'ith an infantile-onset form. This fshares all the clinical and laborarory features of CACT deGciA milder defect is associated with an adult presentationepisodic rhabdoml'olysis. Th e 1s t episode usually does

occur until late childhood or early adulchood. Attacks mayprecipitaced b,v prolonged exercise. There is achrng muscle

and myoglobrnuria that mal be severe enough to caus€ r

farlure. Serurn levels of c reatine kinase are elevated to 5,0

100,000 UiL. Fasting hypoglycemia has not been describedfasring may contribure to attacks of myoglobrnuria. N{u

biopsy shows rncreaseddeposition of neutral fat. The myopa

Dresenration of CPT ll deficiencv is associated with a com



572 r PAnTX Melaholic iseases

mutanon 5113L. An intermediare form of CPT-II deficiencv ore-sents in intanc)/early chrldhood wirh fasrrng-induced epancfailure, cardiomyopathy, and skeletal my'opathy with hvpoketo!ichypoglycemia but does not have the severe developmentalchanges seen n the neonatal presentation. This pattern is morelike that seen n VLCAD de6ciency and management is identical.Patiencs are generally heterozygous for one of the severe rnuta-

tions and one of rhe milder mutations.Diagnosis of all forms of CPT-II deficiency can be made by

demonstrating deficient enzyme activity in rnuscle or other ti ssues

and in cultured 6broblasts. Mutation analysis rs available.

DEFECTSI{ ETECTROIINAilSFERATHWAY

ETECTBONSANSFEB TAVOPROTEINETf)AND ETECTROTRANS.FER TAVOPROTEII{EHYDROGENASEETF{H I DEfICIENCIESGI.U.TARIGACIDURIA YPE . MUTTIPTECYLCOADEHYDROGTNATIONDEFICIENCIES).TF and ETF-DH funcrion to transfer elecrronsinco the mitochondrialelectronrransoort chain from dehvdro-genationeacrionsaralyzedy VLCAb. MCAD. and SCAD,aswell as glutaryl CoA dehydrogenasend at least four enzymesinvolved n branch-chainamrno acrd oxidation. Deficiencies fETF or ETF-DH produce llness hat combines he featuresofimpaired any acid oxrdation and impairedoxidatronof severalamino acids.Completedeliciencies f either protein are associ-

aredwith severellness n rhe newbornperiod,characterized yacidosrs, ypoglycemia, oma, hypotonia, cardromyopathy, ndan unusualodor of sweaty eetdue co sovalerylCoA dehydro-genase nhibition. Somealfectedneonateshavehad facial dys-morphia and polycystic kidneyssimilar to that seen n severeCPT-II deliciencl',which suggesrshat toxic effectsof accumu-lated metabolitesmay occur n utero

Diagnosis an be made rom the urinary organicacid pro6le,which showsabnormalities orrespondingo blocks n oxidationof fatty acids etbylmalonacend C6-C,6dicarboxylic cids),lysine (glutarate),and branched hain amino acids (rsovaleryl,isobutvryl-,and q-methylbutyryl-glycine). osr severely ffectedinfants do flot survive he neonatalDeriod.

Parlraldrhcrencresl L ll ' .rnd rF-DH oroduce disordertharma ' mrmrcMCADde6crenc lr orhermj lder a t ry c id x i -

dation defects. hesepatientshaveatracksof fasringhypoketoticcoma.The urinary organic acidprofile revealsprimarily eleva-cions of dicarboxylic acids and ethylmalonate,derived fromshort-chain artv acrd rntermediates. econdarv arnitine de6ciency s present.Some atientswirh mi ld forms of ETF/ETF-DHdeliciencybenelit rom treatmentwith high dosesof riboflavin,which is a cofaclor for the pathwayof electron ransfer.

DEFECTSN KETOTIEVNTHESISATHWAY

F-HY0R0XY-p-METHYTGT.UTARYT.oA{HMGCoA)SYNTHASEDEFICIENCY MG CoA synthase is the rare-limiti ng step in the

conversion of acetyl CoA der ived from fatty acid p-oxidation in

the liver to kerones. Severalpatrentswith this defect have recently

been identified. The presentation is one of fasting hvpoketotichypogJycemia withor:r evidence of impai red cardiac or skeletal

muscle function. Urinary organic acid profile showed only a

hypoketotic dicarboxylic aciduria. Plasma and tissue carnitine

levels are normal, in contrast to all the other drsorders of fatty

acid oxidarion. A separate synthase enzyme, present in cytosol

for cholesterol biosynrhesis, s not affected. The HMG CoA syn-

thase defect is exoressed onlv in the liver and cannoc be dernon-

strated in cultured fibroblasts, The gene has been cloned, and

mutations in rhe affected patients have been characterized. Avoid-

ing fasting is usually a successful reatment.

p-HYDR0XY-P-I/IETHYLGLUTA8YLOA TYASE EFIGIENCYeeChaoter 5.6.

IIEFECTStI KETOTIETILIZATIOI{

The ketonesP-hydroxybutyrateand acecoaceratere rheproductsof hepatic fatt;t acid oxidation and are importanmetabolic uels or the brain during fascing. wo defects nlization of ketones n brain and other peripheral issuessent as episodesof "hyperketotic" coma, with or withnypoglycemra.

SUCCIYI-COA:ilKEI0ACID COA TBAIISFEBASESC0T}CIENCYSeveral parients with SCOT deficiency havereported. Characeristic presentation is an infanc q'irh recurepisodes of severeketoacidosrs induced by fasting. Plasma acarnirine and urine organic acrd abnormalities do not distingufrom other causesof keroacidosis.Tieatment of eoisodes eouinfusion of glucoreand largeamount' of bicarbonateunril mbolically stable, All patienrs exhibit inapproprrate hyperketomia even between carabolic episodes. SCOT is responsrbleactivating acetoacelate n peripheral tissues using succinyl Cas a donor to form acetoacetyl CoA, Deficient acrivity candemonsrrared n brain, muscle, and f ibroblasts lrom affepatients. The gene has been cloned, and numerous mutati

have been characteflzed.

P-{GT0TH|OLASEDEFICIENCY.ee Chapter 85.6.

Andresen BS, Dobrowolski SF, O'Reillt, L, et al, Medium chain acrfC

dehydrogenaseMCAD) muratrons dentified by MS/MS-basedprospe

screeningof newborns differ frorn rhose observed n patients wrrh cli

svmptoms, denrificarionand charact€rizarionof a new, prevalentmuta

thar results in mild I{CAD deficiencv. Az I Htm C

2001i68:1408-1418.

Bonne{onrJP,Djouad, 4 Prip-BuusC, et al: Carnitine palmitoyltransaera

and 2: Biochemical, molecular and medical aspects. Mol Aspe.ts

2004;25:495-520.

Clayton Pl Earon S, Aynsley Green A, et al: Hyperinsulinism n short-c

L 3-hydroxvacyl-CoA dehvdrogenase eficiency eveals he impcrtanc

beta-oxidation n insulin secretion. Clin Inuest 2001;1081457465.

Den Boer MEJ, Dionisi-\ricj C, Chakapani A, et ai: lviitochordrial tilu

cionalprotein deficiency,A severe ady acid onidation disorderwirh carand neurologic rn"olvenent. I Pediatr 2003i142r684-s688.

Den Boer MEJ, WandersRJA, Monrs AAM, er al: Long-chain 3-hvdro

cyfcoA dehydrogenase e6ciencl.:Clinical presentarionand follow u

50 paienl.s PeAdtri.s 2002;109:99-104.

tslpelegON, Hammerman C, SaadaA, et al: Antenatal presentarionof c

tine palmitoylrransteraset deiclency.Affi J Med Geftet 2001'102:183

Fukao I Mrcchell GA, Scng XQ, ec al: Succinyl-CoA:3-ketoacidCoA u

ferase SCOT): Cloning oI th€ human SCOT sene! e{dary structuraLm

eling of the human SCOT monomer, and characrerization of t

pathosenicmuradons. Geaomics 2000i681144 151.

GregersenN, Andresen BS, Corydon MJ, et al: Mutation analysis n m

chondrial fany acjd oxidation defects:ExemplJfiedbv acyt-CoA dehy

genase eficrencres, ith special ocus on genotype-phenorvpeelation

Hun Mutat 2001t181169 189.

Klose DA. Kolker S. Heinrich B. ec al: Incidenceand short rerm outcom

children rvith symptomatic pr*entarron of organic acid and iany acid

dation djsorders n Germ^ny. Pediat/ics2002t110:1204 1210.Mathur A, SimsHn, Gopahkrishnan D, et aL,MoJecularheterogeneiryn v

long-chainacyl-CoA dehydrosenase edciencv ausingped,atric cardio

oparhy and suddendeath. Cir.ulatioh'19999911337

1343.

Shekhawat PS, Marern D, StraussAW: Fetal fatty acid oxidacion disor

rheir eifecr on maternal health and neonatal outcome, Impact of expa

newborn screening on their diagnosis and management. Pedntr

2005;57:78R-85R.

StanleyCA, Bennett MJ, Mayatepek E: Disorders of mitochondrial fatty

oxidation and relatedmerabolicpath.*ays. n: FernandesJ, SaudubmyJVan den Bergh C, Walter JH (eds). nborn Metabotic Djseases:Drasn

and Trearment4rh edidon: Heidelberg:SpringerVerlag,2005 pp. 175-

Wllcken B, Haas M, Joy P, et al: Our come of neonaral screening or med

chain acyl-CoA deh-vdrogenase eficiency in Ausualia: a cohorr st

Lancet 2007359:3742.

DD



Yar lsZ. Yxmrd, t . Zhro \ et aL: ' ,ospect , le cr c. . ,ng or pedr-r t r rerr i r

chordrrrL roreLr let tcts npregrrr r i cscompl icared ) |vcf drscase.. 11.1

2 0 0 2 ; 1 8 8 r 2 1 62 1 6 6

86.2. DtsoRorRSFVERYoNG HATNlrrv Actosa

PEROXISOMAIISORDERS

' fhepcroxisomal diseases re genetiaallt derermined clisorclcrs

catLsed ither by rhc faiLr.rreo f()rrn or maiLrtarrrhc pero\Ls()nrc

in chiidhood ard r>ccur- ror'c rcquentll and prcscnt e ulder

rlngc of phelotvpe rhen h:s becLr ecognrzedn rhe past

[Tl0l-0GY l'eroxisonraldrsordersare subdivided nto t\\ 'o n]. jor

ca tego r ieslab le 86 2) .

In categorvA, the pcroxisomalbiogenesir isorders PBD), rhc

basicdefcct s rhe ailure ro irnport one or morc protetls inro fbe

orsanellc- ln category Il, defeccsaffect a single peroxisonralprotcin 1h e peroxisorrc s prcsent n all cellscxcepr natLrrcer \

drrocvtes.rud is a srLbcellul;rrrrganclle urroLrnded y e singlc

membrlnc; >51) peroxisr:rmalcnzYmes erc identif iccL Sorne

c z!nrcs ere rnvolved n the pro(luctron dn d dcconposLtiorr )f

hldrogcn pcr<>xide; thers nrt conceruedwlfLr iPid ald rrnrno

ircid metabolsn. N4osr croxisonralenzy cs rrc I sr sl nrhesrzed

rn their Inatllre forrn,rn lree prrlyribosornes url enter t ltc cyro-

plasrn.Proteirts hat arc destirled or the perorisorne onfarnsp e

ci l ic perox;somc argeting seqLrencesPTS).N' losf peroxi\orrrirI

rnarrix proterns contain PTSI. a 3-amino .rcLd equrenccrr rhc

carboxyL ermilus. PTS2 is an rrrlno-ternlindl seqLrcncehir i \

cricical or the xnport oi elzvnlts rnvt>lved rt phsnalog,cn rntl

branchcd-charn farty lcid nr. 'raltolisnr. lDport oi pr(rtcins

involves a complcx serres t rellcrons thar rnvolvesat least . l

Chapter 6 r Defectsn Metabolism f Lipidsr

A:DlS0nDtnSfPtnoxl$Mt |[4PoRT

Allell$Pgertndrome

A2r eonatdldrenoukodyitroply

AlinfantkRel5umtease

A4rRhomer(hondrcd)5pia5iauKtata

B:DEFECsF lL6l.EEno)($oliAttlZYME81lt-link€ddr00leukodyforhyB2rAcyl[oAxi(id5eef( ncy

8l:BrFLrn(ina nzymeeficienr/B4:Peroxsolrah laseefrcnry85 a5i ir ebumseaseB6:2ethllary0A (emaseen[ien(y87i fAP ry ansferaiePnoenq88:Ay CHAPynthaseefi(iei(y89:lvlevalonk( uda810:6lutrk(iduriaypeEllHIEro$luiaype812 (ata5emia

distnrct proteins. These proteins are referred t() as pero

cncodc.l by PF.X gcnes IaLrle86--i sumrnarizes he / ' lX g

rhrrr rrc delective n hunrar discase rarcs.

tPlDEMl0L0GY.Excepr for X-linkccl odrcnoleukodlstrophAl.L)), elL he peroxlsomal :lrsorclerslr TaLrlel6-2 are autosrcccssirc raits- X AII) is th e rnosf comiroll pcroxisorrral

dc ( r t r rhan cs t im a tcdrc idcncc f 1 /17 ,000 - he co rnb incderce ol the other peroxrsomal djsorders Ls esfirrated ft / 0 ,000.

PAIH0t0GY Absenceor reduction l rhc number of peroxisis parhognonrorticor disorders f peroxrsonebroqenesis.r

disorrlcrs, hcrc irre mefilbrinoLrs acs har confain peroris

integr-llnrcrrbralc proteins. vhich ac k chenorrnal complcoi nntrir protcins; these re pcr()\ isonre "ghosts." Parho

charlges re observed n nran! ()rt!: lns nd include proiound

ch.rr.rcrerrsrrcefecrs n neuronal migrdtioni micronodultf

(OMPTEMEilTATIO}IROUP I,IO ATITNRTUIXIDT(I(I

PTROTIN#

l

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(HARACTTRISTI(

]1I Kd AA IPAIC

[]H[.zna nd q nleqc]peroxsomdembTdnerole 5 5l kd

51 52kd nielra eox crulmembke ole l

21-24 d emri5omdlas5octed biquitn-.0nju9ar,r9nzyne

Pis riepiof

ll 27koAAA IPe5€PIS re(eplcr

7l 8- kdPerlxisomrl3ssa{atedrotein

42-kC tegc eorjsomalembrdierolein

trfC zne-bindinqteEalpeoxr50maembraner0lein

ll-12 ld Penrxi5omalmembonerotenvnved per0x5omarolfeftllon

48-kd,f(r ?jnc rnd9 n1egraemxomal emEne rote

lfl I cont; nq 0 41kdperox5ori;nteqralperc](iicmaernbrdftrotern

4l kc nreqra enbrdnemlern

48+Cfo5o r prole

-19c Pephec erox50ma]membranemtein

:i-10 kdhrcxi5cmallnlr sc rnernbraneroler

l5 39 d Per0xi5ornalembrdneroleznr inger rtrf

Percxisrmaen ranerotern,pffylateo

1Dockrnqailoror or1p nd er6p

(KI PHT{OTIPT ftROM

99 15,ALD.IRD 7q11)2 A

|((I IAPAN AMs

t E )r 0 F 5

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2 li,r,rALDA,IALDRIDP

zs,\AL!l

li,i,rALSl Dz5,iiAt. i)

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r & 1 16p216qn 4

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im5.Amnerdim|(l,erned/nEe, ri'tutpI cmMoler V, enntF-phei0r)p€orcla r5i d 0de6 fFe.mome ll?ritt l,1rt edt!lr b 19959316



Pe'odio4lesb5ent0 cduredn lumber

574 r PART r Mehbolic Diseases

(aala5e ''tosol

lnireasedrioaryKretion

rhosisof the iverl enal cyscs; hondrodysplasia unctata; orneal

clouding, congenitalcataracts, laucoma, and recinoparh,v;ongeniralheart diseaser nd dysmorphic earures.

PATH0GENESIS.r is Lkelv that all pathologic changesare sec-

ondarl co che peroxisome defect. N'tultiple pero)(isomal enzymes

fail co function in the PBD (Table86 4). The enzymes har are

diminished or absent are s)-nthesized uc are degradedabnor-

malll. fast because hey mav be unprotectedoursideot the per-

oxisorne. t is not clear how defective eroxisome uncrions ead

to the rvidespread arhologic manifestatrons.

The PBD are associated t'ith geneticall,v deternined import

defects. he PBD have beensubdivided nro 12 complementarion

groups. The molecular defeccs ave been defincd n l0 of these

gror,rpsse eTable 86 3). Thc pattern and severityof pathologic

features var-v virh the nature of the tmporr defeccsand the degree

to rvhich mport is mpaired. Thescgcncdcfects ea d o disorders

that were named before rheir relationship to lhe peroxisome

\{'as recognized.namell' , Z,elhl'cgcrs,vndrome ZS), neonatal

adrenoleukodystrophv NALD), infanrile Refsun disease lRD),

an d rhrzomelic hondrod,vsplasiaunctara RCDP).The 1st hree

disorclers re no\\ ' considered o form a clinical continuum, with

ZS rhe mosr ser.ere, RD rhe leasr severe, and NALD itcermedi

ate. The,v can bc caused b,v 11 diiferenr gene defecrs,u'hich

invoh'emainly rhe inporr of proteins hat contain the PTSI tar-

gecing rgnal; hc genedefects annot be distingLrishedn the basis

ofclinicalieatures. he ciinical ser.eriry ariesv' ith the degree o

v'hjch prorein mport is impaired.Mutations thar aboLishmporr

reraincd, eads o the somewhat mildet phenotypes.A defect n

PEX7, r'hich involves he import of proteins that util i ze PTS2,

rs associatcdwith RCDP -PEX7 defects har leave mporc par-

cially ntact are assocrared ith milder phenotypes, om eof u'hich

resemble lassicRefsum disease.

Th e geneticdisorders har involve singleperoxisomalenzymes

usualJy ave clinical manifestations ha! are rnorc rcstrictedan d

relaccd to thc biochemical defect. The primar,v adrenal insuf6-

cienc,v f X Al-D is causedb, vaccumulationof ver,v on g chain

fatty acidsVLCtA)

in rheadrenalcorrex, and the peripheralneu-

ropath,v n Refsum disease s caused b,vrhe accumulation of phy

r rn r . . r . i d n 5 .h t tann ce l l s r r Jm l r l rn .

PBDwith Milder or AtypicalPhenotypes. ervborn rnfancs . 'r.rth

Facialappearance high forehead, unslanringpalpebral issures,

hrpopJasric upraorbital ridges.and epicanrhal olds; Fig. 86 31,

severeweakness nd hyporonia,neonatalseizures, nd e,ve bnor-

malit ies (cacaraccs,laucoma,comeal clouding,Brushfieldspots,

pigmenrary rccinopatht-,arrd nerve d,vsplasia). ccausc of chc

hvpotonia an d "mongoloid" appearance. o*'n svndrome may

be suspected. nfants rrrrh Zelhveger s,vndromc rarelY live more

than a ferv months. More than 90ot" shou' poscnatalgrorvth

failure. Table ll6--5 sts he rnain clinical abnormalit ies.

Patients vith neonatalALD shor.r' ferver nd, occasiooalldvsmorphic features.Neolatal seizures ccur frequenrly.S

degreeof psvchomorordevelopmenr s present; unction rem

in ch eseverelyor proioundl,v etarded range, and developm

mav regressafrer 3-5,vr of age, probabl,rr rom a progres

leukod,vstroph,v.el'eral atienrsare now in a stable,albeit

abled, sate in their 3rd or 4th decade. Hepatomegaly, impa

liver unction, pigmelrary degencration fthe retina,and seve

impaired hearingar e nvariabl,v resenf.Adrenocorrical unc

is usuallv imoaired. but overt Addison disease s rare. Cl

drodvsplasia unctata dnd renal cystsare absenr.

Patientswith infantile Refsumdisease ave survived o rhe

decadeor longer.Thev are able to walk, afthough gair may

ataxic and broad based. Cognicive funcrion is in the seve

retarded ange.A1 1 ave sensorineural caring lossan d pigm

tarv degenerarion f the retina. They have moderatel,v ,vsphic fearures hat nal include epicanrhal olds, a f lar bridg

the nose, and lo.rv-ser ars. Earlv h.lpotonia an d hepatome

rvirh rmpaired function are common. Levels of plasrna cholest

and high and lou'densit l ' l ipoprorein are often mocler

reduced.Chondrodvsplasia uncrataand renal cortical cvsts

absenr. Postnlortem studv in infantile Refsum drsease er

mrcronodular ir.ercirrhosisand small hvpoplasricadrenals.

brain sholvs no malformations,except or severebypopLas

the cerebellar ranule ayer and ec()pic locati{)ns f the Purk

cells n the moleclrLar dyerTh e mode of iohenhnce is auc

mal rccesslve-

Iigtrr. ll(. I lilrr tatients $irh Zellu'eger cerebrohepatorcnalsvndr

Note thc hlgh forehead,ep'icrnrhal o1ds, nd h,vpoptasia f nrpmorbit.l ri

and rnrdiace (t-ourtes! of Han\ Zellweser. N{Di



ftom eflds HA!Grcbo-heorm:eia/elwetsi yrdrcmenta indb0thim ilonsequerrerdpen!50"41fu(rl,rni it1r5.lne6O0fAmnerd;m,1984

Some prricnts u' idr PtsD drsordcrshave milder ancl rr\pic:lI

phcnortpe:,. lhev rral prcsent with periphcrel netlroPith) {rl

rvirh retinop:rrh,-.urparrecl ision,or cafaracfs n chilr lhootl.adrr

lescence,r rclult ltoodenrl hevebcendragnoscdo hare Ch.rrcot

l\. larieToorh disease rr Llshcr svndrc>rne. onrc parieors hare

Chapter 6 t oelecls n Metaboli srn l Lipids

srLrvrvedo rhe -5rhclecade. elects r PEX7, which rnost

rronlv lead ro dre I{CDP phenotype. nirv.rlso ead ro a m

phenorlpe rvrrh cLinicaL anlfest. lt i()ns inrilar o thoseof c

cal Reisurndrseaseph,vranovlCoA hvrlroxvlase e{icicncv

Rhrzon re l i cho f ld rodysp las iarnc ta ta HCDP) h is d iso r

cher.rcrerizecl y rhe preserrce f stippled ioci of calcif icwirhrrr rhe h,vrline carrilagc and is associatcd vith cfi,v

carar.rcrs72' llol.and rrulr;. lc rnalformations ue o contrac

Vcrtcbral bodicshrvc'a coronal clcft l i l led Lr,v arnlage rha

result of an ernbrl,onrc rrest, l)rsproportiorrafeshort st

.rffccts hc proxinral parts of fhc cxrrcnrrt i.-s I i ig. 86-4i). RoLrgic.lbnormaLiries onsrsrof shorteLrrni{f the proxunal

boLres,netaphlseal upping. tnd drsturhedossilication Fig'1ll i. Height, u'eight. rnd hc.rl circumfercncc re es s ha n h

percentile, nd these hildrcurc levcrcl) rcrardedmcncalb'

changessuch as those observed Lr chrhyosliorm erythrod

af c lrcsent in =2.5!6of f itrtnts.lsolatedDelectsol Peroxi sonral attyAcid 0xidation.

lhc d

dcrs rbclcd R1 through tli isecTablc S6 2) cech nvoLve l

rhrceenzl.rnesnvolverl n per<>xisomalarrv acrdoxidanon.'

c l r r i ca l nen i f es ta t ro ls csc rnb le hose of thc Zc l lwcgc rclronrc/rconaralALD/Inienrile Rcisum disccse ontinuum;cirrrbe clisrirrgursheclon r disorders i pc.r'orisonreiogenelel-.or.rnrrv csts. Dciccts oi biiuncrionel cnzvmc erc c() r

rnrl dre found in =li ' l i, () f patrenrr rvirh rhe lellwe

svl t l lme/neora al ALL)/irridnfile l{elsunr diseasephenoPirricr)ts irh isoldtccl .\ L .o A oricl:rscdcficicncvhavea s$+it nrilder phenot,vpc hrrt rcsernblcshar of nconatal i\LD

ls0latcd Defectsof PlasmalogenSynthesis.Plasmakrge

lLp id ; n wh ich rhc ls r ca rbono i g l , vcc ro ls inkcd o an a lrrrth.r th.n a iacryacid Thcy rre s ynthesized hrougha com

serreroi leactions, rhc lst two steps of rvhich ale cefrllze

th c peroxisomaLenz\mes dihydroxvacetonc phos|h:rte

trrrtsieraseaiJ s\nthrsc. L)eliciencv )i elfhef oi fheseenzr L r . lr n l t i r n L r l l , s . - l c r d ' , , f r ( r ' \ ' r \ l c l ' r r . . l i n

inclisrirrgLrishale ironr rbe peLorrsornirl rnport rl isorclerRThLs etrcr disorder s crru\edb_v dcft-ct n PFX7, thc .cckrr pcr ()\ i\onrc targcrirrqsclluelce 2 l t shares he severecrencr of plasnaloeers \vrth disordersB.trand 85 but. in

(Ast li vfir(HII{fORMATIONAEOUTII{EfTATUREWASAVAttAEtt

GJEsINWHI(HTHE TITURTIVAS RT5ENI

ABI'IORMATTATURE Nt)

|lgh ore|le,rd 6l

Flal ri:pui 16

Largeon nel is).lideLriun5 tt-

Sh aow drd l rdqes ll

Low/bro,rdaa bridqe 2l

Eocal thus ]6

Hgh ,{hedF dte l1-

Exiernrarilefolmrty 411

llcrognalhia 18

lieCundantkinfoldrfne(k 1l

Erushhedpots 6

[a]a.arl/(rdyorneJ l5

Gaucotu 1)

Abnolmairern,rqmerrdt$n 15

Optc s(palr r 2l

SeveEypo:ord 95

AbncnalMcrutspon5e )t

Nypcrsllexarareflexa 57

Poolucklnq 11Gavaqeieding )t

:pripi isezrles 6 l

liyihomorcfretrrd,rton 45,mptred earlnq ll

fystaqmus 3'.

% N0.

5 ] 5 Et4 l l50 5529 ,rl20 ill2 l lt2 l5l5 l9t6 18t] t, l5 5

lt l0I il l 620 li8l 947l )65C 55

68 i4ll 2554 55l9 451 8 9l2 lJ

91

8 l

r00r009)9i9rlilrl1i08l86:t411

t[096

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t0 l408t

r . l : , r '. . A. Nc\vborn i , r t . l t r ! " , r I hrzonlc lL. .hondrod!s

pld i r , r fun. t r t . r lRr : l l ) l ) r \ofe rh . !L\ . f r 'hor tenr lg of the pro\

rnr , l l Lnl - .s . he dep.es leLJ rLc lgc i rhc rosc , hvpcr ons,n. . rn.1

lv idcs tnead sct r lurg L n lLsrNs- 11. ( , tc rhe nrnrk€d s l rorre. ng

oi rhc humcrur arrd eprphvseal 5r t t lnq r t t l ic rhouLder . r j r l

e lborv ;o,nts . iCour : r ' r ot lohn ] ' ] . )o,s r . \ ' l l ) r




rion, has defecrs of phytanrc oxidatit>n.'l

he fact rhat disordcrs

84 and 85 are associrtedu-irh he full phenrxlpe of RCIDPsug-

gests hat e delicrency f plasmakrgenss sliEcrenr o producc r-

ClassicRelsumDisease. he defectrve nzyme phvtaLroyl ir, i\

oxidase) s iocalized o the peroxisorte. Thc nranifestationof

classicRefsurndiseasencludes mpalredvision irom retinirispi g

merrrosa, chchyosis, elipherll n.uropathy, irrarir. and, occa-

sionaLly. ardiac arrhyrhmias. ln conrrast to rnfanrile Refsum

drsease, ogrit iue funcrion is rrorrrdl and there are rro congenital

malforrnarions. lLassicRefsum disease frcn does not rnanifcsc

unol youLrgadr.rlthcx>d,ur visual disturhancessuch as nighrblindness, chthyosis, nd peripheralneuropadrynray rlreaclvbe

present n chrldhood and adolescence. arll cliagnosiss impor

tallt lrecause nsritution of i phvfarlic acid resrric rrd dier can

rcvcrsc hc pcripheral neuropadrvan d prevent he p()grcssio of

rhe visLral nd ccntr'al rcrvous ysternmanifcsterions. hc classi

ca l Rcfsum discascphcnoc-vpcra v :rlsobc causcdhv dciccrs n

PI..X7.2-MethylacylCo AHacemase eliciencf- his cli sorder s caused

by en enzvme clelict that lcrds to thc accunrrrlationol the

branched-chain attv acids ph,vtarican d prisranrc cicLlr.nd i. le

acids.Paticnrsprcscntwith adult typc pcriphcral ncuroparhvan d

may also havc li!r, lne[tdry degenerati<>n:i rhe rerrDa

IAIIORAI0RY lN0lNGS. aboracorl cests bI pcroxrsonraldisor

ders cen bc vicwcrl ar rhrcc cvcLs f cornllcxirv.l-evel1: Docs he PalrentHavea Peroxisomal isortlet? his can

he resoh'ed bv noninvasivc tcs[s that a.c generallv availablc

(fable Eri 61. \4ersurenrent f plasrnaVI CIFA s th c nrostcorn

rnonlv usedassay Wbereasphsna VLCFA levelsarc ele!ated i

mn[,\ 'paticnts vith peroxisomal chsorclers,his s n<x:rJrvayshe

casc.The most i rrpt)rtant excepfLonsre RCL)P. n"vhich

VLCFA

lcr.els re lormaL, but plasma phyranic acid lcvclsar c incrcascd

al d rcd l>loodccll plasmalogen evelsare reduced. n sorneofher

peroxrsomal drsorders, hc biochcmicirl abnormaliries are strll

nrore resfricfed.Therefc:re, panel o1 tests s rcconrrnended nd

inciLrdes hsnrr lcrcls of Vl-(lFA al d of phvtanic,pristanic,ancl

pipccolic acids ancl levels of p)asmalogerrsn red blood cells

Tandenr Lrass sfectronrctry techniqucs also permit c<;trvcnicnr

quan t i r i r t i ( )nib l l c : r c ids n p lasm a nc l r rL re . h i spane l f t e : i r s

cau bc pcrfi)rmcd on 2 nr[. samples f ven<>us]ood in(l pernirsdeteccionoi nrosr pcroxisomal chsorclers.nd ornal results

nakc thc prcsence f a peroxrsomaldisorder unlikclr ' .

[euel i Whfit s he PreciscNotureol the Peroxrsonlal isoder]

Table 86 6lists thc main biochemical bnormalit ies n rhe varior.rs

peroxisomaldisordcrs.Whcr combined u'Lth he clinical presen

tation, thc jLr5t nenrioned alel of tests s ofrerr utf icient o iderr

t it ,v the precisenarure of the defect-ElcvarL'dplasma VL(-FA

levelspermir thc frccise diaglosis of X ,AI ) ir rrralepctients.

-\4arked reduction of err,throc,vrc lasoralogcn evelscombired

lr-ith clevaredplasma phytanic acid perrnrtsprccrscdiagnosJsn

a patierrr vidr thc clinical featuresof RCL)lr. Classic Refsunl

disease an be di.rgnosed l demonstrationoi rncrcascd lasrna

phyranic acicl corrbincd rrith normaLor rcrluced evelsof pris-

crnic acid levels, vhile n D bifunctional enzrrne deficiencl aLrd

2 merhylacv CoA raccrnasc cficiencl' ,he leveJs f prisranrc ndphyranrc acid rle bodr incrcascd.Precise clenri6cation f some

peroxisonal disordersmay r'equiremorc cxccnsil 'e tudres rrcul-

rured skin libroblasts.This mal bc rcqrLrrcd or rhe driferenria-

tion of PBD trorlr dcf-ects n biiunctjonal elz,vne. In PBf), rhe

pacierrc's erorisomcs rrc absenr an d catalase s rD rhe solult le

fraction,whcrcas n bifunctronalenzvmedefecr!peroxisomcs rc

present and catalase s in the particrrlatc racriol. l ibroblasr

stLrcliesre requircd ro idcntifv rhe nature of rhe rnoleculardelect

in PBI). V'hether such specialrzedturlicserc clinjcaLlvvarranred

depencls n indrvic|.ral ircurnsranccs. r'ccisc clinjrion of rhe

defecr Ln a probard may improre th e precisicn of prcnatal

diagnosis n at risk prcgnancics,alci ir rs requrred for carrier

derection. It is also oi value il ;ert irrg progrrosis. Prccisc

Fbrob 5tJ

AtD,adren0hLrhd\qr0rhyYtifAer 0i9i"anfaqa.d5

characterizarorr s of prognosric value iir patjcnrs wirh PF

detects. hrs deiecr s prcscnt n =60?i of PBD paricrrrs, ntl abhali of thc PI:Xl clefe*s have rhe G843D allele,which is ass

ulqcl1r' idr signrficanrly ri lcler henotype han is lound i n ot

mutatron5.LcvelS:What s the Molecul;rrDetqct? able86 3 shoq.s hat

m<>lecularefects n rroscof the PBD har'c bccn dcfincd. Dcl

rion of rhe rnolecular efect n the probalcL, vhich s rolr 'ofier

in scvcr al aborarories, sessentialor carner rlefectiot and sp

prenatalclr gnosrs.

DIACN0SIS Ihere ar c scvcral noniuvasivc aLrorator,vests

pcrnrir prcciseand earlr ciiagnosis 1 pelorrsonraldisordcrs

Iable 36 5).-fhc

chalLeng,en PBD is to clriferenriatehe fr

thc largc varictv of orher condit ions thrt cerr causc hvpoto

DISTASI ISSAY

Zelvq{ersyndrome Pa5maNeonatdl

adrenol*odystmphylnfantheBumiseaie

Rhizcmelc Ph5ma{hondrody5pla5apun(ata RBls

fibtublan5

X nkedLDhemuy,Jona5mafibftrbla5i5

]/L(FA

Pnytanadd

ft 5tanacdPpmliracrd

Be & d

Pasmaoffnvel5

v(FA er'e

VfFA xddtion

Fla5nalen yntieri5

Fh!,1dni{.r anl( xdat n

Gtaia5ecdlizatioi

lmmunoqn(i€m,r(ry[omplelllettalton

DNA

Ph/t in(a(id

VLTFA

PlasmaqeIevel5

Plalrralcgenynihe5i5

PhIanacc xidaton

ON A

VLIFAve

vLIFA](idatonALDP rrn,lrearrvrtl

DN A

VL[FA

!L[FA !el5

ALDP munoreartvity

DNA

VL(FAPhytan(addDTnan iod

Srearid5VLFAievels

Pr 1ana(dDxdatoD

[ata seori zation

Inryme

Vt(IA

/L(FA veVl(FAxcation

Enzyme

Pr5tandi ld

thicdr

PrL$rLL(aaid{iditloi

Enrlme

Phfani(rd

Prst ina(d

Inr/me

FINDING

,nctea5e0

Aqe ependentin

Aqe egendel-:t(rca

r[rea5ed

fcreasedabrorm

Vamby eireased

nrftased

0efta5ed

DerEa5eC

D$r..aseC

lytosoli.

Ferox0me5blent

5e abh86- l

seeTabh86-1

lnfta5ec

N0mal

Decreased

De(reasedDe(rea5el

Pf,Yl eteo

n(rcaied

Derrea5edAb5e[f70%

,4tarimutit,of

Varableaed!en85

Vardblercredse90

VarableP(rease

,1ffO1nutatiorjncea5ed

nctr5ed

nateaSedrf ,ra5e4,rbnorma

fftaiedDe(rcaied

D-bifurctronalclen

l]efirenq

n('a\gd

n(r,.a5edDereised

A.f ftA iiCa5r efu

lnrreaied

lncreaied,bncrfl pa

0ereaged

h,leih)" cy tA ori

dehallndeaied

Decr..a5eCPh)'lancyloA cfi en

NB(e,Fibrobia5E

Bfunctonanzyme P 5madete(

X nkedAlDnererozyq0rc

Ary tA oxdaie

deh(ien(y

Pla5ma

iil'obiJ6

Phrma

FbrobranJ

2'Vetrrlary:oA Pbirnrracemai,!eliaen(y

FibrobLarts

l:a5:i(eEum5edie Pliina



seizures, failure to thrive, or dysmorphic features. Experienced

clinicians can readtly tecognize classic Zellweger syndrome by

its clinrcal manifestations. PBD patrents often do not show the

full clinrcal spectrum of disease and may be identifiable only by

laboratory assays.Clinical fearures that mav serve as indicatrons

for rhese diagnostic assays nclude severepsvchomotor retarda

tion; weakness and hypotonia; dvsmorphic features; neonatal

seizures; retinopathn glaucoma, or cataracts; hearing de6crts;

enlarged liver and impaired liver function; and chondrodysplasia

ounctata. The Dresenceof one or more of these aboormalities

increases rhe li[elihood of this diagnosis. Arypical mrlder forms

presenting as peripheral neuroparhy have also been described.

Some patients wrth the isolated defects of peroxisomal farry

acid oxidation (group B) resemble those wrth group A disorders

and can be detected by the demonscratton of abnormally high

levels of VLCFA.

Patients with RCDP must be distinguished from patients with

olher causes f chondrodysplasia unctata ln addit ion to war-

farin embryopathy and Zellweger syndrome, rhese disorders

include the milder autosomal dominant form of chondrodyspla-

sra punctata (Conradi-Hunermannsyndrome),which is charac-

terized by longer survival, absenceof severe imb shortening, and

usually inract intellectl an Xlinked dominant form; and an X-

linked recessive orm assocratedwith a deletion of the terminal

Dortion of the short arm of the X chromosome. RCDP is s -

pected clinically becauseof rhe shor tness of limbs, psychomo r

retardatioo, and ichthyosis. The most decrsrve aboratory tes s

the demonstration of abnormally low plasmalogen levels in red

blood cells and an impaired capacity to synthesize plasmalogens

in cultured skin fibroblasrs. These biochemical defecrs are not

present in orher tvpes of chondrodysplasiapunctata. Chon

drodysplasia punctata may also be associated s'ith a defecr of

3$-hvdroxysteroid-As,Atisomerase, n enzyme involved in

biosynchesisof cholesterol,

COMPLlCAT|0NS.Patienrs wich Zellweger cerebrohepatorenal

r ynd rom ehavem u l r ip le i sab i l rnesnvo l r ingm usc le one . wa l

lowing, cardiac abnormalities, liver disease,and serzures.These

conditions are treated symptomaticall-v,but the p.ognosis is poor,

and most patients succumb in the 1sr few months of life- Patients

wirh RCDP may developquadriparesis wrng to compre5sion I

rhe base of the brain.

PBEVENTI0N.eeChapters83 and 84.

TBEATMENT. he most effective therapy is the dietary treatment

of classic Refsum diseasewith a phytanic acid-restrrcted die!.

For patients with rhe somewhat milder variants of rhe peroxi

some import disorders,considerable uccess as been achieved

with multidisciplinary early incervention, including physical and

occupational therapl hearing aids, alternative communication,

nurrition, and support for the parents. Altbougb mosr patients

continue to function in the profoundly or severely erarded range,

some make signilicant gains in self-help skills, and several are in

srable condition in their teens or even early 20s.

Srudies to mitigate some of the secondary biochemical abnor

malities include the oral administration of docosahexaenoic acid

in a dosageof 50-100 mg/24 hr eirher as the ethyl ester or in rhe

in tbe peroxisorne, There are anecdotal reports of ctinicaL

improvement. The oral admrnisrracion of choLc acid and chen-

odeoxychoLc acid in a dosage of 100-250 mg/24 hr, wirh the aim

of reducing the levelsof presumably toxic brle acid intermediares,

may be effective.

Chapter6 Delectsr Motabolisml Lipids

GENETIC0UNSEIING,ll the peroxisomal isorders, xhyperoxaluria ype 1, can be diagnosed renatally n the ls2nd trimester.The tests are similar to thosedescribedor pnatal diagnosissee able86-5)and usechorioric villus samor amnioc)tes.More than 300 pregnanciesavebeenmonitoand more than 60 aflecred eruses ave been dentifredwithdiagnosrrc rror Because f the 257o ecurrenceisk,coupleswan affectedchild must be advisedabout the availability ofnalaldiagnosis. eterozygoresanbe denti6edn X-ALD anrhosedisordersn which the moleculardefecthas been dent(see able86-3).

ADRENOTEUKODYSTROPHYX.TINKED}

X-ALD is a genetically determrned disorder associated with

accurnularion of saturated VLCFA and a progressive dysfunc

of the adrenal cortex and central and peripheral nervous svs

white matter.

ETI0L0GY The key brochemical abnormality is the tissue amulatron of unbranched saturated VLCFA. with a carbon c

length of 24 or more. Excesshexacosanoic ci d (C26:0) rsmost striking and charactenstic feature. This accumulation

fatty acids is caused by genetically deficient peroxisomal dedarion of fatty acjd, The kev biochemical defect involves

impaired function of peroxrsomal hgnoceroyl CoA ligase,

enzyme lhat catalyzes the fornation of the CoA denvativeVLCFA. The gene that rs defective (ABCDI ) codes for a per

somalmembrane ALDP). More than 400 distinctmutationsh

been idenrif ied, and most familes have a mutation tha"privare" (uniqueco hat kindred) and areupdaredon the we

http://wwwx-ald.nl. The gene has been mapped to chromosXo28. The mechanism by which rhe ALDP defect leads ro VLC

aciumularion and the pathologvof X-ALD is unknovvn.

EP|DEM|0L0GY he mrnimum incidenceof X-ALD in mal

1i21.000. and the combined ncidenceof X-ALD males anderozygous females in the general population is estimated to

1n7,000- All races are affecred. The various phenotypes ooccur in members of the same krndred.

PATH0L0GYCharacteristic lamellar cvroplasmic inclusions ca

demon',rratedwith the electron mic.osc,rpe n adrenoco

cells, escicularLeydig cells, and nervous systemmacroph

These inclusions probably consist of cholesterol esrerified w

VLCFA. They are most prominent in cells of rhe zona fascicu

of the adrenal cortex, which ar 1st are distendedwith Jipidlater arroPny.

The nervous system can display two types oI lesions. In

severe childhood cerebral form and in the rapidly progres

adulr forms. demyelination is associated with an inflamma

responsemanifesied by the accumulati.rnof perrra.cr., lar

phocytes that is most mtense in rhe pariero-occipital region

rhe slowly progressive adult form, adrenomyeloneurop(AMN), che main finding is a distal axonopathy rhat affects

long tracrs in the spinal cord. The inflammatory response s m

or absent.

PATH0GENESIS.he adrenal dysfunction is probably a direcr

sequence of the accumulatron of VLCFA. The cells in the z

fasciculata re distendedwirh abnormal l ioids. Cholesteroli6ed wirh Vl-.Cl'A is relativell resirtant o adrenocorlicothormone (ACTH)-stimulated cholesterol esrer hydrolases,this limits rhe capacity to convert cholesterol to accive srerln addition, C26:0 excess ncreases he viscosity of the pla

membrane and thrs may interfere with receptor and other c

lar functions.



570 PARTX MeraholicDiseases

There is no correlation between the neurologrc phenotype and

the nature of the mutation or the selrrity of the biochemical

defecc as assessedby plasma levels o{ VLCFA or berween the

deeree of adrenal i nvolvemenc and nervous svstem involvement.

lhi severiryof the illnerr an d rareof progression orrelarewith

the lnlensltt/ of the inflammatory response, The inflammatory

response mav be cytokine mediated and may involve an autoim-

mune response triggered in an unknorvn way bv rhe excess of

VLCFA. A CD I l ip id anligen has been mplicared. Nlitochondr

ral damage and oxidatrve stress also contribute. Approximatelyhalf of the paciencsdo not expenence the inflammatory response.A modifier gene that sers he "rhermostar" for the rnflammatory

response s postulated.

CtlNlCAt MANIFESTATI0NS. here are five relatively distrncr phe-

notypes, three of which present in childhood r,r.ithsymptoms and

signs. In all the phenotypes, development is usually normal in the

1st 3-4 yr.

In the childhood cerebral {orm of ALD, sy-mptoms are 1st

noted mosl commonly between he ages f 4 and 8 yr (2 1 months

is the earLest onser reoorted). The most common initial manifes

tations are hvperactivicl', rvhich is often misraken for an artention

deficrt disorder, and u.orsening schooI performance in a child u hohad previotLsly been a good student. Auditory discriminarion is

ofren impaired, although tone perception ispreserved.

Thrs maybe evidenced by difficulty in using the telephone and greatly

impaired performanceon inrelligenceests n items that are pre-

sented verball,v.Spatial orienration is often impaired. Other rnrtial

symptoms are disturbances f vision, acaxia,poor handu,'rrt ing,

seizures, nd strabismus.Msual disrurbancesar e often due to

involvement of the cerebral cortex, which leads to variable and

seemingly nconsistent vrsual capacit;', Seizuresoccur Jn nearly allpalients and ma).represent he 1st manifestatronof the disease.

Somepatientspresent vith increasednrracranialpressure r with

unilareral mass esrons. mpared cortisol response o ACTH stimulation is present n 857o of patients,an d mild hyperpigmenta-

tion is noted. In most pariencs uith this phenotype, however,

adrenald,vsfuncion s recognized nlv afrer he condit ion s diag-

nosed because of che cerebral s,vmptonrs. Cerebral childhood

ALD tends to progress rapidly with rncreasing spasticity andparalysis, isual and hearing oss, and loss of abili rv ro speakor

su'allow. The mean rnrerval berv'een the 1st neurologic symDcom

and an apparentl,vvegetative state s 1.9 yr Patients ma1' conrm this apparentlyveg€talive tate or 10 yr or more,

Adolescent ALD designatespatients rvho experienceneurolsymptoms between he agesof 10 and 21 yr The manilesraresemble chose of childhood cerebral ALD excepr that prog

sron is slowerAbout 10% of patients present acuteJywith scatusepilepti

adrenal crisis, acute encephalopath,v,or coma.

Adrenomyeloneuropathy 1st manifesrs in late adolescencadulthood as a progressive paraparesis caused by long tdegeneration n the spinal cord. Approximately hali of palienls also have rnvolvement of the cerebral \,\.hltematter

The "Addison only" phenotype is an important and undiagnosed condrtion. Of male patients with Addison disease,2may have the biochemrcal defeccof ALD. Many of rhesepati

have intact neurologlc systems, *ereas others have subtle nelogrc signs, Many acquire adrenomyeloneuroparhv in adulcho

The term "asymptomaticALD" is applied o persons vho hrhe brochemrcal defecr of ALD bur are free of neurolosicenducrinedisrurhancqs,Nearly al l personr wirh the gene

-d

eventually become neurologrcalll' symptomatic- A few hremaned asymptomatic even in che 6th or 7ch decade.

Approrimatelv 50'o of female heterozlgotcr acquire adrome rhat resembles drenomyeloneuropachJut is mrlder

of later onset. Adrenal insufficiency is rare.

IAB0BATORY ND RADI0GRAPHICINDINGS. he most spe

an d rmportaor aboratory inding s rhe demonstrationoF ab

mallv high levels of VLCFA in plasma, re d blood cells , or

tured skin libroblascs.The test should be performed i

laboratory that has experience with this special ized proced

Positive results are obtained rn all male patients with X-ALD

in =85% of female carriers of X-ALD. Mutation analysis ismosr reliablemerhod for che dentif icatron f carriers.

CT and MRl. Parienls ,vrth childhood cercbral or adolesALD show cerebral *hite matter lesions that are characterrvith respect to locatjon and attenuahon parrerns on MRI

807o of parienrs, he lesions ar e svmmetric and rnvolv eperiventricular whire matter in the posrerior parietal and oc

tal lobes.About 50% sholv ocacionof a earlandof accumucon t ras rm a te r ia lad jacen f nd an te r ,o . , , t he po r te r ior h r

dense esions Fig. 86-.5,4). hi s zone corresponds o rhe zonc

Fisure86- i . ,4, Conuast enhanced t abmalitics in adrenoleukodrsrophy IALD)q'pical parietcoccipital location, shor.ing metric biJareral ypodense nactive zones H

The enhancing active periphery zone of hdensirv s demarcarcdby arrt*rs Conpareanterior zone of hvpodensry (drrouheads)

that on the MRI in B. CC, corpDs caLlosu

MRI oi the samepatternand area shown b,

NIRI T2 r,r'eighted nage shows a high-inte

signaL i rhe abnormall,vbrighr parieto-occwhite matter. Subcordcal nvolvement is b

identified on MRL SeparatronoI acrive z

ma_v e bener apprecJated y C! because

inacrive and acrive zonesare seenar high s

areasorr N'IRL k is assumed. ou'ever, hat

najor disdndions afforded hy CT rt'ill als

demonsrrablewhen IV enhancement prram

netic enhancement)becones readilv avail

Nore e },lpoden\e involverne|r of CT 1aheads^nd dttotus n A) .ompared !$rh rhe

resolved esioDs n MRI in B (From Kuma

RosenbaumWE. Naidn S, et al: Adrenoleuk

srrophy: Corresponding N{R irnaging srrh

Rad a ogt 19 /',165 497 504.)



incenseperrvascular l1'mphocytic infiltracion where the blood

brain balrier breaksdown. In 127o of patrents, he nrtial lesions

are irontal. Lnilateral lesions hatproduce a masseftect ugges-

tive of a brain lumor may occur. MRI provides a clearerdelin-

eation of normal and abnormal white matcer rhan does CT and

by CT (Fig. 86-58).

857o of patientswith the

evels of ACTH in plasma

an d a subnormalnse of cortrsol evels n plasma ollowing inrra

venous injectron of 250pg of ACTH

{Cortrosvn)

DIAGN0SIS ND 0lFFEBENTlAtlAGN0SlS The earhestmanifes-

rations of childhood cerebral ALD are diflicult to disringuish

from the more conrmon artentron deficir disorders or learning dis-

tarion during the neonaralperiod.

Cerebral orms of ALD mav presen!as increased ntracranral

pressureand unrlateral mass esions.Thesehave been misdrag-nosed as gliomas, even after brain biopsy,and severalpatients

have received radiotherapy before the correct dragnosiswa s

made. Measuremen!of VLCFA in plasma or brain biopsy speci

mens s rhe mo.r reliabledifferenriaring esr.

Adolescentor adult cerebralALD can be confusedwith psy-

chiarric disorders,dementingdrsorders, r epilepsy The 1s cclue

to the dlagno s of ALD mav be rhe demonstration of whicc

mafter lesions y CT or MRI; assaysof VLCFA are conlirmarorl'.

ALD canno be distinguished clnicaLly from other forms of

Addison drsease; t is recommended that assaysof VLCFA levels

be oerformed in al l male Datients ,rth Addison disease Al-D

parientsdo not usuallyhave anribodies o adrenal issue n their

plasma.

C0MPI-ICAT|0NS.n avoidablecomplication s the occurrence fadrenal Jnsufliciencl '. The most diflicult neurologrc problems are

those elated o bed resf,contracture, oma, and swallowrngdi s

turbances.Other complicarions nvolve behavioraldisrurbances

and injuries assocratedwith defeccs of sparial orientation,

impaired visron and hearing,and seizures.

TREATMENT, orticosteroid replacement for adrenal insuf6cienc;,

or adrenocorticalhypofunction is efleccive se eChapter -576). t

Eone Marrow Transplantation. one marrow transplantation

(BMT) benefits parients who shov early evidenceof th inflam-

macory demyelinarion that rs characteristi c of the rap lv pro-

gressiveneurologic

disability in boy and adolescents rvirh the

cerebral X-ALD phenotl'pe, BMT is high risk procedure, and

patients must be seleccedwith great care, The mechanism of

the benelicial effect is incompletely understood. Bone

marrow-derived cells do express ALD! the protein rhat is deli-

cienc n X-ALD; =507oof brarn microglial cel lsare bonemarrow

denved. It is possible that replacement of affected cells bv cells

that conrarn lhe normal genechanges he brain mtlteu suffrcientl;;

ro correct the brain merabolic disturbance. The favorable effect

may also be caused by modificarion of the brain inflammatorv

response. Five co 10 yr follow-up of boys and adolescents who

had earlv cerebral involvement has shot'n stabilizacion and, in

some instances, rmprovement. On the other hand, BMT has not

shown favorable effecrs n patients who had already severebrain

involvement and may accelerate diseaseprogression undet these

Chapter 6 r Defectsn Mol.holismof Lipids

circumstances. The nonverbal IQ has been found to be of

dictive value, and transplant is not recomnended in patients

nonverbal IQ significand,v below 80. Unfortunateh! in more

half the patienrs who are diagnosed becauseof neurologic sy

loms, the illness rs so advanced tha! they are not candldates

transplant.

Consideration of BMT is most rele\.anl in neurologic

asymptomatic or mildly involved patients. Screeningar-rrsk

tives of svmpromatic palients idenrilies rhese parients most

quenrly. Screening by measurement of plasma VLCFA leve

patienrs wrth Addrson disease may also idenr if,v candidace

BivIT. Because of rrs rrsk (10-20% mortality) and the fact

up to 50% of untreated patrenrs with X-ALD do not dev

inflammatory brain dem,veLinatron, ransplant rs not re

mended in patients who are free of demonstrable brain invo

menc.The MRI rs also of key rmportance for the crucjal dec

of *'hether transDlan! should be oerformed. MRI abnorma

precedeclinically evidenr neurologic or neuropsychologic ab

rnalitres. The brain MRI should be monitored at 6 mo to

intervals in neurologically asymptomaric boys and adoles

becrveen he ages of 3 and 15 yr, If the MRI rs normal, BN

not indicated. If brain MRI abnormalties develop, the pa

should be evaluated ar 3 mo intervals to determine if the ab

malicy is progressive, n combinacion rvith careful neurologic

neuropsychologrc evaluacionl and if earl,v progressive nvo

ment is conlirmed, transplanr should be considered.Mag

resonance pectroscopl improver the capacil\ lo derer

whether rhe brain involvement is progressive. It is nor kn

whether BN{T has a favorable effect on the noninflamma

spinalcord involvement n adults with the adrenomyeloneu

th y phenotype.

Lolenzosoi l Therapy. he administration of Lorenzo's o

asymptomatrc boys reduces the rrsk of developing the childh

cerebral phenocypeby a factor of two or more. Lorenzo(4:1 mrxture of glyceryl trioleate and glycer,vJ rierucace)

bined rvich a dietary regimen is recommended for neurologi

asvmDtomatic bovs rvho have a normal brain MRI and

younger than 8 yr'old, but must be supervrsedcarefully. Adr

funcrion and brain MRI must be monirored. Patients

develop progressive lvlR[ abnormalities are evalualed

hemaropoietic stem cell cransplant wheo changes are still m

early phase.Lorenzo's oil has not been shown to alter di

progression n patientswho alreadyhave cerebraI nvolvem

OtherTherapies. nterferon-p and immunosuppressive ther

have not been found to be effective. Therapies r.ith lovas

and with 4-phenylbutyrare have been proposed and are b

rested in clinical trials. Gene rherapy has shown promise in

tured cells and the mouse model of X-ALD buc is not yet a

able for human trial.SupporliveTherapy.The progressive behavioral and neuro

disturbances associated with the childhood form of ALD

exrremely difiiculc for che amill'. ALD patienrs require the e

lishmenr of a comprehensive management program and par

ship among the family, phvsician, visiting nursing staff, sc

authorit ies,and counselors, n addrtron,parenl support gr

are often helpful (United Leukodystroph,v Foundatron,

HighJand Drive, Svcamore, L 60178). Communicacion

school authorit ies s imporrant because nder rhe provisio

Public Law 94-142, children with ALD qualifv for speciavices as "other health impaired" or "mult ihandicap

Dependingon rhe ra!e of progression f the disease, pecialmrght range from relatrvely lowlevel resource se ices with

regular school program to home- an d hosprtal-based ea

programs for children who are not mobile.

Management challengesvary with the stage of rhe illness

early stages are characterized by subtle changes n affect, be

ior, and attention span. Counseling and communication

school authonties are of prime importance. Changes n the s

wake cycle can be benefited b.v the ;udicious use ac nigh



580 PABTX Metabolic isoaros

sedatives uch as chloral hydrate (10-50 mg/kg),penrobarbital

{5 me/ke), or diphenhydramine2-3 mglkg).As the leukodysuophyprogresses,he modulation of muscle

tone and support of bulbar muscular unction are malor con-cerns.Baclofen n gradually ncreasrng oses 5 mg bid to 25 mgqd) is the most effectivepharmacologic gent or che reatmentof acuteepisodicpainful musclespasms.Other agenrsmay alsobe used,wrth careberng aken o moni tor the occurrence f srdeeffectsand drug interactions,As the leukodystrophyprogresses,bulbar muscular control is lost. Although initially thrs can bemanagedby changrng he dier to soft and pureed foods, moscpatients eventually require a nasogastric ube or a gasrrost-omy. At least one third of patients have focal or generalizedseizureshat usually eadily respond o scandard nriconvulsantmedications.

GENETICOUNSETINGt{D PREVEI{TI0N.eneticcounselinsandprimarv and secondary rerentionof X-ALD are of ciucialimportance.Excendedamily screening hould be offered o allat-risk relatives f symptomatic arients;one program ed to theidentificacron f more han250 asymptomatic ffectedmalesand1,200 women heterozygous or X-ALD. The plasma assaypermits eliable dentificarionof affectedmales n whom plasmaVLCFA Levels re ncreased lreadyon the day of birth. Identifi-

cation of asymptomatic male5 permits instirution of steroidreplacementherapy when appropriateand prevents he occur-renceof adrenalcrrsis,which may be fatal. Nloniroringof brainMRI also permits rdentiEcation f patientswho are candidatesfor BMT at a stagewhen this procedure as chegreatest hanceof success. lasmaVLCFA assav s recommendedn all malepatientswith Addisondisease. -ALD has beenshown o be hecauseof adrenal nsufliciency n >25% of boys with Addisondisease f unknorvncause. denti6cationof womenheterozygousfor X ALD is more drfficuk than that of affectednales. PlasmaVLCFA levelsare normal in 1-f-20% of heterozygous omen,and ailure o nore hishas ed ro serious rrors n senetic ,.run-seling.f Vl CFA evels renormalborh n plasmalnd culturedskin frbroblasts, he risk of false-negativeesults s reducedbutnor eliminated.DNA analvsrsDermitsaccurate dentilicationof

carriers,provided hat the mutarionhas beendefined n a familymember. nd s cheorocedure ecommendedor the dentificationof heterozygouswbmen. Mucation analysis s available on aseffice basls.

Prenaral iasnosis f affeccedmale etuses an be achieved ymeasurementf VLCFA levels rr cultured amniocvres r chori-onic villus cells and by mutation analysis. Vhenever a newpacientwith X-ALD is identified,a detailedpedigree hould beconstructedand efforts should be made to identilr all at-riskfemalecarriersand affecredmales.These nvestigations houldbe accompanied y carefuland sympatheric ttention o social,emotional,and ethrcal ssues uring counseling.

Peroxisomal Disorders

Baumganner MR, Poll-The B! VerhoevenNM, et al: Clinical approach to

inherited peroxisornal disorders: A series of 27 pztients. Ann Ne rol

1998;44:720-730.

FerdinandusseS, Yliantrila MS, Gloerich J, et al, Mutarional speccrurn f D-

bifuncnonal protein deiciency and structure based genotypephenotype

anAlysis, ,r1 Hr'11 Geset 2006t78:112-124.

Maninez M. Pineda M. Vidal R. et a| Doco$hexaenoic acrd-A new thera-

peutic approach ro peroxisomal-disorderpatients: Exp€rience with two

cases.Nerlolos] 1993 4 1389-1397

NIoserHW: Genorypephenorypecorrelarions n disordersof peroxisone bio-

&enesis.Mol Genet Metab 1999;68,316-327.

Modey AM, Brites P, Gerez L, et al: MDrarional specuum in lhe PEXT gen€

and funcrional analysis of mutanr alleles n 78 parients with rhizomelic

chondrodysplasiapuncrat^ rype 1. ,1m J tu1ft Genet 2002;70:612424.

PreussN, Brosius U, BiermannsM, er al: PEXI mutarions in complem

non group 1 of Zellweger spec m patLentscorrelate rvirh seven

disease. Pediatr Res 2002;51,:706-714.

SteinbergS, Chen L, We, L, Moser A, er al: The PEx genescreen:Molecdiagnosisof peroxisome biogenesisdisorders n rhe Zellweger synd

spe.JJtm. Mol Genet Metab 2004.83252163.

Valter C, GoorjesJ, Moojjer P.{: Disorden of peroxisome biogenesis umutations n PEXI: Phenorypes nd PEXI proteln levels Am J H tft G

2OO1;69:3 48 .

WandersRJ, JansenGA, SkjeldalOH: Refsum disease, eroxrsomes nd

tanic acid oxidationi A review I Neurooathol Exo Ne

2001;60:1021-1031.

Adrenoleukodystrophy (X-Linked)

BezmanL, Moser AB, Raymond cV, er a| ,{drenoJeukodystrophy:ncide

new Duration fare, and fesulrs of extended amily screening.Azn Ne

200r;49:5r2-517.Boehm CD, Cuttins GR, LachrermacherMB, et al: AccurateDNA basedd

nostrc and carrier resring or X linked adrenoleukodvstrophy.Mo/ G

Meab 1999;66:128-136,

Kemp S, Pujol A, V/rrerham HR, et al, Xlinked adrenoleukodystrophvm

tion database: Rote in diagnosis and clnical correlations. Hun M

2001;18:499-5r .Moser AB, Kr€irer N, Bezman L, et al: Plasmavery long chain fatw aci

3,000 peroxisome disease patients and 29,000 concrcls. Ar'n Ne

1999;45:100-110,

Moser FIri(, Lo€s DJ, Melh€m ER, er al: X linked adrenoleukodyscrOvervrew and prognosrsas a tunction ol age and brain magnetic eson

irDaging abnonnali.y: A srudy involving f72 parients. Ne"rcpedia

20O0;3r:227 -239 .

Moser HW, Raymond GV Dubey P, AdrenoleukodysFophy: New approa

to a neurodegenerative isease.,JAMA2005j294:3131-3134.

Moser H\v, Raynond CV, LD SE,er al, Follow-up of 89 lnrenzo's Oil tre

asymptomaric adrenoJeukodysrrophy parients. Arch Ne

2005j62: l073-1080.petersC, CharnasLR, Tan Y, et ai, Cerebral X linked adrenoleukodystro

The inte.national hematopoieticcell transplanlation experience rorn 1

to 1999.Blool 2004;104:881-888.

SrephensonDJ, Bezman L, Raymond GV Acute presentarjono{ childh

adrenoJeukodystrophy. ewopedia*i.s 20003r:293-297.

Van Geel BM, AssiesJ, Haverkon EB, et al: Prosressjonof abnorrnaliri

adrenornyeloneuroparhy and neurologicallv asymptomatic X-lin

adrenofeukodystrophydespite treatment ivirh "Lorenzot oil." J Ne

Ner/osarg Psychiatry 7999,67 290-?99.

86.3. orsoR0EBsFLlpopfiorElNEtrsor-rsnrNTRAt'rsPoRrWill iamA. Neal

EPIDTMIOTOGYF TOODIPIDSNDCARDIOVASCUI-ARISEASE

The relationship betweendietary fat consumprionand placholesterolwas demonstratednearlJ'a century ago. ! ellAmericans ad higher atesofcoronary heartdiseaseCHD) tDostlr.arEurooeanswho subsisred n limited rations.The Se-ountries Studyof geographic, ocialclass, nd ethnicdifferern CHD around the world found strong associations etwaveragentakeof saturated ats, plasmacholesterol, nd mority from CHD. In 1950, the mear total blood cholesrerol eamongAmericanse'as 20 mg/dl. By 1991, che eveldeclinea mean of 205 mg/dl-.

ln 1977, the Cooperative Lipoprocein Phenorl'prngStshowed chat her€ s an inverse elationshipbetweenHDL CHD. Clinical trials of dietary and drug inrerventionsdirecowardmodulation of cholesterol evelswere begLrn uring1970s, ultimately providing rhe basis or screening nd trement standardsas promulgated by the National Choles



Educarion Program (NCEP). l'urther refinement of the molecu-

lar basis of l ipoprorein merabolism has better characterized

phenotypic aboormalit ies an d more directed inrerventional

sffategte

Of all ommon chronic diseases, one is so clearlv nfluenced

male gender, hough it is increasrngly apparent that hearr disease

is under recognized in women. Tobacco use confers a twofold

higher liferime nsk. Sedentary activiry and high intake of satu-

rated fats, leading to adrposity, increase risk through differencesin th e plasma evelsof hpoproreins hat ar e atherogenic Famil,v

history is a reflecnon of the combined rnfluence of lifescyle and

geneticpredisposit ion o earlv hearcdisease.Risk of premature

heart disease ssociated it h posirive amily historJ is 1.7 trmes

hieher rhan in families with no such histor,v.

The pathogenesis of atherosclerosis begins durrng childhood.

Korean and Vietnam war casualties rvere noted to have surprrs-

inglv advanced afty streak rn dplaque ormati.,n rn rh ecoronarr

arieriesan d aona. Th e lohn' Hopkinc PrecursorrStudv demon-

srraced that white male medicaLstudents with blood cholesterol

levels in the lowest quartile showed only a 107o incidence of

CHD three decades ater, whereas those in the highest quartile

had a 40% incidence. The Pathobiological Determinants of

Atherosclerosisn Youth (PDAY) Srudy demonstrateda signi6-

canc relarionship berween tbe weight of the abdomind lat pacl

and the extent of atherosclerosis found at autopsy on subiects

15-34yr of age. The BogalusaHeart Study of >3,000 black

and whire children an d adolescentsha s provided the most

comprehensive longitudrnal data relaring the presence nd

severicy of CHD risk facrors wirh semiquantiliable severi of

arh€rosclerosrs,

Th e "feral originshvpotbesis" s basedon rhe observation ha r

babies born wrth lorv birthweight have a higher incidence of heart

disease s aduhs-Epidemiologic tudies upPorr he dea hat pre-

natal and earlv poscnatalcondit ions ma v affecr adult health

starus. Children *'ho are large for gesratiooal age at birch and

exposed to an intrauterine environment of eirher diabetes or

maternal obesicy are at increased nsk of eventually developing

rhe "metabohc syndrome" (insulin resistance,yp e lI diabetes,

obesrty, CHD). Breasc-feeding preterm infants confers a long-

term cardioprotectivebenelit 13-16 yr laret. Those adolescents'w.howere breasr-fedas infants had lower C reactive prorein con-

centratiors and a 141" lower LDL to HDL ratro compared to

those fed infant formulas,

Poverty is also associatedwirh numerous negative health oLrt-

comes. The Younq Hearts Proiecc n Northern I reland has shown

rhat behavioral ;isk factors are influenced bv socioeconomic

status. and they are well established by adolescence,even rhough

no biologic differences are apparent.

Chaptei 6 r Delectsn Metabolism l Lipids

ETOODIPIDSITD IHEROGEI{ESIS

Numerous epidemiologic rudres ave demonstrated he ass

tion of hypercholescerolemia, reierring to elevated total b

cholesterol, rvith atheroscleroric disease.Advances in clinical

oratory rechniqLres or measurement of orher selected ipopro

parricleshave increased ur understanding f the role of b

lipids in relation to hearr disease. he ability co measure

components wirhin classesof lipid parhcles, as $'ell as mar

of rnflammation,have further elucrdared he processof ath

genesis nd plaque upture leading o acutecoronary syndro

Atherosclerosis ffecrs primarily th e coronary arteries but

often involves the aorta, arreries of the lower extremities,

carotid arteries.

The early s tage of development of alherosclerosisrs choug

begin with vascular endothelial dysfunction and intima rn

thickness, which has been shown to occur in preadolescent

dren with risk factors such as obesity or familial hvperch

terolem,a. The complex process of penetration of the int

lining of the vesselmay be due to a variety of insults, inclu

the presenceof highly toxic oxrdrzed LDL particles. Lymphoc

and monocytes perterate the damaged endothelial lining, rv

tbey become macrophages laden wrth LDL lipids and

become foam cells. Such accumularron s counterbalance

HDL partrcles apableof removing iprd deposicsrom tbe v

wall, Fundamental to plaque formatron is an inflamma

process elevatedC-reaciiveprotein) nvolving macrophage

ch earrerialwall. Th e deposit ionof l i pid withrn the subend

lial l ining of the arterial wall appearsmacroscopicallyas

screaks,'hich ma y to some degreebe reversible.A later sra

plaque developmenr involves disruption of arterial sm

muscLe ells stimulated by rhe releaseof t issue cytokines

growrh facrors. The atheroma is composed of a core of fatty

stance eparated rom the lumen by collagenand smoorh mu(Fig. 85-5). Growth of the atheroscleronc laque mav resu

rschemia of the tissue supplied by che arcery, Chronic inflam

tion within the atheroma, perhaps caused by infectrous ag

such as Chlamydn pnebmonite, results rn plaque inslabiliqv

subseouen! ruoture. Placeletadherence eads to clor formatio

the sire of rupture, resulting in myocardial infarctron or a c

Dtovascular venl.

PTASMA IPOPROTEINETAEOTISMIfOTRAI{SPORT

Abnormalitres of liooorotein metabolism are associatedwith

betes mellitus and premature arherosclerosis, ipoproteinsoluble complexes of lipids and proteins rhar effect transpo

fat absorbed from the diet, or syorhesjs by the liver and adi

Adventitia

fisurc 86-6. The early stage oI developrnentof

atheroscle.osisbeglns rvrrh penetrarion of rhe

incimal lining of rhe vessclbv innamDitory ceLls

Deposrtion of lipid {jthin the subendothelial

Lrnrng f the artcrial *'all e"entualty leads o drs-

ruprion o{ smoochmusclecells co form an sthero

matous hpid core thar impitges on the lumen.

Chronic inflanmation leads ro plaque instabilitv,

setring he srage or plaque rupture and complete

occiusionoi the vessel umen by clor lormahon

Monocyte/Macrophage

lnt ima

Tunica medra

Subendlayer

Endolheli

Lipid core



Ei

582 PABT . MetabolicDiseases

tissues,or utrlizationand storage.Dietary ac s transportedromthe small ntestine schylomicrons. ipids synthesizedy the iverasvery ow densrty poproteins VLDL) are catabolized o inter-mediatedensity ipoproteins IDL) and low-density ipoproreins(LDL). High-density lipoproteins (HDL) are fundamentallyrnvolved n VLDL and chylomicronmerabolism nd cholesteroluansport, Nonesterifiedree atty acids FFAs)are metabolicallyactive lipids derived from lipolysis of triglyceridesstored inadipose issuebound to albumin {or circulation in the plasma

(Fie.86-7).Lipoproteinsconsrst f a centralcoreof triglycerides nd cho-

lesteryl sters CE)surrounded y phospholiprds,holesterol, ndproteins Fig.85-8).The densityof the several lasses f lipopro-teins s inversely roportional o the rario of lipid to protein (Fig.86-9) .

Phospholipid

Figule86'7. The exogenous, ndogenous, nd reverse hole

pathways. The exogenousparhway transports dietarl far

rhe small intesnneas chylomicrons o rhe peripheryand the

The endogenouspathway denores the secretion of verldensiry ipoprotein (VLDL) from rhe liver and its caraboli

inrermediaredensity lipoprotein (IDL] and lo$ density lipo

tein (LDL). Trigiyceridesare hydrolyzed frorn rhe VLDL pa

bythe action oflipoprotern lipase LPL)in rhe ascular bed,ving free fatty acids (FF.\s) or utilization and storage n m

and adipose rssue.Hish-densiry lipaprotein (HDL) merab

is responsible or the transporr of excesscholesterol from

perlpheral cissuesback to rhe liver {or excrerion in the

NascentHDL-3 particlesderived from the Lver and small i

dne are esteriied to more macure HDL-2 parriclesby enz

mediaced novemenrof chvlomicron and VLDL into the

core, n'hich is removed rom the circularion by endocvtosi

Constiruent roteinsare klown as apolipoproteins Table7). They are responsibleor a variety of metabolic unctionaddition o thefuscructural ole, ncludingcofactorsor inhibof enzymatic athways,and mediatorsof lipoprotein bindincell surface eceptors.ApoA is the major apoliprotein of HApoB is present n LDL, VLDL, IDL, and chylomicrons.Ap100 rs derived rom the liver, whereasapoB-48comes iomsmall ntestine.ApoC-I, CJI, and CJII are smallpepcidesmtant ir lriglyceridemerabolism. ikewise,apoE,which rspre

in VLDL, HDL, chvlomicrons, ndchylomicron emnants,an important role in the clearance f triglycerides.

Uuerterifiedcholeslerol

1 20

1 1 0

1.06

1 .O2

1.006

1.00

E

'a

c

oo

#HDL

5 1 0 2 0 4 0

APOB-100

Low-Density ipoprotein

Figure 86-8. Schematicmodel of low-density ipoprotein (LDL). Lipoprotein

consistsoI a central core of cholesrerylesrers, urrounded by phospholipids,

cholesrerot. nd Drorein.

80 1

Diameter, m

Figure 86-9. The densir-v f the severalcLassesf lipoprotein is inversely

portionat ro th€ ratio of lipid to protein. As lipid is less dense ban pro

rhe more lipid contained in the parcicle ncreases ts size and decreas

density. HDL, high-densir.vpoproteinj LDL, lorv-densiq' lipoprotein;

int€rmediatedensity ipoprotein; VLDL, very low densitl lipoprotejn.



Chapter 5 . Defectsn Metabolism f Lipids

(oMPO$Tn

LIPOPROTTIN-

I|llomoo15

[hyom n remfan$

ttD-rD lLlt

HDt

$unclrte$ e[hylomkonrLivetifienineVLDI!tDr[iwr,ntenineLDLthylol|]i(ont

'i po!rteB.rn! q Df ertn 0E of

ft{, hqh.lenlry p0prctn Dl, rFrmed ledmr y Fpnir n;LDl,0w le$ ty poprrtn]VLDt,?ry o,,v enritvQopote

LIPIO

98-ts9 l %909l89194l-68

AP0umPRoTgt{5

( , i , t I , ,A ,A ,AB48,tI J . [ , t , t ]

3100l-,r- ,A-r\r,a , D

srorage n rnuscleand adipose issue.Hvdrol,vsrs t =80% o

TG presenc n VLDL perriclesproduces f)l- partrcles onta

.ur equal amounr of cholesterol nd TCI-The remarning en

IDI- is conr.erted o I I)L h)r deliverr ro pcripheral issueso

rhe liver.ApoE is artacheclo the reulnant DI- particle ro a

l. inding to the celLan d srLbsecluentncorporacion nro rhe

some lndividLralswith deficienc,v f eicher apoE2 or he

trigl'ceride lipase HT(iL) accuntulereDI - in rhc plasma.

I DI particlesac.olrnt for =709i, oi thc plasma choleste

normal jndividuals. l.Dl reccprors re presentoD the surfac

Lre.rrly l l cells.N' losrLDL rs taken up b,v he liver, and rhe

is rrrnsported ro peripher'alissLrcsuc has the adrenalglandgonrds iol steroid synrhesis.Dlslipidcmia is grearlv rrf lue

bi LDL-R activirv The cif iciencvu' irh rvhichVLDL is conv

t r r r r , D l r s . r l . o m p n r t , t n rr r r p r . l , ' n t e o s r a s i ' .

HD LAN DREVEBSEH0LESTER0tRANSP0RT.s hcparicsecr

of hpid parricles nto ch e bile is rhe onll mcchirnisrn v u

cholesterolcan be removcd fronr rhe hodv. lransporr of e

cholesrerol rom the peliphcral cclls rs a r.rtall,vmportent

t ion of IIDL. HDL is hcavil-v aclenq.rth apo,A. conra

lLp.opr,rceins,vhrch rs nonarherogenrcr contrast to B llp(

rcins (iholescerol-por)r irsacntHDI- parricles secrefedby

lrter end small nrestireare esterii ied o more nratr.rrc DL-2

riclesbv rhe actiorrof rhc cnzvnc leci rhin-cholesrerol cyL

tcrasc L(lAI). u'hLch .rcrlitaresnorernenrof chvlomicron

VLDL rnto the HDI corc. HDL-2 mav trarsfer choLesrcrybacl to lpoB lipoproreiLrs redilted bv cho)estcryl ster ra

proteir (CE1P), of the cholcsteKt-richparriclenay bc rcrn

irrm rh e plirsnrahy endocytosis. omplering reverscchole

rrrrrl port.Low I ID L rnai be gerrericdeficcnc,v apoA-I) o

ondar. to i ncreased lasna TCi.

HYPEBLIPOPROTEINEMIAS

HYPERCHOLESTEBOTEMIATABLE6.8)FamilialHypercholesterolemiaFH). H is a monogenrc u

nal co dominarrrdisordcrcluseclb,v nurarions ffecting he

SlZt(nm)

i301,20010 1t0l0-8025-3518255)0

DtNtlIY9/rrLl

<095<t 01106095-10C6r11x-r 191019 061I 125 r0

PR()IAN, : l

6"87,10't l

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TRANSP0BTF EXOGENOUS0IETARY)lPIDS All dietarv iar rvith

th c exceprionof r uedium-chain riglycendes s cflicieLlrLt rrried

tissuc. Free fattv acids are oxidized. resterif ied br storage as

the chylolnicron, apo(i parrrcles:rre ecirculatedLrack o HDL

Thc subsequcnr oltribr.rriol of apoE from ll l)L to the re rli lnr

meal, an exceptionbeing ndividuals with a disorderof chrLomi

cron rnetabolism.Posrprandial vperlipidemras a risk frcror ior

arhrrosclerosis. bnormal transport of chvlomicrons an d therr

ren'rnantsra v rcslrLtn their absorpfion n() rhe blood ves.cl.vll l

as oam ccLls. ausecl v rh e rngescion f CF-bl macroPhlges, he

carliesrsrirgc n rhe developrnenr i fatt,vsrreaks

TBANSPORT0FND0GEN0USlP lDS BOM HE IVEB ' fhe k r r rn r

t ion and secretiorr f VLI)1 frrrm the liver dnd irs carabolisnr rr

IDL and I-DL parrcles des.ribe lhe eldogenous lipoprorcirr

path\\ 'ay.Fatq- acicls rsecl tbe hepatrc brmation ol ! ' l Dl rrc

ancl r consrsts f trglyccricles, holesrervl srcrs, hospholipicls.

and apoB 100. Nascentparnciesoi \rLD[- secrccd into rhe cir-

culatit>n ombrne r' ich llo]iprorei

Vl-DI particle is dctermineJ l.tr

prcsent,prrrgrcssivel,vhrinklng rn

th e :rctiorl oi l.PL. yielding frcc

imi ahypercho5lerolemi,rimiial, lele(veApoB00Autosomrcces5i\€yp.orch0l€5tercleitDSltoiteroemhlyqenhypedohneonEtunllaombinedyperlipldemt(HL)

fam lal $betalipoproteinemiafuflrdl h.v mrunerniaFreder(ksonrypeFamilqpertrI re.idemiaFrc,ieftksonype V)fumi lhyperlry.eddemiaFredericKonype lfumil lhecircpaseefeicy

11!04

t l tai ] i l

< N.llll,i)0-i)

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t i ! '

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< r ill!',l la

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LD L

LDtLDL,TCtDt,r.GrctT16116ttVtDL

Tendonanthorna5,I|JtTendonanthomas,I|1DTendonaflhomrs,l-|1D.Iendon

)(dnrhomas,IHDtf D(rlD

iubaerupliveanthoma5,eripheraa5curdisea5eirupnveanth0,Ta5,ep,rtorpn0meqaly,,rncredt5l(l]ihnlh|rmast{HDi|])

ADAD

ADAD

ADADAF

AD, iu|05omadonnant ,Afa! Io9m.rResve]LH! , r0r0| ' ] r iedl |df3R]LJ i ,0wnel l5 ly |pDEm, I6, l f ) f



584 PARTX Metaboliciseasss

Figure 6 10. Achillesendon anthoma hererozygousamilialhypercholes-terDlemia).FromDurringtonP: Dydipidaemia. an.et2O03;j6Z7l7-731.1

receplor. ft is characterized by strikingly elevated LDL cholesterol, premature cardiovascular disease,and tendon xanthomas.

Molecular studies have identified five classesof mu!ations affect-

ing the ability of LDL cholesterol to bind with the LDL receptorOf the nearly 800 murations described, some result in failure of

syflthesisof rhe LDL receptor (receptor negative) and orhers cause

defecrive binding or releaseat the lipoprotein-recepror rnterface.

Receptor negative mutations result in more severe phenotypes

than recepror defecti ve mutations.

HomozygousFH. FH homozvgotes inherit two abnormal LDL

recepror genes! esulting in markedly elevated plasma cholescerol

levels ranging between 500 and 1,200 mg/dl. Tnglyceride levels

are normal to mildly elevated, and HDL levels may be shghdy

decreased. he condit ion occurs n 1/1,000,000persons.Receptor negative palents have <2o/o rrortr].al LDL receptor activ ir,v,

whereas those who are receptor defective may have as much 257o

normal activirr and a bener prognosi(.

The prognosrs rs poor regardless o{ the specific LDL receptor

aberration, Severeatherosclerosrs nvolvins the ao.tic roor andcoron.rryarreries r pre\ent by early ro mid-;hildhood. These hil-

dren usually present with xanthomas, which may cause hicken-

ing of the Achilles tendon or extensor tendons of the hands, or

cutaneoLrs esions on che hands, elbows, knees, or br:trocks (Figs,

85-10, 86-11, and 86-12). Corneal arcusmav be presenc. amil,v

Fisure 36-11. Srria€ palnar xanrhomata. (From Dulljngron P: DysliFi-

daemia Lancet 2003;362:7L7 7 37.)

history is informarrve becausepremature heart disease s stronprevalent among relatives of both parents, The diagnosis may

confirmed bv measuring LDL recepcor acivity in cultured s

fibroblasts. Pheoo4prc expression of the disease may also

assessedby measuring receptor activity on the sulface of l)phocytes bv using cell sorting technrques.

Untreated homozygous patients rarel_r- urvive !o adultho

S;rmproms of coronarv insufficiency may occur; sudden deat

common. LDL apheresis o selectively emove LDL particles fr

rhe circularion is recommended for many children and has bshown to slow the progression of atherosclerosis. I-iver t raplantation has also been successful n decreasing LDL cholest

lerels. but complicarions related ro immunosuppression

common. HMG CoA reductase inhibitors are ofren effec

depending on the specific class of LDL receptor defecc presCombination therapy with ezetimibe, selectively blocking cho

terol adsorption in the gut, usually results in further mod

decline in LDL levels; t has largely replaced tbe use of bile a

sequestra11ts.

Heterozygous H.Heterozygous FH rs one of the most comm

single gene mutations associared with acute coronary syndrom

and atherosclerotic CHD in adults. Its prevalence is =1/500 in

viduals worldwide, but the frequeoc,vmay be as high as 1/250

selected popularions such as French-Canadians, Afrikane

and Christian Lebanesedue to the founder effect of unique n

mutatio11s.Heart disease accounts for more than hall oi all dearh

Western society, The pathogenesis of CHD is both environm

Figure 86-12. F,ruptivexanthomata Dn ertensor surftce of forearn. lFDurrington P: Dyslipidaemia.Lakcet 2003;362:717-731 )



Chrlter 06 | Dolocls n mdabolism ol LiDidsr

An estimated10 million peoplehave FH worldwide. Symptoms

of CHD usuallyoccurat themeanageof 45-48 yr in males,and

a decadeater in females,

oarenta hypercholesterolemia. Plasma evels f LDL cholesterol o not allow unequivocal

Holland. The diagnosiswithin well-definedFH families s pre-

ability of FH, verified by molecular genetics,s derived frorn

a U.S. population cohort and may not be applicable o othercounttles.

(LDL-C155 ngidl).Treatmentof childrenwith FH shouldbeginwith a ratherrig-

orous low-far diet (see ater). Diet alone s rarely sufficient or

decreasing lood cholesterolevels o acceptableevels LDL-C

<130 mg/dl). The Expert Panelon Blood CholesterolLevels nChildren and Adolescents (National Cholesterol Educarion

by 20-30 mg/dl. Thismedicationhasnot beenevaluated y c

trolled clinical trials n children.HMG CoA reductasenhibihave become he drug of choice or treatmentof FH becautheir remarkableeffectivenessnd acceptableisk profile, Tis sufficient linical experience ith this classof drugs n chilro document hat they are aseffective n children as adults,the risks of elevated epaticenzymes nd myositisare no grethan in adults(seebelow).

FamilialDefective poB-lm {FIIE}. DB is an autosomaldonant condition that is indistinguishablerom heterozygouLDL cholesterol evels are increased, riglyceridesare noradults often develop endon xanthomas,and premature Coccurs.FDB s caused y mutation n the receptorbinding e

of apoB-100, he ligand oI the LDL receptor,with an estimfrequency f 1/700peoplen Western ultures. t is usuallycaby substitutionof glutamine for arginine n position 350apoB-100,which results n reducedability of the LDL recero bind LDL cholesterol,hus mpairing ts removal rom theculation.Specializedaboratory estingcan distinguishFDB fFH, but this is not necessary, xcept n research ettings,treament is the same.

Autosomaliecessiye yp€rchol€stsrolemiaARH}, his rare dition, caused y a defect n LDL receptormediatedendoclin the liver, clinically presentswith severe ypercholesteroat levels ntermediateberween hose ound in homozygouheterozygous H. It is dispropoJtionately resentamongdinians,and s modesdy esponsiveo treatmentwirh HMG reductasenhibitors.

Sitosterolgmia. rare autosomal ecessiveondition charaized by excessiventestinal adsorption of plant sterols,sterolemia s causedby mutations n the ATP-binding castransportersystemwhich is responsible or limiting adsorof plant sterols n the small ntestineand promotesbiliary erion of the small amounts adsorbed,Plasmacholesterol emay be severely levated,esulting n tendonxanthomasandmature atherosclerosis. iagnosis an be confumedby meing elevated lasmasitosterol evels,Treatmentwith HMG reductase nhibitors is not effective,but cholesteroladsorinhibitors such as ezetimibe and bile acid sequestraneffecrive.



586 PABT r MetabolicDisoases

small effects of many genesare impacted b; environmental rnflu-ences (diet), Plasma cholesterol evels ar e modescly elevated;triglvceride levels are normal. Polygenic hypercholesterolemiaaggregates rn families sharing a comrnoo lifestyle but does notfollow predictable hereditarl' pafterns found in single genelipoprotein defects,Treatment o( children with pollgenic hvper-cholesterolemia is directed tou.ard adootion of a healrhv liFescvle:reducedo ta land \ f l t u ra ted at on rum p t ro r r nd a t l ea r t h i , ' fphysical activitl, dail;'. Cholesterol lowering medication is rarelynecessal)'.

HYPERCHOI-ESTEROIEMIAITH YPERTRIGTYCEBIDEMIAfamilial onbinedyperlil idemiaFCHI).hi s s an autosomal

dorninant condition charactenzed bv moderate elevation inplasma LD L cholescerol nd trrgll.c erides, nd reduced plasmaHDL cholesterol. ft is the most commol primary lipid disorder,occurnng rn =1/200 people. No single metabolic aberration hasbeen identilied linking FCHL wich atherogenesis, but it is rvelldocumented thac =20o/. of individuals who develop CHD bvo0 ' r o i aHe ha re FCHL . fam i l r h i s ru r ' ' , f p rem aru rehea r rdisease s t,vpically posrtrve; the formal diagnosis requir€s that atleasc $o lirsr-degree relatives have evidenceof one of three r.an-anrs of dvslipidemia: (1 ) >90th percentilepLasmaLD L choles-rerol; (2 ) >90th percentiLe-DL cholesterol nd trigll icerides; nd(3) >90tb percentile rngl,vcerides. Individuals su.irch from one

phenotype to another. Xanthomas are not a feature of FCHL.Elevated plasma apoB levelsrvith increasedsmall dense LDL par-

t icles support the diagnosis.

Chrldren and adults with FCHL have co existing adiposi4.,

hypertension, and h,vperinsulinemia, suggesting the presence ofthe metabolic syndrome. Formal diagnosis of this multipler s,vn-drome as defined bv the NCEP's Adulr Treatment Panel III {ATPIII) idenrifres six major components: abdominal obesicl', athero-genic dyslipidemia, h1'pertension, insulin resistance w.ith orwirhour impaired glucose olerance,evrdence f vascular nflam-mation, and hvpercoaguabiliry t is escimatedhar 30% of overweight adults fuliill criteria for rhe diagnosis of metabolicsyndrome, including rwo rhirds of those rvith FCHL. Hispanicsan d South Asians from rhe Indian subcontinentare especially\ u \ cep th le .

The mechanisms associating visceral adiposity with che nera-bolic s,vndnrmeand type II diaberes are not full,v understood. Aplausrble unifying principal is that obesiry causes endoplasmictetrculum scress, eading to suppression of insulin receptor sig-naling and thus insulin resiscanceand heightened inflammatoryresponse. Hor,! thi s relaces to atherogenesis is unclear lt rsassumed that hypcrcholesterolemia and, rvith less certainty,h-vpertrigl;-ceridenia confer risk for cardiovascular disease inpatients wrth FCHL. When features of rhe metabolic syndromeare ncluded in logistic modelssharedenologrc earuressuch asincreased isceraladiposir,v ecomeapparent.Visceraladrposityincreaseswith age and its importance in chrldren as a risk facrorfor heart disease nd diabetes s Lmired by th e relative paucrtyofdara. Though longicudinalmeasurement f lvaist circumferenceand rhe presence f incra-abdomrnalat as decermined v MRI is

being conducred n tbe research etcng, body mass ndex (BMI)remains the surrogate for adipositv in the pediatric clinicalsertlne.

The metabolic syndrome is a dramatrc illustrarion of che nter-accion oI generics and rhe environmenc. Geletrc susceptibilit,v sessenrial s an exolanation tbr Drematureheart disease n ndi-

viduals rvith FCHL. Unhealthy lifesq,rle,poor diet, and physicalinactivity contribute ro obesitl and atrendant features oi themetabolic syndrome,

The cornersconeof management is lifesc_vlemodificatron. Thisincludesa diet low rn saturated ats, trans fats, and cholesterol,as well as reduced consumption of sirnple sugars- Increaseddietary rnrake of fruits and vegetables s importanr, as rs t hr ofmoderate phvsical accivitv darly. Compliance among children and

their parents is ofcen a problem, but small incremencal stepmore likely to succeed han agglessivew.eighcJoss rrategiesverv importanc that the child's caregivers partrcrpate inprocess.Plasma rrigl,vceride evels are usuall,vqurte responsidietary restriction, especially reducrion n the amount of srened dnnks consumed. Blood cholesterol levels mav decrea

Fanilial DysberalipoproteinerniaFDBL, ype ll Hyperlipopromia).FDBL is caused y mLrtationsn th e gene or apolipopr

E (apoE), rvhich when exposed co environmental influencesas high fat, high calonc diet, or excessrvealcohol inrake, rein a mixed rvpe of hvperlipidemia. Patients cend o have elevplasma cholesteroLand trigl,vcerides o a relativelv similar deHDL cholesrerol s rypically normal in conlras! !o orhet caof hvpetriglyceridemia associated u.ith low HDl,. This rareorder affecrs=1/10,000 persons-ApoE mediates emovaL f lomicron and \rLDL remnants from the circulation bv bindinheparrc uriace receptors- he poll m.rphic apof g"n" .*pr.in three isoforms: apoE3, apoE2, and apoE4. E4 is che "normallele present in the majority of rhe population. The a1isoform has lower affnic,v for the LDL receptor and its frequis =7%. About 1% of the population is homozygousapoE2/E2, che mosr common mutarion associated with FDbut onl,v a minority express rhe disease.Expression requires

crpitating iJlnesses uch as diabetes,obesity; renal drseashvpothyroidism. Indir.iduals homozygous lor apoE4/E4 arrr:k for l are-onset lzheimer disease.

\Iost parrencs .irh FDBL present n adulthood wirh distincxanthomas. Tuberoeruptive xanthomas resemble small grape

clusters on the knees, burtocks, and elbows. Promrnent orare l low d rsco lo ra t ion f the c rea ' e ' o l rhe hands pa lm arthomas) s also ypicallypresent.Atherosclerosis, ften presewith peripheral vascular disease,usuallv occurs in che 4rh ordecade,Children ma;''present u.ith a Less iscinctrve ash and erally have precipitatrng llnesses.

The diagnosis of FDBL is established by lipoproteJntrophoresis, r'hich demonsttates a broad beta band conrairemnant Lpoproteins.Direct measuremenr f VLDI- by ulcratrifugation can be performed in specialized ipid laboratorie

VLDL/total triglyceride ratro >0.30 supports the dragnosis. Agenotyping for apoE2 homozygosity can be performed, conling rhe diagnosis in rhe presenceof the distinctive ph1'sical

ings.A negative esuk does ro! necessarily ule out che disa \ o ther mura t ion \ in aF ' , f m av caL r \e \ en m ore semanilesrations.

PharmacoLoeic reacmenco1 FDBL is necessarv o decreasl i ke l ihood f . i rp ,o - rL ' . a the ro \ c le ro \ i sn aJu l r \ . HM C (

reductase nhrbitors,nicotinic acid, and f ibraresare all effecFDBL is quJrc esponsive o recommendeddietary rescrictio

HYPERTRIGIYCEBIDEMIAS.he familial disordersof crielvcer i ch l i pop ro te in , nc lude , r t hcommon and ra re v . r r ian r , lFrederickson classification sysrem. These include chylomicromi a (rype ), famrhalhypertriglyceridemiatvpe V) , and chem

severe combined h,vpertriglyceridemia and chylomicrone(t,vpeV). Hepatic lipase (HL) deficiency also resulrs Ln a simcombinedhyperlipidemia.

tamilial ChylonicronerniaType Hyperlipidemia}.hrs are sigenede lec t , i kc f am i l i a lh lpe rcho les t c ro lem ia ,' du r r ' , mtions a{fecting clearance o{ apoB-contaimng lipoproteins. Dciencv or absenceof lipoprotein lipase (LPL) or i ts cofaapoC-ll, which facilitates lipolvsis by LPL, causes severe elrion oi crigllceridenc h plasma chylomicrons.HD L choleslevelsare decreased. s clearance f theseparticJes s markdela,ved, he plasma is noted to have a rurbid appearanceafter prolonged asrrng Fig. 86-13). Ch,vlomrcronemiaauseLPL deficrency is associated wlrh modesr elevation in trigerides. u.hereasrhis is not the case vhen rhe cause is deficien



Chapter36 Deleclsn MetabolismfLipids

c\ac\! i\ c corrsLtrn|i{Jnoi io(1.1fr(l ()thcr !r 'cctcrlccl lr inkr,r i c ( ) 1 i1 r ( ) I lo en . ( )L ln f r r aop lc h ( r ( l . rnL L rpe rs izcdr iL

r r ru l rp l c 2 oz r ' r r r s i : t ce rcnc . l rL r jnk . . r i l r ' l cssenono f

l)r.r.f.c'()itcn resLrlrs]l drrnritre fa L rr rigl-vcerideevclsas

.' . i \ \ 'crghf l rrron!l hose who .trc oltcsc. lDL cLlrlcstcrol

\ \ r l f r nJ t o r i scas l \ ' l l s t aL r i l i zcs

l)cil irtr ic dise:rsesdssocirteJ *itI hvperlipidenri. inc

h r po th r o ic s r l , neph ro t i c v r r c i ro r r ra .i l i a rv a r res ia , l , v

\ror ,rtc diseirse,Nienrann-l\ck cliseitsc. .rv'Sechs liscitsc

fcl)ric lI l-\LrservtherndtosL]s! epanris, lrtcl artorcxie Lre

i l . r l , l L r> l { ) ) .( . c r reLnm ed ica r io rs cx i r ce rh r teh rpc r l i p rde r l r r , r c l r

rsorrerinoin ,Accutanci. hiezrLlc iur crics, ()r.t l cof frirccfrrcroidr, j3 blockers. rrrnrurlo\Lrppressi s. xnd pro

nhrl-.Ltorsse(l in th c trcaoncnr ol HI\ i

Ire.rrnrcnr f hyl-ertrgLr crirlcnri,r Lrchrlclrcrr ereh re(l

nrcrll. .rrioLrLrnless cvcLs >1.00() rri l, /dl-persist aftcr die

r.!tri! tr(nr of iars, sugars, 1nal .rfLroh\ rafes.accompaDi

incrc,r.cdphysicaL cti\ ' ltv. n \uch eascs. he airr rs to prc

.l-rr\orles f pdDcrextit is. he uornnton Lrsc f l ibratesan d n

rr r. lulrs u,irh hvpelniglr.endenria is rrot rccommended n

Llrcn H\' lCi (loA reclucrascrhrhrtori rre rcasonilbLy flect

Iruerrrrg tr ' igl,vcerrdeerels. rd thcrc is coLrsidcrlbl,v ore e

ncnec docuurcncing he sirtcrr rrrd cif icecv >f h is classof lorrcrin!, rneclicatiorrsn .hllJrcr

HcpaticLipase0elicrerrcy Hcpirric lrprsc rledciency s a r i l r . irrrrosomdl ecessrtecouclit ion caLrsing le\,ation D

t. i.r\nri cholesterol rn.i rri i{ lrccrJeJ. Hcparic lipaserrilr,r l,zcs rriglvcerides nc l phos]'holiprclsn Vlf)1, remn

r rnc l L )1 . , r cvcn t ing he i r o r \ c r \ i ( ) r rn r LDL . l l l ) 1 . cho le

lcrc s rcnd to be ucrelscLl . lrrher d1.1n ecreascd, uggesti

i l i lgnosrs. I-ahorarory conlifmafr()f lt ,- 'srablishedbt nreas

i l l : r c t i v i t yn hcpa r inLze r ll r sn r r

O ISORDLBSFHDTM ETABOISM

PflrnaryHypoalphirliproteireoriasoi:rtcclou HI)1. chole

s .r i. lrr i lr.r lcondit ion rhrt oircn follorvsa patterrrsullir,cs

ru:,rsoLD:rI omtnlnr ir lherrt.rnce ut lri]v occur indepc Llc

irrnrlr hrstorf. It is rh c nrosrcoDrnorr lisorcler f HDI- mc

li:nr k rs lefinecl isHDI cholcsrelrl <ll.)fh pcrccnlle lor gc

i - , ,1 - . r r i l lLlh plasr: ra orr prr ienr rrh rcute. rL ' .Lomi rr . i' . r rn l r r r r

l )Lrr r i rsrorr : )rsl i rrr. laerria- ; r rdJ l r l () l rra' l r l7 t j l l

a [ rscrr t a ] - . ( )C ll. Borh arc i rurosoLre l raccsslve aondi f l ()rr\ \ \ ' i !h i

f r c q u e n o o f - 1 . 1 1 . ( l ( 1 0 . 0 0 t 1 .I e d i s c a s eL r s L r i r l l \ r c r c r r r \ ( i L L r i n g

chrlclhoot l u' i th rrcute pirncrc.rt i r is. Fi rLLptJr'c anthorrri ts orr thc

i l r ls! k ccs, anLl L)L l r ( )a l (5 l l i t r l . )e prescnt . al1(l thcfc nr i l ! [r r

por tar l vcDoos s!src| l r rr] i l \ i lLrl lxrcrt ! olel f l t intake, i l r ld , l ( l l l l l l l

israrion of f ish oi ls r l r i r\ .1lso bc b encf icial

Fan i l i a t Hype r t r ig l ycenden r iaF l jTG, ype V l l ype r i i p idem ra '

l i {T ( i i s r r . l u tosom r j on r rnen t l i so r t le r f L r l l Lno$rc t io loS \ .

t L r i ch occLL rsn . - l . r . i i ) 0 nd iv idL r r l ; .r i . ch l rac t c r r zc . l' r l l c l r

t iorr oi pLasrrrarighcericlcs>' l(Jrh

l-.crccntilc2.5(l-l.0ll i) rrrq, 'ct l

(l .qcl. )ltcrracc()nrF;rrr;( ' { l'r . l jghr r' levarjon ll plasrllrr lolts

rerol rnd <>rv [)[-, l: ] l l( i docs rrot Lrslrellvna.llc\t Llnnl r(1L1ll

hoocl. hough ir 1scxprerse.l rr =10')i, ol eiiecrccL hllclrtn- lrr

collt fesf o F(-l l l , , l H'I (, is rror hought ttr bc highlr .rthcr )gcrrre-

It is rnosr ikely causecl rrd.ic.ri!c brcekdorvnof Vl L)l or less

degrcc relativc wirh h!pcrrrLgl\ ' . : tr idcmra.-HT(i shoLrld -'c lr.

Jisc,rse. hc cli ifcrentiation s r.rir l l)- ossrL.len cl i l ic l l sfotLnd\'

r r rha tLoucr I ) l - cbo lc ' t c ro l c rc l srccom p lnv l l f ( i . hL r r r c . r

su rc r re r t o i nonna I i ] l ( J l l e rc l r i n l t lT ( l rna - r . e hc l l - i L r l r r

levclsoi c rr lornicrons ls wcll es Vl-l)l l ' .rr ic lcs (ljreclcrcl'on

r lpc \ r ) r r r r \ occas io l l t b c c r t co r rn fe rcc l .r i g , l l ce r i . l cc rc l . . r r r '

o i t cn>1,000n rg / t l L . he , -1 isc , r res i r r . ' l v cen l ch l ld re r r 'r rco r r -

f r -as t( Jchv lo rn rc ro r rc rn i rl r cL l . r i . ks ( ) r r!Pc l ) , I l ' l - o r r l ( ) ( . l l

dcficiencl is ro r pfeseur Thc\e L..rtrcnrs ifcrl dcvcl{rPcrrrfr \r

x i l r f hon l r s r r ac lu l rhoo r l .hc r -casypc IV hvpe r t r t g ,hec r, l c r l l i , r

indivi,JLrlls lo no f Acure pirrcrc.rrit is nrt be dr e frc\cnfrrrsi l l ness .As w i th od rc r hypc r r ig l ' ce r rde rn i ' r \ ,xccss i \ c .1 l . oh ( ) l

c()nsul] lption ncl e.rr-ogcnLrcrilIr catl e\rccrbafc thc diseesc-

Secrrnclalv .rusc:oi rrltrsicrrrhvpertriglvccridertiir horrlt l tc

lu l cc lou t bc f i r r cn r i r kLng ( l rdc r r ( r s rsf tHT(1 . A c l i c rh igh i r r

criJenri.t. Adolcscerts iur! l adulrs rhoulcl bc qtrcstiorrcLllr()ttt

I {: . ?

HYPMCHOTTSTEROLEi$IA-lpctiyrcdrjmrrPlfr!r:i itni'cme

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588 PAnTX Melaboliciseases

and agewith normal plasmauiglyceridesand LDL cholesterol,r00hethert is assocrared ith more rapid athetosclerosiss uncer-tain. It appears o be related o a reduccion n apoA-I synthesisand ncreased atabolism f HDL. Secondary auses f low HDLcholesterol, uch as the metabolicsyndrome,and rare diseasessuch as LCAT deficiency nd Tangierdiseasemust be ruled out.

FamilialHyperalphalipoproteinemia.his is an unusual condi-tior conferrirg deceasedisk for CHD among amily members.Plasma evelsof HDL cholescerol xceed80 mddl.

Familial poA-lOeficiency.uration\ n rh eapoA-l genemay

result n complere bsence f plasmaHDL. NascentHDL is pro-duced in the liver and small intestine.Free cholesterol romperipheral cells is escerified y LCAT, enabling formation ofmarureHDL particles.ApoA-I is required or normal enzymaricfunctioningof LCAT. The resultantacctrmulation f free choles-terol m rhe circulation eventually eads to corneal opacities,planarxanthomas, ndprematureatherosclerosis.omepatients,however, ay havemurationsof 4poA-1 hat result n very rapidcatabolism of the protein not associatedwith atherogenesrs,despiteHDL cholesterolevels n the 15-30 mg/dl range.

TangicrDisease.This is an autosomal co-dominanr diseaseassociated rth levelsof HDL cholesterol 5 mgldL- t is causedby mutations n ABCAI, a protein thar facil itares he binding ofcellular cholesrerol o apoA-L This results rn free cholesterolaccumulation n the reticuloendothelial ystemmanifestedbytonsillar hypertrophy of a distinccive orange colo! andhepatosplenomegaly,ntermittenr peripheral neuropathy mayoccur from cholesterol ccumulation n Schwann ells.Diaeno-si sshouldbe suspectedn childrenwirh enlarged range onsil*and extremely ow HDL cholesterolevels.

FamilialLecirhin-GholesterolcyhransteraseIGAT)Deficiency.Mutations affectrng CAT interferewith theesterification f cho-lesterol, berebypreventing ormation of mature HDL partrcles.Thrs is associated ith rapid catabolismof apoA-I. Free circu-lating cholesteroln the plasma s greatly ncreased, h ich leadsto corneal opaciries and HDL cholesterol evels <10 mgldl,PartialLCAT deficrencys known as"fish-eye"disease, ompletedeficiency auses emolyticanemiaand progressiveenal nsuffl-ciency early in adulthood. Thrs rare disease s not thought rocause premature atherosclerosis. aboratory confrrmation is

based n demonstration { decreasedholesterol sterificationnrlreprasma.

Cholesteryl stelTranslerProtein CETPI efciency.Mutationsinvolving the CETP geneare localized o chromosome16y21.CETP facilitates he transfer of lipoproteins rom mature HDLro and from VLDL and chylomi-ron anicles.hus ulrimatelyregulating he rateof choles terol ranspon to the iver for excre-tion in the bile.About half of matureHDL2 particlesare directlyremoved rom the circulationby HDL receptorson the surfaceof the iver.The other half of cholesteryl stersn the coreof HDLexchangewith triglycerides n the core of apoB lipoproteins(VLDL, IDL, LDL) for transport o the liver Homozygousdeli-ciencyof CETP has beenobserved n subsets f the Japanesepopulation with extremely high HDL cholesterol levels(>150meidL).

GONDlTlOlls SS0CIATEDITH OW GHOIESTER0t.isordersofapoB-conrarning lipoproteins and intracellular cholesterolmetabolismare associated ith low plasmacholesterol.

Ahetalipoproteinemia.his rare autosomal ecessive iseasescaused y rnutations n thegeneencodingmicrosomal riglyceridetransferprotein necessaryor the cransfer f lipids o nascent hy-lomicrons n thesmall ntestine nd VLDL in the iver Thisresultsin absence f chylomicrons, LDL, LDL, and apoB,and very owlevelsof plasmacholesterol nd triglycerides. at malabsorption,diarrhea,and failure to thrive present n early childhood. Sprn-ocerebellar egeneration,econdaryo viumin E deficiency, an-ifests n loss of deep endon reflexesprogressing o ataxia andlower extremiry spasticityby adulthood. Patientswirh abeta-

lipoproteinemiaalso acquire a progressive igmenled ednthy associated ith decreased ight and color vision and etual blindness. heneurologic ymproms nd retinopachymamistaken or Friedreichataxia. Differentiation rom Friedrataxia is suggested y the presence f malabsorptionand athoc;tosis on peripheralblood smear n abetalipoproteinMany of the clinicalmanifestations f the disease re a resumalabsorption f fat-soluble itamins,suchas vitaminsE, A,K. Early treatmentwith supplemental itamins,especiaJly, msignificantly slow the development of neurologrc sequVitamin E is normally ransported rom the small ntestine oliver by chylomicrons,where t is dependent n the endogeVLDL pathway for delivery nto the circulationand periphtissues. Parents of children with abetalipooroteinemiahnormalblood ipidan dapoB evels.

Fanilial Hypobetalipoproteinemia.amilial homozygoushybetalipoproteinemias associated ith symproms ery similathose f abetalipoproteinemia,ut the rnheritance attern s asomal co-dorninant.The diseases causedby mutations ngeneencoding poB-100 ynthesis.L i s disringuishableabetalipoproteinemian that heterozygous arentsof probahave plasma LDL cholesteroland apoB levels ess than normal.There are no symptomsor sequelae ssociated ithheterozygousondirion.

The selectivenability to secrere ooB-48 rom rhe small ntine resulls n a condition resemblingabetalipoproteinemhomozygous ypobetalipoproteinemia.ometimeseferred oAndersondisease,he failure of chylomicron absorptioncasteatorrhea nd fat-soluble itamin deficiency. he blood e"eapoB-100,derived rom normal hepatocyte ecretion,s norin this condition,

Smith+enlH)piE SyndmmeSLoS).Patientswith SLOSohave multiple congenital anomaliesand developmentaldcausedby low plasmacholesteroland accumulated recur(Tables 5-11 and 86-12).Familypedigree nalysis asreveits aucosomal ecessivenheritanceDattern. Mutations inDHCRT1t dehydrocholesrerol-A-educrase)ene esulr n dciencyof the mrcrosomal nzymeDHCR7, which is necessacompete he linal step n cholescerol ynthesis.t is not knowhy defecrsn cholesterol ynthesisesult n congenitalmal

mations,but as cholesterols a major componentof mvelin,n



CEI{TMLIERVIX'sYsT[TIkonralbe ypopla5iaEn rqedentride5Aqmesi5l Dlpusallo5um(ereb€lhrypopasiaHolopm5en(ephdly

CANDIOVASOI.ARAl',rrrventli(ularana

se(Undumtr seplaeh(t%tentuclu5rte 5u!llembranou5ertdolarpplalefeo

URINARYTNACTReMlypoplasiaf apLrsiaRenalord(aly5t!

fiydmnephrosisllreteclupcalion

GASTnotrT6TllllLHirschsprungi5ed5ePylofCeno5sReiBctofy5motifilyl:ho16lafi(ndondolenatcrogc55iveivelisedse

PUullot{AnYPulmonaryypoplasia

Abnomalbationfi.lDofttt{E

Adrenansuffrdenry

ko. Pad D, lLE R offmann f: nh€dl€i sodeE fdd?]ko bi6,nlh{n \AnpedidrE l:f\l,tl1l 111

somcrvhathigher frequency n Hispanicsand lolver Lrcideocc n

indrvidualsof Airican descenr.

vival rs unlikel,v 'ben the pLasma holesrerol evel s <20 g/dl.

Laborirtor-vneasutcment shoLrldbe performed bv ga chr,r

macography, s standard echniquesor lipoprotein assa-v cludc

-"naut.rrr" lt t oi cholesterolPrecursors, vhich na v vield ialsc

posit ive esult.N4ilder ases nay nor preseur nril late chiJd

Pheoorypic ariance anges r<)mmicrocephal,v.ardiacan d

malforniarion, an d ruult iplc organ sysrem ailure to onll

dysmorpbic teaturesand mild Jevelopmentaldelav Treacntenc

Chapter 6 r Defectsn Melabolism l Lipids

includes upplemental ictar-v holesrerol eg gvolk) and pr>ss

H\lC; CoA reductasenhibirion to pre!ert rhc svnthesis f ro

prccu15ors roximal to thc cnzyrnarrc lock.

DISOBDERSF NTRACELLUTARHOI.ESTEROLETABOLISM

Cerebro(endinousanthomatosis.his aLltosomal ecessivc

orrlcr presentschnically in latc adolescence vith tendon xa

fhorrls. cttaracts, an d progressrveneurodc.qenerarion.t

ceusedL-v issueaccumLrlation f bile acLd nternrediateshun

into cholestanoLesult ing rom nlutations rn the ecne fol ste

27 hrdrox,vlase. Ihrs enzymc s neccssarl or normal mirochclrral "nrhesis f bile acids Lr be iver.Early rcatmenrwirh ch

oJeoxrcholic acid reducescholesrerol cvels aLrdprevents

de-velopment f sy.rnptoms.

Wolman Diseaseand Choleslerol sterSl0rageDisease CE

Thcsc autosomal ecessive isordersare causedby lack of ly

sonralacid lipase,Afrer LD[- cbolesterol s incorPorated nto

cell bv endocytosis, r is deli"ered lo lvsosornesu'here ic

hydrol'zed b,v ysosomal ipase.Failure of hycLnrlvsis ecaus

conDlere absence f the enztme causes ccumularionof cho

teryl csters vvithin thc cells, Hepatosplenornegall, teacorr

aLrd arlure o thrive occur during early infancl, lcading ro de

hr , rhe age of 1y'r. ln CESD, a l ess severe orm rhrn Wolm

discasc, here s lou but derectable cid lipaseacrvicv,

Niernann-PickDisease ypeC'fhrs

is a disordcr of inrrace

Ier cholcstcrol transporf charac[erizcd b,v accuntulation.h r l c . r c r , ' l anJ ' ph rngon r t c l ' n n lh . ( cn t r J l nc r t ' , u t a

rcticuloendorhelial -vsten1s.eath froru this autosomal eces

ncurologic disease :suallyoccursbt adolescence.

||POPR0TE|N ATTERNSN CHILDRENND AD0LESCENTS-a

l l6- l i , derivedprimaril,v rorn the Lrpid ResearchClinics Po

lanon Studies,shoo.s thc disrnbution of Jipoproccin evel

Anencan youtb at various ages. btal plasma cholesterol

r.rpidh lionr a mean of 6i 3mg/dl ac birrh co a level appro

nrarcLr wice fhar by rhe end of the neonaral ptri ' rd. A v

gradu:rl r ise in cotal cholesterol evel occurs unfil puberty

rvhich rine the mean levcl reaches160 mg/dl, Total cholesr

falls cransicnrly uring pubertv. n malcs due to a snall decre

in HL)L cholesterol. nd in femalessecondar,vo a slight fal

LDL cholesterol.Blood cholesrerol e' .els rack rcasonably

as individuals age,High blood cholesterol ends o aggrega

fanilies. a reflecrion i eeneticaDd environmental nfluences

Ar :rcceptable oral iholesteroLanrong children and ado

cents is <170 mg/dl,; borderline is 170-199 mg/dl; and h

>200 Lr/dL. An acceprable DL cholesterol s <110 mg/dl; b

tof,i-oEilstUPoPnfiHil GflttxStTYP0PftorE0t0ttsrEflot

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168 181 r89116 r90 191

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590 PABTX. Metabolic iseases

derlJne110-129 mg/dl; and high >130 mg/dl.. HDL cholesterolshould be >40 mg/dl.

Bt00D GHOLESTER0ICREENINc. CEP's Expert Panelon BloodCholesrercl Levels n Children and Adolescenrs established suide-l i ne ' , o r cho le , , re ro l ea \u fem en rha r we rep r . rb l i shedn 199 l .The panel recommended a sele.tiue approach to screening basedon the follo\a1ng critena:

Saeenildren nd dolescentshore arcntrrgrandparenttave o(umentedoronaryarterydiseareeforche qe f55 r.

Screenheoffspringf a parcnt hohas eenoundo hav.a blood olegterolevel f>240mg/dt.

Smen(hildnnnd dole(entsforwhomfamilyhistoryr unobtainable,pattkuladythosewith

otherir* adors,

The American Academy oI Pedrarricsand rhe American HearrAssocration (AHA) have endorsed rhese criterra. Application ofthese criteria will result in the screenins of 2J7o of Americanyou lh . rep fe \en r ingho\e m os t r ke l l ro ha le a f am i l i a lba r i s o rtheir hypercholesterolemla. predicted 597" of children wirhelevated levels of blood cholesterol will avoid detecrion becauseof che ack of universal screening, and rherein lies the source of

>240 mgldL is considered by some to be coo insensirjve and dif-ficult to apply.

The rationale is basically sound, lhough admirredly the guide-lines are fraught rvith problems of compliance. lf familv his-rory of n'idespread premature arherosclerotic heart disease tsobtained, offspring are Jndeedat signilicandv greater risk of dys-lipidemia than children without such family' history..The converseapplies to children who do not fulfill criceria for screening; theyare not likely to have a suong genedc predisposition ro heartdisease. The 59% of children with hypercholesterolemia notde rec ted 1 l i n i . i an ' f o l l ow ing hegu ide l rnesre I i ke lv o haveonly modest elevacion of cholesterol due to environmental influ-ences such as diet and sedenrar)' lif€style. Pr imary preventionstrategies pplicable o the population as a whole include daily

physical activicyand a diet low in saturated ats. Children an dadolescents or whom there may be consideration of using cholesterol lowering medication rvill nearly always be correctly ident rFedb1 io l l ow rng u r ren r u ide l ine ' .

Early dragnosrsand treatment of individuals rvho are at risk ofpremature CHD becauseof genetic susceptibrliq is an importantpublic health strategl It is esrimated that no more than 2070 ofpeople with heterozygous familial hypercholesterolemia are diag-nosed,and <10% are being adequately reared. detailedstud_vfrorn the United K ingdom has established the cost-effectivenessof "cascade screenng," which means tracking and tesrrng amilymembers of FH probands. Ic is even more cost-effecti ve to screenvounger people becauseof more life y€ars gained attet preventrveffeatment.

It is well documented that many parents are unaware of their

o$.n cholesrerol levels, making the use of that criterion problem-atic. The evidence that cholesterol screening of children maycausepsychological harm to the child is less han compelling, asis the concern that universal screening mighc lead to overuse ofcholesterol lowering medrcation, The n'orrisome eprdemic ofchrldhood obesity, approaching 50% in some disadvantagedhigh risk populations, supports broader screening to identif).those with the metabohc syndrome- A fasting lipid profile rarhertban nonfasting total blood cholesterol measurement is indicaredif screening s beiog conducted becauseof obesity as a risk facror

not specrfy he age at which at-risk children should be tesred.Five

-yearsof age is a reasonable age !o screen since dietary intetven

tions for those children with hypercholesterolemia can be sapplied at chrsstage of neurodevelopment.

RISKASSESSMENTND TBEATMENT FHYPERTIPIOEMIArecommends nsk assessmen! ased on LDL choles ol levels86 -14 ) . he f o l l ou .up n te rva l nd m od i f i ca r ion d ie r s dmioed by the sevelry of dyslipidemra. Borderline hyperchterolemia {LDL 11,0-129 ngldLl should prompc iniriation ochild on the AHA Step I diet:

(aloriesonrum.dt at hooldot x(eed096ftotal(aloderonrumeder ay.(alorie!onqrmedr atlntedatshouldot xeed lD6ftotalcalorieter ay.Totalholcrterclntakehoold e initedo<300 g/dlper ay.

Instruction regarding avordance of other risk lactors for disease such as tobacco use should be provided. and the sh<'uldbe reevaluatedn I yr .

Persrstenceof elevated LDL cholesterol >130 ms/dL indicthe need or more comprehen\ile elaiudtion an life.rvle mf i ca t ion . H rs to ry and phys ica l exam rna r ion nd . rdd rIaborarory tests aimed at rulng out s€condar,v causehyperlipidemra seeTable 86-10) should be performed. Ofamily members should have blood cholesterol screening. I

LDL cholesterol level does not achieve the rmnimal eoa. | ]0 mgidl. the AHA Step l drer*hould be recommendeddiet allows lhe same average fat consumption of no more307" of total calories, bur restricts saturared Iats to <7-87toral alories and cholesrerol intake to <200 mg/day. Follollab c ts, meastrremenr of height and weight for the calculaof body mass ndex (BMI), and dieta._vhistory should be sculed at 3-6 mo intervals.

The 2004 revision of the NCEP ATP III raised rhe mrnacceptable eveLof HDL cholesterol from 35 mg/dL to 40 mgIf low HDL cholesrerol Js present, counseling directed rowweight management, tobacco avoidance, and daily physical aitv shor:ld be orovided.

No restricrion of fac or cholesterol is recommended for inf<2 yr of age becauseof rapid grorvth and development, espe

rnvolving he cenlral netvous systemand the possibil iq of doping failure to thrive. Overfeeding should be drscourahowever, as, increasingly, infants and toddlers are exceeu,'eight for height standards published by the U.S. CentersDisease Control and Prevention- The myth that "a bigger bis a healthier baby" persists.

of poor growth or compromised nutritional status. The prosrive, well-controJled Dietarv Irtervention Srudy in Child(DISC) compared chrldren consuming a low-far Step I diet sublectsconsuming che"Lrsual" dier, containing 33-34o/" ol ries as fat and 137. as saturated Iat. No differences betw

groups wlth regard to height, weight, micronurrients, or psylogic well being were observed. Children on the lor-fat dietlower LDL cholesterol levels.

The Commrtee on Nutrition oI the American AcademPediatrics suggests hat as children >2 yr consume fewer calofrom far. thev should ear more grain pi oducrr, {ruirs. regeralow-fat milk produclsr beans, ean meats, poultry, frsh, and oprotern-rich foods. Low-carbohydrate, high-fat diets becomepopular in th e lascdecadeas a means o achieveweredr.rction.Unlimiced fat intake is strongly discouraged, as s ustricted sugar and carbohYdrate consLlmption. Carbohvdrshould comprise --55% of calories, achieved b,v consumcomplex carbohydra!es such as pasta, cerrain vegetables, ptoes, e8umes,and whole grain cereals nd bread.



Chapter6 oelectsn Metabolisml tipids

BiskAssessmenlPosiliveamily istoryl Parentalig hBloodCholesterolr Premalure VD

l igurc l iL l1. l low chart of chssLi ical ion,

educatiol, .rnd f<,lli,w up oi chilclrenb.rsed n

l o r d e - s r ' l , n o o r o r e r l D l ." ' r ,

r , ' | l

levels.CVD, cardiovascular isease;HDL.

high'dcnsi t -!ipoprotcin. FrornVi lLrans CL .

HagmanLL, Danrcls R,er al : Cardbvascular

henkh io chi(dhoorl. Cir.:rlarr)" 1001i106:

1,+l-16t)

frozen vegctables rrd soupsshould be selected or l orv sodiurn

conrent,

the entjrc iamilv rarher fhan cn ildjvidual child -r\ regular irne

Th e rise n sedentar,vclrvity emong oLlryouth is conlributing

"lf low HDL cholesterols deiected, hen patientsshouldbe counseled egarding igarettesmoki

low saturated at diet,physicalactivity,and weighl management if overweighl).

tFor patients 10 yr old andwithLDL-C> 19 0mg/dL or >160 mg/dLwithaddit ional sk actor

diet does nol achieve he goal, hen pharmacologicntervention houldbe considered

hypertension,Thc Narional Associarion or Sport and Ph,

EdLrcatior NASPE) recommends hat children should acc

lare ar leasr 60 minutes of age-appropriate hysicalaclivit

nlost daysof rheweek. Extendedperiods >2 hr ) of daYtime

tivif\r are dlscouraged, s is >2 hr of televr sionand other f

of scrcen rme,DrugThelapy Tables 6-14 nd 86-151, he NCEP ExpercP

fo r rllhiidrenand Adolescents ecommends hat considerati

f ion, at leasr 6 mo, has not achieved herapeDticgoals

rherapvshould be considered vhen:

' LDLholesterolcmains190mg/dl'LDLdole(erolremains>16{mg/dLandthereitaPotit ivefemi

di0va(ulariseareCVD)before5 tofage t wo rmore thet sk adolsot

presentfler igorourttempttt ifestyl. odif(ation.

Thesearbitrarv but sensible uldelines re basedo[ lhe s

Repeat ipoprotein nalysis

wilhin5 yr .Provideeducationon recommendedeatingpatternandrisk actor reduction.

Repeatlipoproteinanalysisandaverageprevrousmeasurements

Risk actor advicelProvideSlep-OneDiet andother risk actor nterventioRe-evaluate tatus n one y

Doclinical valuationhistphysical xam,ab ests). Evaluateorsecondarycauses.

. Evaluateor amilial isorScreen ll amilymembersIntensivelinicalntervenStep-One,henStep-TwoSetgoalLDLcholesterol:. Minimal:13 0mg/dL. ldea l : 110mg/d l



59 2 PABTX Metaboliciseases

MECIIANISMFAOION

|1MCoA cduxa!enhibftoE5tarn5)

Bie (d5eq,testants:

iiole5lranine[ohntpc

l,icclnac

ii|ft arid edvt,ve5:6emfbroz

F 5 h o 5

ft ohnerc biorptionnhrbit|)|l

fuelamibe

t!l-lowenriuxp'olantLfL,0rrft pa5e,iG,Iq}teide]VtDt,lrrylowdmsirypDler

ar e encouDtered nd family hi story oi early cor-onarv iseasc sprevalenr-

Corsiderable experienccwith drug therapl. rn childrcn an d

cacy. D fhe pasr. rhe mainst; lv of drug rherapl wa s bile asequcstrarttsLrch s cholesFralnincan d cholesripolbecaLlsehrverenot sysrcrr icalll ' rhsorLred.rterruption of the enrerohepcrrcLrlatiorr i Lri]e crds promotessvDrhesisn thc lir.cr oi nbile:rcicls ronr cholesterol.Gastroinrcstinal ide eff icrs and tefe\ultcd in less han desirable ornplrance. \ren vheD here ,t eu . v iab le p rons .

HN'lG CoA rerluctasenhibrtors,knorvn as statins,are rcma

abl,v cifecrive n lorvering LD[, cholcsrcrol evelsand rcducplaque nflanlmation, hereb,vcducilg rhe ikelihood of a sudcoronery event iLr an at-risk adult lr ' irhirr u,eeksof srart ingmedication. As a class, hey u'ork I ' t blocking the intrahcpbiosynthcsis l cholesrerol, herebvstimullt ing th e proclucrionlote Lf)L recel)rors n thc ccll lLlrface.The N(IEP ATP accafes rllgrcssivc orvcring ol l-DL ro <70 rng/cll in indiviclurvith knowr coronary he:rrtdiscese. his informarion is rclcrbecause hildrcn u'ho iulf i l l crrterra or considcratron f choterol lowering rnedicanon \rll allnost alwai,s hrvc inheflreclcondrfi(u ironr ()ne pnrcnr Not urfrequentll ' , vhcn pro"idicare or l l1echild. questjons o re up abont screening ncl rcment of parentsor grandparcnts.Statinsare equallv cficccivchildren,capableof lou'ering -DI cholesterol evels ,r half wlnecessar,v.hey also effect nlodesr eduction n rrigl,vccridcs

incortsistent ncrcase in HI)l cholesrerol. Sratins have beshown to impr(rve ntirne-nrcrlia hickness n crrotid irrterie

failLrre, hould bc rakcn nto considerationbcforc prescribiDgdrug. Thcre has beel no evidence o datc, ho,"vever,har compcatrons are aLr,v nore lrcqucnt in children than in adLrlts. skeLeralnrLrscle iscorriort seens r() bc sornervhat ess ofproblern.Stiltrnsare concraindicarcdn pdtienrs vith acti!c l i( l lsease nd during prcgnarrcvalrd lactarion. Childrerr shohave liver enzyrnes lolirored rcgularll, anclcreatirc plr(rsphinasc (CPK) measnred i musclc ache or weakness ccurs I iverzv rcscar be allowed o rise rhreeioldbcfore discolt inuing drug. It should be reernphasizedhr r children rvirh nroclcst vations n cholesrer()1,Lrch s that sccn n polvgelic h_vper

lcstcrolemia, re nor candidates or stetins as a rule becausthcir sideeffet profile.

()thcr cholescerolou'eringmedicariols such as r'r icofurrc ancl f ibrareshave heen used ar lcssoften iu chrlt lrer thrn bacid scqucstrants nd stxtins-Nicorinic acid has been usecl etivcly in children u'rth rrarked hvpcrtriglycendeLria r risk facute pancrearif is, holgh dictary resfrlcrionof complcx srrgand cirri)oh)drates usrrallv resulrs in signif icant lo,,verugrriglycericle er.cls.

F.zctjnibe s useful n the pediirtricpopularron beceuscof ei6cacr' an d lo w side effect pro6le. F-zctirnibc educes plasl. l)t- cholesrerol v bloci. ingsrerolabsorprion n elteroc,vtes.drrrg,s nratketecl s an adjuLlct t) starins$,hen adulr subjectsnor achievingsuff icienrblood lipJd orrerirrg \, ith stauns rlo

Jt eiterolandV|DLrynthesis1|1 ar|( IL c(eflcBTB andexrrelon

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J lnrcninab5orptio[hr] 5lerol

['lDt(ATt0t{

tlevated0l

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!levared16

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te,/atedDL

STARTTD

5-80 q qh

4-12 Ca'5 4C l aJrl]2,000

600 q d

I 10 aail

lC |rg aily

DRUGftD|lE nIYPEr FfE(T frrfi

sIAT[iSikn RarhNervo!5y5iern

Lver

GJ$mintea r,r(lMus(5

lmmune5y5temPmteinindrng

Lcssf oftentorioi,rep Ltudaia, ead&he,enpheral

neilr0pa(ny

Hepilil,lo55bppetiie,wehlcsr nd roeaie5iI serum'"l rotrdrrhras.\_0,^4Io 'periffer,' .ppq n o[_1"ncmallan!le

Ab0ofitlndld ,mii5ea,iairhea

4(5aled cfwedknel5,yorri5u5Lralyrth er,Jinleatine

i{nase 1,000/L),habdrrny0y5w th |rnaurlure

Lupu5likendromeol/artatn,5"r!ana1rn,0rl!va5ta)

Dir i fpd i l l T 0f ! "drr L! 'd\ ldrr., r :a : r. l i lvd'rdrnl

BITIA(IFBINDINGESIIIS

l;astroleii0a ra( Abdomnalfulns5s,nau5ea,tlas,(on(ipaton,hemo4hoidl,anaistLrre,tiatlo aid!e( tul1ltdmi0 hedbsorlii0nfyiiirnin n hiden

M d\p _ro-1rorrJr ' 'p ldep,dlrol ! i ; th,dn[eerdb".c

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Flu5hrng,drykin, rur{1r5,(hthyosis,rantho5i5iqr n!

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Na5arJIufline5l

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nterfercncev/nhindinqfwarldnn,qu nq edudronn l.e

dosefwdrfariny 10%

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Largeclinical rials of ezet imibe sedasmonotherapyn children

havi not beenconducted. everthelessherearesufficient eports

in the iteraturedocumenting he impressive ffectivenessf this

medicationu'iihout worrisomesideeffects hat the cliniciancan

<L30 mg/dl or, more deally,<110 mg/dl. There s no reason o

push LDL levels ower as s recommendedor high-riskadults'

2004tl60421429

De lonsh \, Os e L, sramosi . et i l : f f fcacy an d safewof ' tat in therapv n

.ttitai.n wirh familial hvpercholesterolemia. Crcularion

2002;1Q6:2231-2237.

DemerathE, Muratova V SpanglerE, et al: School-based besitvscreeningn

ral Appalachia.Preu Med 2003;37.553-560.

Durringron P, Dyslipidaemia.Lancet 2003;362:717 37

coldberg AC, Aditi S, JLL, et at: Effcacy and safetyof ezecimibe oadminis-

teredwith simvastarinn Pati€nrswirh Primary hyPercholesterolemia: ran-

domized, double-blind, placebo controtted vl:.l Mavo Clift Pto'

20O4t79:520-629

crundv SN{. Hansen B, Srnith SC, er al: Clinrcal managemenroI metabolic

syndrome:ReporcoI rhe AmericanHeart Association4'{anonalHeart, LunB,

Itlood Instrtute/American Diabetes Association Conferenceon kientific

IssuesRelatedro ManagemerJ:.Circul|tioll 2004;109:551-556

H ins PN, Heiss G. Ellison C, et al: Coronary arrerv disease isk in famil-

cornbrned hyper)ipidemia and famitiat hvP€rtriglyceridemia,A case

control comparison irom the National Hean, Lung, and Blood Insricure

Gmet 2004;66:483487.

Merkens LS, Connor WE, Linck LM, et at: Effecrsof dietarl cholesterolon

plasma lipoproterns in Smith-l€mli-OPitz syn&ome Pediat Res

2O04l,56:726-72.

Raitakari OT: Arrerial abnormalities in children with familial hvpercholes-

ftrcmi?, Lan et 2004\363:342-343Sinshal A, Cole TJ, Feffir€ll M, et al: Breast milk feeding and lipoProrcin

profile in adolescents orn pretermr Follow up of a prospective andornized

st)d\. Lan et 2O04i363,1571-15 8.

wiesman A, Hult€n BA, de Groot E, et al: Effcacy and safetvoI stat rherapv

in children wrth familial hypercholesterolemia fAMA 2004;292: 1-331

86.4.LlPlDosEs.argaret . McGovernndBobert , Desnick

fhe lvsosomalipid storage iseasesre diverse rsordersac h

du e o a n inheriLede6ciincy f a lysosomal ydrolaseeadingto che ysosomalaccumulationof the enzyme's articular sub_

strate iable 85-15).With the excePrion f Wolmandisease nd

cholesterolester storagedisease, he lipid substrates hare a

common structure hat includesa ceramidebackbone 2-N-acyl-

.ohineosine)ro mwhich hevarrous phingolipidsrederived y

subrriuLion f hexose",horphorylcholine.r oneor moresiahc

acid residueson the terminal hydroxyl gror:p of the ceramide

Chaderm . oefectsn Metabolisrnl Lipids 5

alterationsand characteristic linical manifestations f rhe ip

storagedisorders see able 86-16).Progressiveysosomalaccmularion of glycosphrngolipidsn the cenrral neflous systeleads o neurodegeneradon,hereas toragen visceral ellsca

lead o organomegaly,keletalabnormahrres,ulmonary nliltr

tion, and other manifestations. he storageof a substrate n

specific issue s dependent n its normal distribution n thebodDiagnosticassaysor the identificationof affectedndividua

relyon the measurementf rhespectficnzymaric ctivit ' In is

lated leukocltes or cultured fibroblasts, For mosr disorde

carrier dentifrcatron nd prenataldiagnosis re available;a spcrfic iagnosissessentialo permrt enericounseling.he chacterization f thegeneshat encode hespecific nzymesequirfor sphingolipidmerabolismpermit the development f therpeuticoptions,suchas ecombinant nzyme eplacementheraas well as he potentialof gene herapy. dentilicationof specdisease-causingutations mproves iagnosis, rena!aldetectiand carrier dentificatron. or somedisorders Gaucherdrseait has beenpossible o make genotype-phenotypeorrelatiorhatpredicr iseaseeveriryndallowmorePreciseenetic ou

seling. nheritance s autosomal recessive xcep! for X linkFabrydisease.

GM1GAt{Gtt0SlD0SlS. M1 gangliosidosismost frequentlypr

sents n early nfancy (type 1 disease) r-rt as beendescribed

patientswith a juvenileonser type2). Both areautosomal ecsive raits; each esults rom the deficientactivity of F-galactdase,a lysosomalenzymeencodedby a geneon chromosom(3p21.33). lthough he disorder s characterizedy patholo

accumulation of GM1 gangliosidesn the lysosomesof bo

neural and visceral ells,GM1 ganglioside ccumulations mo

marked n the brain. n addrtron, eratansulfate,a mucopolys

charrde, ccumularesn lirer and rs excreted n the urineparientswith GM1 gangliosidosis. he p-galactosidaseeneh

been solatedand sequenced; utationscausingeither ype 1

rvpe2 disease ave been dentified.'iheclinical madfestationsof the infantile form of GM, ga

gliosidosis type 1 disease)may be evidenr n rhe newbornlrepatosplenomegaly, dema, and skin eruptions (angiok

atomata), t most tequentlypresentsn the 1st 6 mo of life wi

developmental elay ollowed by progressive sychomotot etadation and the onsetof tonic-clonrcseizures. wpical faciecharacterizedv low-ser ars, rontalbosring. depresseda

bridge, and abnormally ong philrrum. Up to 50% of paciehavea macular cherry ed spot. Hepatosplenomegalynd sketal abnormalities imilar o chose f the mucopolvsaccharidoincluding anterior beakingof the venebrae,enlargement f t

sella urcica,and thickeningof the calvarium,arepresent.By t

end of the 1st yr of life, most patientsare bhnd and deaf, wsevere eurologrcmpairrnent haracrerized y decerebrateigitv. Death usually occurs by 3-4 I'r of age.The juvenile-on

form of GM1 gangliosidosistype2) is clinically distinct, 'ithvariable age at olset, Affected parientspresentprimar y wneurologicsymptoms nclLrding taxia, dysarrhna,mental refdarion. ndspasticity. eterlorations slowipafienr(ma ysur\

chrough he 4th decadeof life. Theseparients ack the visceinvolvement. acial abnormalicies. nd skeletal eaturesseentype 1 disease. here rs no spec ific featment or either ormGM 1gangliosidosis,

The diagnosisof GM' gangliosidosis hould be suspecteinfanrs with typical clinical featuresand is confirmed by tdemonstrationof the deficiencyof p-galactosidase ctivrtyperipheral eukocytes r cultured skin fibroblascs.Orher disders that sharesomeof the featuresof the GM1 gangliosido

include Hurler disease mucopolysaccharidosisvpe I), I-cdisease,ndNiemann-PickiseaseNPD) yp eA, whrch anebe distinguished y rhe demonsrration f their specific nzymdeiiciencies.Carrrersof che disorder are detectedbv the msuremenrof the enzvmaticactrvitv n white blood cel ls or c



5S4 PABT Metabolic iseases

L+l

i+) +(+)

+ +

+ + +(+l

ft(]MEN(LATURE

MUOLIPIDOSTS

l urol ) o5e!,l r d5Ei ierlu.o d.r5i Llj5tudolr4e:

i uao $! ! t

SPtlll'lG0LlPlD0StS

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UPtDST0RAGEt50n0tnS

Nlerdnn(k lF L1=i&D)

!io man isea!e(p'cd |olir{n05,5,infdnthtrntayJox

f lantal('i0d pofLrnir ,h:e iinte(lanskl

Be5rhlr! i5[y)

a?r0 ipofL.(,(r .iuvenieSpieFr?yef''rcqt)

Gmd polul rncrj . ;dri (r i j , fur/ j

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)[i ndErd ear?

l i r f t i51

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P lexcsarnida5aJAri I

(' u.c(ercbm5il.5.

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tur-e(lskin hhrobLastsr renatal dragnosis s rccourplishc.l by(leterlnination i thc cr)zvDa c acfir. it ,vn ctrlrurcd rrlr locr tes or.ho r io r i c \ r l l r -

I t i i 1 l l 1 , i t r i : r i r ' lS rL l l lS !5 he ( iN41 a rg l i l l s i c los . ' sc l rLch a r -Sachsdiscese rrrI Sandhoff discasc: lch risults irorn th(- Llcfictenc! ol [3hcrosarrriDiclase criv]tv end t hc 1r-sosorrelac(urlrLr|rLron r (i\ '12 galgiiosides, pirt iculir lr rr t rhe ccnnalnervoLrs s\stenl. Eorh disorders have becn ci.rssif ierl nt oirt i lrt i le-, jrLvenile.and adulf onser f i)frns barccion fre aqe atonset f lnd clinical fcanrres. B llerosaminicl;rsc ().cLlrs s ttv()isoz-vrues:B hcxosarnirrit lase, r,r 'hichs cornposcrl f ole u andon e l i s b nir, an.l B herosarninrclasel, rvhich hrr t.r,o J3 ub ,Lr ifs. F Hexosamiljr lasc dcficicncl esLrltsrom nrirr:rt iorrs th cn subul)itard causcs' lrri,Sirchs lisease,vhcre:rs rurrrrionsr tlre

B srbuLritgelc rcsult r the rle6cielc,v f both p lrcrosr lr inril:rscsA ald B :rnd ceuseSandhoff diseasc.Borh rre aLrfosonr.rlccc!silc rr:rits,u,rrh T.ry-Sachs iscascharrng a preclilccrion l rhe

.\rhkelazi jcwish popLrlunon,wherc rhc cerrier t iequcnr Lrour1/25

l\ '1ore han i(l rLrtarols have beel iclentif iedi t(rsr rre.r.rtcd rvirh rh c iLrfenriLcorurs oI cliseasc. hr.ec rrurr

irc.oLrnror >.lSll; of nrutarltalleles rnongAshkc az i ]crvisr crsof la.v-Sachs iscirsc.rclurlng one allclcassocrareclvrrlclrrlt olser forrr. \ ' f tLterLonshat carr se he subacutc rr chkrrnrs result i l enzy.nre)r()tcinswifh resi drLal nzrrrrrt ic at r ' , . t l r c I . \ , , " r r 1 ' . r ' r r c l r t c, , i r hh s r r t r r r . , l r , d ,

l)arcrts rvith rhe rlannlc form of Ta1'Sachs listaschrr..ical manilestations n rLriercyof loss ri not()r skll1s, ncrs(rrt le re.tction.and rllecularpaLloratrcl eti nal chcrrv red

isccTab le86 16) .A f iec t . ' Jn ianLs sua l l , ,l cve l rp o r rna l l4 j rno oi erc rvhcn decreased vc corltocl t1ldaD exi!,ftcsr.rrrlc cspor;c to noise thyperacusis) rc lroted.Macr-ocenor rssociared virh hvrJftrcephalus,rr y rlevelop. n rhe Lrol lr le. seiztrres equlrine rnlicorvu)sant rherapv dcvclop.rodegencratior s fclr ' rrlcss,wirh Jearh occltrlng by rhe ag



pNAcgal-a l -

l aNANA

Neuraminidaseceramide-------> gal- NAcgal

ChaflEr 6 r Dstoctsn Met.bolism l Lipids

B-Hexosaminidasei|ooarsS8ndhofi,and others)

- glc-ceramid€

Polysialogangliosides

PC-ceramide

Sphingomyelinase

Niemann-Pickisease

NANA

II

Gmgangliosideeuraninidase

*gal - glc-ceramide

Tal

I

Lactosylceramide-galactosidase

gangliosklosis,.abbe isease

Flgure 86-15. parhwaysin the maabolism of sphingolipids ound in nervous issues.The name of the eruyme caralyzingeach reaclion is given wrth the n

of the subsrrace credon. Inborn errors are depictedas bars crossingcbe eacdonsarrouts, ar'd the narneof the associated efect or deleccss Siven n lhe ne

6on. The gangliosidesare named eccording to che nomenclarureof Svennerholm.Anomeric configurations are gtven only ar the largest staning a compo

cal, gabc;s€] glc, glucose;NAcgal, N acerylgalactosamine; ANA, N-acetvlneuraminicacid; PC, phosphorvlcholine

or 5 yr. The iuvenile-onserorm initially presents ith alaxia and

dysaithriaand mayno! be associated ith a macula!cherryred

spo!.The clinical manifestations f Sandhoffdisease re similar to

A and B determination, ndeed, or Tay-Sachs isease, artrer

screening f all couplesn which at leastonemember s of Ashke-

naziJewishdescents recommended efore he nitiation of p

nancy o identifycouples t risk. Thesestudies anbe conduby the derermination f the levelof $-hexosaminidase acl

in peripheral eukocytes r plasma.Molecular studies o identhe exact molecular defect n enzymatically dendfied car

should also be performed o permit more specificdenrificaof carriers n the amily and o allow prenaul diagnosism atcouples by both enzymaticand genotypedeterminations

incidence f Tay-Sachs isease as beenmarkedlyreduceds

the introduction of carrierscreening rograms n the AshkeJewishpopulation.Newborn screeningmay bepossible y msuringspecific lycosphingolipidmarkers.

GAUCHERISEASE.his diseases a multisystemiciptdosiscacterized y hematologicproblems,organomegaly, nd skeinvolvement, rhe laner usually manifestingas bone pain



596 PARTX MotabolicDiseases

c r p p p pfuc- gal NAcglc- gal- glc ceramide

l " INAcgal

BloodgroupA glycosphingolipid

.t-galactosaminidaseq-galactosidase

NAcglc- gal-glc- ceramide

I etooosrouposty""-:-i,j::3

TI

-]jj"'""rT!I 8)

g-galactosidase

GMIgangliosidosis

GMa angliosidosis,ertainypes

d g pNANA gal-glc- ceramide

Pc-ceramide--_-_-] l--------------+-eramide F sphingosine fattyacid

Niemann-Pickisease IT",b", rseas"1

blood cells.Seealso the legend or Figure 86-15.

ga l NAcglc- gal- glc-ceramide

Trihexosylceramidea-galactosidase

Figure 86-16. Parhways n the degradarion of sphingolipids ound rn visceralorgans ,nd red or whirefucose;h-Acglc, -- acetylglucosamine.

juvenileor Norrbotcnian orm. All areaurosomal ecessiveraits.Type 1, which accou ts tor 99lo of cases, asa strikingpredilec-tion for Ashkenazi ews,with an ncidence f about 1/1,000anda carrrer requencyof 1/18.

Gaucherdiseaseesults rom the deficientactivrtvof the lvso-somalhydrolase, cid p-glucosidase, hich is encodedby a genelocatedon chromosome q21-q31.The enzymaticdefecr esuftsin the accumulation f undegraded lycolipid substrates, artic-ularly glucosylceramide,n cellsof the reticuloendolhelial ystem.This progressive eposition results n infiltration of the bonemarrow,progressive epatosplenomegaly,nd skeleral omplica-tions. Four mr:tadons-N370S, L444P, 84insG, and IVS2-account or =957o of mutanr allelesamong AshkenaziJewishpatients, ermittingscreeningor this disorder n this population.Genotvpe-phenotypeorrelations avebeennoted, providing hemolecular basis or che clinical heteroseneity een n Gaucherdiseaseype l. which has a wide rangeof ieverityand agearonset, Patientswho are homozygous or the N370S muration

Lactosylceramide-galactosidase

GM1 angliosidosis,rabbe isease

glc-ceramide

o p p p pfuc- gal- NAcglc- gal-glc- ceramide- - fuc-gal-

t ^

gal I Fabry iseaso

Blood roup glycosphingolipid

P . ' S PNAcAal- gal- gal-glc- ceramide

I cnmsroe

_Lq-hexosaminidaseand B

GM2 angliosidosisSandhoff) NAcglc gal- glc-ceramide

tend to have later onset, with a more indolent course tpatients with one copy of N370S and another common allel

Clinical maoifestations of type 1 Gaucher diseasehave a vable age at onset, from early childhood to late adulthood, w

most sympromatic patients presenting by adolescence.Atsentation, patients may have bruising from thrombocytopenchronic fatigue secondary to anemia, hepatomegaly withwithout elevated liver function test results, splenomegaly,bone pain, Occasional patie[ts have pulmonary involvementhe time of presentatron. Patients presenting in the 1st decadequently are not Jewish and have growth retardation and a mmalignant course. Other parients may be discovered fortuitouduring evaluation for other conditions or aspart of routine exinations; these patients may have a milder or even a bencourse. In symp[omatic padents, splenomegaly s progressive

can become massive, Most patients develop radiologic evideof skeletal involvemenr, includrng an Erlenmeyer flask defotmof the djsral femur.Clinrcallyapparenrbony involvemenr,wh

gal gal glc-ceramide--_ll--------------r-at- gtc-ceramide

GM 3 angliosideneuraminidase

Sphingomyelinase



Fisure 6-17. Cells rom hespleen f a pacient irh Gaucher isease. char-

acteristicpleen ell s shownengorged ith glucocerebroside.

lieence are normal.-Thepathologic hallmark of Gaucher diseases the Gaucher cell

in the reticuloendothelial system,particularly in the bone marrow

(Fig. 85-17). These cells, which are 20-100 pm in diameteq have

a characteristic wrinkled paper aPp€arance resulting from che

presenceof irltracltoplasmic substrate inclusions. The cytoplasm

of the Gaucher cell reacts strongly positively with the periodic

acid-Schiff stain. The presenceof this cell in bone martow and

tissue specimens s highly suggestiveof Gaucher disease,although

it also may be found in patients with granulocltic leukemia and

myeloma.

Gaucher disease ype 2 is much lesscommon and does not havean ethnic predilection. ft is characterized by a rapid neurodegen-

erative course with extensive visceral involvement arld dearh

within the 1st 2 yr of life. It presents in infancy wi th increased

tone, strabismus, and organomegaly. Failure to thrive and stridor

caused by laryngospasm are typical. After a several-year period

of psychomotor regression,death occurs secondary o respiratory

compromise. Gaucher disease type 3 presents as clinical mani-

Iestations that are intermediate [o those seen n rypes 1 and 2,

with presentation in childhood and death by age 10-15 yr. It has

a predilection for the Swedish Norrbottnian population, among

which the incidence is 1/50,000. Neurologic involvement is

present but occurs later and with decreased severiry compared

with type 2 disease.Type 3 disease s further classified as types

3a and 3b based on the extent of neurologic involvement and

whecher there is progressivemyotonia and dementia (rype 3a) orisolated supranuclear gaze palsy (type 3b).

Gaucher diseaseshould be considered in the diflerential diag-

nosis of parients with unexplained organomegaly, who bruise

easily, have bone pain, or have a combination of these conditions.

Bone marrow examination usually reveals the Presence of

Gaucher cells. All suspected diagnoses should be confirmed by

determination of the acid p-glucosidase activity in isolated leuko-

crtes or cultured fibroblasts. The identification of carriers can be

achieved by enzymatic assa5 wirh confirmation of results by mol-

ecular resting in most Jewish families. Testing should be offered

to all family members, keeping in mind that heterogeneity, even

among members of the same kindred, can be so gleat that non-

symptomatic affected individuals may be diagnosed. Prenatal

ChaDter6 D.tectsr ile{.holism fLipids

diagnosis s available by dererminationoI enzyme activitychorionic villi or culturedamniotic fluid cells,

Treatmentof patientswirh Gaucherdisease ype 1 incluenzyme eplacement herapy,with recombinanracid l3-gludase (imiglucerase).Most extraskeletal symptoms (orga

megaln hematologicndices)are reversed y an initial debulkdoseof enzyme 60 IU/tg) administered y intravenous nfusevery other week. Monthly maintenance nzyme replacemimprovesbone structure,decreasesonepain, and induces opensarory rowth n affected hildren.A smallnumberof patie

have undergone onemarrow transplantation,which is curabut results n significantmorbidity and mortality from the pcedure,making the selectionof appropriatecandidatesimiAlthough enzyme eplacement oesnot al ter the neurologicpgression f patientswith Gaucherdiseaseypes2 and 3, it beenused n selected atientsas a palliativemeasure, articulin type 3 patientswith severe isceral nvolvement.Alternatrealments,ncluding he useof agentsdesigned o decreassyrthesis of glucosylceramide y chemical inhibition of g

coslceramide ynthase, re being evaluatedand efforts are aunder way to developgene herapy or type 1 disease.

NEIMANI{-PICKISEASENPD}. he original descriptionof Nwas what i s now known as type A NPD, a fatal disordeinfancy characterized y failure to thrive, hepatosplenom

and a rapidly progressive eurodegenerativeourse hat leaddeath by 2-3 yr of age.Type B is a non-neuronopathic oobservedn childrenand adults.Type C is a neuronopathicothat results rom defective holesrerolransport.All the subtyare inherited as autosomal ecessiveraits and displavvariaclinical earuresse e able86-15).

NPD typesA and B result from the deficientacrivity of asphingomyelinase, lysosomalenzymeencodedby a genechromosome1(11p15.1-p15.4).heenzymaticefectesuthe pathologc accumulation f sphingomyelin, ceramide hpholipid, and other lipids in the monocyte-macrophageysthe primary pathologicsite.The progressive eposrtion f spgomyelin n the central nervoussysrem esults n the neurogenerative ou$e seen n type A, and in non-neural issue nsystemic iseasemanifestations f type B, includingprogres

lung diseasen someparients.The acid sphingomyelinaseensequenced, nd a varietyof mutations hat cause ypesA anNPD are known.

The clinical manifestationsand course of rype A NPDunrform and is characrerized y a normal appearance t b(ahhough rhe newborn period is sometirnes omplicatedprolonged jaundice). Hepatosplenomegaly,moderate lphadenopathn nd psychomotor etardationareevidentby 6of age, ollowed by neurodevelopmentalegression nd deat3 yr. Wirh advancing ge, he ossof motor function and he drioration of intellecrual apabilit ies reprogressively ebilitaand in later stages, pasdcityand rigidity are evrdent.Affeinfanrs oseconractwirh their environment. n con trast o stereotyped ype A phenotype, he clinical presentationcourseof patientswith type B disease re more variable. M

are diagnosedn rnfancyor childhood when enlargemenr fliver or spleen,or boch, s detectedduring a roucinephysexamination.At diagnosis, ype B NPD patientsusually hevidence f mild pulmonary nvolvement,usually detectedadiffuse reticular or finely nodular infiltration on the chest ograph, Pulmonarysymptonrs suallypresent n adults. n mpatients,hepatosplenomegalys particularlyprominent n chhood, but with increasing inear growth, the abdominalpr

berancedecreases nd becomes ess conspicuous, n miaffectedpatients, he splenomegaly ay not be noted until adhood, and rheremay be minimaldiseasemanifestations.

ln some ypeB parients, ecreasedulmonarydiffusioncauby alveolar nfiltration becomes vident n late childhoodor eadulthoodand progresses irh age.Severely ffected ndivid



598 PAnTXr Mebbolic Dise€ses

may experience significant pulmonary compromise by 15-20 yr

of age. Such pacientshave low PO2 values and dyspnea on exer-

tion. Life-threatening bronchopneumonras may occur, and cor

pulmonale has been described. Severely affected patients may

have liver involvement leading to life-threatening cirrhosis, portal

hypertensron, and asc ites, Clinicall,v significant pancytopenia due

to secondary hypersplenism may require partral or complete

splenectomy; this should be avoided if possible becausesplenec-

tomy frequently causesprogressron of pulmonary disease,which

can be life-threatening. In general, type B patients do not have

neurologic involvement and have a normal IQ. Some patientswirh type B diseasehave cherry red maculae or haloes and subtle

neurologic symptoms (peripheral neuropathy).

Type C NPD patients often present with prolonged neonatalyaundice, appear normal for 1-2 yr, and then experience a slowlvprogressive and variable neurodegeneratlve course. Their

hepatosplenornegaly s lesssevere han tbat of patients with types

A or B NPD, and the-v may survive into adulthood. The Lrnder-

lying biochemical defect in type C patients rs an abnormality rn

cholesterol t.ansport, leading to the accumulalion of sphin-gomyelin and cholesterol in their lysosomes and a secondaryparrial reducrion in acid sphingom,velinaseactivi!y (seeChapter

86 .3 .In type B NPD patients, splenomegaly is usually the 1st man

ifestation detected. The splenic enlargemenr is noted rn early

childhood; however, in l'ery mild disease, be enLargement ma,vbe subtle and deteccionmay be delayed untrl adolescence r adult-

hood. The presenceof the characceristic NPD cells in the bonemarrow aspirates supports the diagnosis of type B NPD. Parients

\.rth type C NPD, however, also have extensive inliltration of

NPD ceLls n the bone marrorv and, thus, all suspected cases

should be evaluated enzymatically to confrrm the clinical diag-

nosis by measuring rhe acid sphingomyelinase acrivity level in

peripheral leukoc,vtes,cultured fibroblasts, or lymphoblasts, or a

combination of rhesecells. Parients with tvpes A and B NPD have

m arked l l dec reasedeve ls l - l 0 " i , r . whe r iaspa r ien rs i rh rupe

C NPD have someu.hat decreasedacid sphingomyeJinaseactivi-

lies, The enzymatic identification of NPD carriers is problemaric.

In families rn which the specific molecular lesion has been identified, ho\a.ever, amily members can be accurately tested for het-

erozygote status by DNA analysis. Prenatal diagnosrs of types Aaod B NPD can be made reliably by the measurement of acid

sphingomvelinase activif_y rt cultured amniocytes or chorionic

villi; molecular analys is of fetal cells can provide the speci fic diag-

nosrs or serve as a confirmatory test. The clinical diagnosis ofqvpe C NPD can be supported by the demonstration of filipin

stain positivicy in cultured libroblasts and./or by idendfying a spe-

ci6c mutation in rh e NP C gene.

There is no specific treatmert for NPD. Orthotopic liver trans-plancation in an infant with type A disease and amniocrc cell

transplantation in several type B NPD patients have been

atrempted rvirh little or no success.Bone marrow ttansplantation

in a small number of trpe B NPD patients has been shown to be

successful n reducing rhe spleenand liver volumes, he sphin-gomyelin content of the liver, rhe number of Nlemann-Prck cells

in the marrow, and radiologically detected infiltration of thelungs. ln one patient, horveve! liver biops ies taken up to 33 mo

post transplantation showed only a moderate reduction in stored

sphingomyelin. To date, lung transplantat ion has not been per-

formed in any severelv compromised patient with cypeB disease,

although two patients who underweflt whole lung lavages with

variable results have been reported.

Future prospects or treatment of rrpe B disease nclude enzyme

replacemenr and gene therapy. Treatment of rypes A and C

disease s presently precluded by the severe neurologic involve-

ment,

FABRYDISEASE, his condition is an inborn error of glycosphin-

golipid netabolism characterized by angiokeratomas(relang-

rectatic skin lesions), hypohidrosis, corneal and lenticuLar op

nes! acroparesthesias,and vascular diseaseof the krdnel', he

and/or brain (seeTable 86-161. The drsease s an X-linked re

srve rart tha! is maflrfested n affected males and has an estimprevalence of =1/40,000 males, Later-onset affected males w

residual c-galactosidase A activity may present with car

and./or renal disease ncluding hyperrrophic cardiomyopathyrenal failure. Heterozvgous females for the classrcphelotype

be asymptomatic or as severely affecred as the males, the vabihtv due to random X-i[activation. The disease results f

the delicient activity of cr-galacosidase A, a lysosomal enzencoded by a gene ocated on the long arm of the X chromoso(Xq22). The enzymatic defecc eads to the systemic accumulaof neutral glycosphingolipids, primarily globocnaosylceramparticularly in the plasma and lysosomes of vascular endoth

tion, leading to the major diseasemanifestations. The CDNAgenomic sequences encoding c-galactosidase A have identimore than 200 differenr mutations in the d-galactosrdaseA g

that are responsible for this lysosomal storage disease, nclud

amrnoacid substitutrons, gene earrangements, and nRNA srng oetecls,

Affected males with the classicphenotype have the skin lesiacroparesthesias, hypohidrosis, and ocular changes, whe

males wrth the later onset phenotypes lack these frndingspresent with cardiac and/or renal drsease rn adulthood-classic angiokeratomas usually occur in childhood and ma,v

to early diagnosis, They increase n size and number wi rh age

range from barely visible to several mm in diameter The les

are puncta[er dark red to blue-black, and flat or slightly rai

They do not bJanch with pressure, and the larger ones may sh

shght hyperkeratosis. Characteristicall]', the lesions are m

dense between the umbilicus and knees, rn the "bathrng tru

area," but may occur anywhere, incLrding the olal mucosa.hips, thighs, buttocks, umbilicus, lower abdomen, scrotum,glans penis are common srfes, and there is a tendency towsymmetry. Variants without skin lesions have been describSweating is usuall y decreased or absent. Corneal opacitiescharacteristic lenticular lesions, observed under slit-lamp exa

nation, are present n affected males as well as n =707. of asl'tomahc heterozygotes. Conjunctir.al and retinal vasc

tortuosity is common and results from the systemic vasctnvolveme11t.

Pain is the most debilitating symptom in childhood and a

lescence. Fabry crises, lasting from minutes to several d

consist of agonizing, burning pain in the hands, feet, and pro

mal extremiries and are usuall,v associatedwith exercise, atigfever, or a combination of these facrors. These painful aparesthesias usually become less frequent in the 3rd anddecades of hfe, although in some men, they may become mfrequent and severe.Attacks of abdominal or flank pain may s

ulate appendicitis or renal colic.The major morbid symptoms result from the progres

involvement of the vascular system. Early tn the course of

disease, casts, red cells , and lipid inclusions with characterbirefringent "Maltese crosses" appear in che urinary sedim

Proteinuria, isosthenuria, and gradual deterioration of renal fu

tron and development of azotemia occur in the 2nd through

decades. Cardiovascular f indings may inc lude hvpenension,

ventricular hvpertroph,v, anginal chest parn, myocardral ischeor infarc tion, and heart failure. Mrrral rnsufficiency rs the m

common valvular lesion. Abnormal electrocardiographrcechocardiographic findings are common, Cerebrovascular mfestations result from multifocal small vessel nvolvement. Ot

features maf include chronic bronchit is and dyspnea, lyphedema of the legswithout hypoproteinemra, eprsodic diarrhosteoporosls, retarded growth, and delayed puberry Death m

often results ftom uremia or vascular diseaseofthe heart or br



Before hemodialysis or rena transplantation, the mean age at

death for affected rnen was 1yr' Later onset cardiac varianis

with resrdual u-galacrosidaseA activiry have cardiac diseaseand

may have mild proteinuria but usually have normal renal func -tion for age, Thi cardiac manifestations include hyperrrophy of

the left ventricular wall and interventricular septum, and elec-

trocardiog hic abnormalities consislent *ith cardiomyopach,v-

Others ha had hypertrophic cardiomyopathy or myocardial

angiokeracornasof the scrotum (Fordyce disease)or from angiok-

eratoma clrcumscriptum. Aogiokeratomas identlcal to lhose of

Fabry disease have been reported in fr.rcosidosis,asparryJgly-

cosaminuna! Iate-onsecGMr gangliosidosis, galactosialidosis, cr-

N-acetylgalactosaminidase deficienry, and sialidosis. Latel onse!

variants have been rdentified among chronic hemodialysis

pacients. Like the cardiac variants, these renal varianrs lack the

early classic manifestations such as the angiokeratomas, acro

paresthesias, vpohidrosis,and corneal opaclt ies The dragnosis

of classic and variant patients is confrrmed biochemicall,v by the

demonstrarron f markedly decreased t-galactosrdase activit,v

in plasma, isolated leukoryces, or cultured fibroblasts or

lymphoblasts.

Heterozygous iemales may h e corneal opacines, solated skrn

lesions, and intermediate activi s of cr-galactosidase in plasma

or cells. Rare female heterozvgotes may have manifestarions as

severe s rhose n aifectedmales.Asymptomatic at-rtsk females

in families affected by Fabry disease,however, should be opti-

mally diagnos by the direcr analysis of their family's specifrc

mutarion. Pre tal detection of aftected males can be accom

plished bv chedemonsrration of defrcient o-galactosidaseA activ-

ity or the family's specrfic Sene mutarion in chorionic villi

obtained in the ls! trimester or in cultured amniocltes obtained

by amnrocentesis n the 2nd rrimester of pregnancn Fabry disease

ca n potentidlly be dececred newborn screening.

Tieatment for Fabry drse was once nonspecific and limired

of 1mg/kg er.ery other week.

FUG0SlD0SlS.his is a rare autosomal ecessrve isordercaused

by the deficrent accivity of c fucosidase and the accumulation

oi fucose-containrng glycosphingolipids, glycoproteins, and

type, with the most severely affected patients presentng rn the

1st yr of life with developmental delav and somatic fearures

similar to those of the mucopol;rsaccharidoses.These features

rnclude frontal bossing, hepatosplenomegall', coarse facial fea-

tures, and macroglossra. The central nervous system storage

results in a relentless neurodegenerative course, with deach in

childhood- Patients lr'ith milder diseasehave angiokeratomas and

longer survrval, No specific therapv exisrs for the disorder, which

can be diagnosed bv the demonsrration of deficrent cr-fucosidase

activity in peripheral leukocytes or culcured fibroblasts. Carrier

Chatter 6 . Delscb n Metabolism l Lipids

identif ication rudies nd prenataldiagnosis repossible y d

mination of the enzymacic cciv ity.

SCHIN0tERDISEASE. his is an aLrtosomal ecessrve eurode

eratrve disorder that results from the defrcienr accivitv of

acetylgalactosaminidasend the accumulationof sialylate

asialoglycopeptidesnd oligosaccharidesse eTable 86-15)

gene for the enzyme is mapped to chromosome(,22913 1-1.3 2), The disease s clinically heterogeneous,and

major phenotypes have been dentr6ed. Type I disease s an mlile-onset neuroaxonal dystrophy. Affected infants have no

development for the 1st 9-15 mo of life followed b,va rapid

rodegenerarive course that resuhs in severe psychomotor r

daoon, corcical blindness, and frequent myoclonic seizures.

l[ drseases characterized y a variable age al onset!mrld r

dation, and angiokeratomas. There is no specific therapy

eicher form of the disorder, The diagnosis is by demonstr

of the enzymatic deficiency in leukocytes or culcured

fibroblasts-

METACHR0MATIC EUK0DYSTR0PHYMLD).This is an autos

recessivewhite matter disease caused by a deficiency of arv

fatase A (ASA), which is required for the hydrolvsis of sul

gl,vcosphmgolipids. Another form of MLD rs caused b,v a

cienc;r of a sphingolipid actrvator protein (SAP1), rvhirequired for che ormation of rhe subsffate enzyme complex

deEciency of this enzymatic activiry results in the white m

storage of sulfated glycosphingolipids, which leads to dem

nation and a neurodegenerativecourse. The ASA gene s on

mosome22 (22q13.31qter); pecif icmutations are knou'n t

inro rwo groups rhat corlelate with diseaseseverity,

The clinical manifestatiors of tbe late inlantile form o{ M

which is most common, usually presents between 12 and 1

of age as irritabilitJ', inabrlity to walk, and hyperextension o

knee, causinggenu recurvatum.Deep tendon reflexes re d

ished or absent. Gradual muscle wasting, weakn€ss! and h

tonia become evident and lead to a debilitated state. A

diseaseprogresses,nystagmus, myoclonic seizures,optic atro

an d quadriparesis ppear,wirh deach n the 1scdecade f lif

Table 86-16).Th e iuvenile orm of the disorderhas a more lent course with onset rhat may occur as late as 20 yr of age

form of the diseasepresencsas gait dJsturbances,mencal de

ration, urinary inconrinence, and emotionat di fiicultres. The

form, which presents after rhe 2nd decade, s similar to the

nile form in its clinical manifesrations, althou8h emotxtnal

culries and psychosis are more prominent features. Deme

seizures,diminished reflexes,and optic atrophy also occur in

rhe juvenile and adult forms. The pathologic hallmark of M

rs che deposition of metachromatic bodies, which stain str

positive with periodic acid-Schiff and alcian bLue, n rhe w

matter of the brain. Neuronal rnclusions may be seen n the

brain, pons, medulla, recina, and spinal cord; dem,velin

occurs in the peripheral nervous syslem. Bone marrolv t

plantation has resuhed in normal enzymatic levels in p

heral blood buc no clear evidence for clinical efficacy in of che neurologic coursei support ive care remains the pri

rntervenuon.

The diagnosis of MLD shor,rldbe suspected o patients wit

clnical fearures of leukodvs trophy. Decreasednerve condu

velocit ies, ncreased erebrospinal lui d protern, metachro

deposics n sampled segmentsof sural nerve, and metachro

granules n urinary sedrmenr re all suggestive f MLD. C

marion of rhe diaenosis is based on the demonstracion o

reducedactivity of ASA in leukocyces r culturedskin librob

Sphingolipid activaror protein deficiency is diagnosed by

suring the concentrauon of SAP1 in cultured fibroblasts us

specific antibody to the prorein. Carrier deteccion and pre

diaenosis is available for all (orms of the dtsorder.



m0 r PARTX MctabolicDiseases

MUITIPLESULF SE DEFICIENCY his is an autosomal recessivedisorder that results from the deficiency of three enzymaric acdv-ities: arlrlsulfatasesA, B, and C. Sulfat ides, mucopolysaccharides ,steroid sulfates, and gangliosides accumulate in the cerebralcortex and visceral tissues, resulting in a clinical phenotype withfeatures of leukodysrrophy as well as those of rhe mucopolysac-charidoses. Severe chthyosis may also occur. Carrier testng andprenatal diagnosis by measLrrement fthe enzymaric activities canbe performed. There is no specific treatmenr for multrple sulfa-tase deficrency other than supportive care.

KRABBE 0ISEASE. This condition, also called globord cellleukodysrrophn is an autosomal recessive fatal disorder ofinfancy. lt results from che deficiency of the enzymatic activity ofgalactocerebrosidaseand the whire matter accumulation of galac-

rosylceramide, which i s normally found almosr exclusively in chemyelin sheath. The galactocerebrosidasegene is on chromosome14 (14q31), and specif icdisease ausing mulalions are known.The infantile form of Krabbe disease s rapidly progressive andpatrerts present in early infancy wich irritabil ity, seizures, andhypertonia (seeTabJe85-16). Optic atrophy is evident n th e lstyr oI hfe, and mental development is severely impaired, As thediseaseprogresses,opcic arrophy and severe developmental delal'become apparent; affected children exhibit opisthotonos and die

before 3yr

of age. A second, ate infantile form of Krabbe diseasealso exisrs and patients present atter the ageof 2 ;'r Affected indi-viduals have a diseasecourse similar to thar of the earll, infantile

form. Bone marrow cransplantation has been attempted in severalpatrents wirh later onset disease but without signifrcanc results,Umbilical cord blood transplantation of presymptomatic parients

in the 1st 2 mo of life results in ensraftmenr and normal bloodgalactocerebrosldase evels. Developrnental milestones, cerebralmyelination, and cognitive funcrion up co 3 yr of age have beennear age-appropriate expectatrofls. Nonetheless, some patien!sdemonsrrate mild ro noderate language delays and mild to severegross motor deLavs.The diagnosis of Krabbe disease elies on thedemonstration of the specrficenzymaric defrciencv n u'hite blood.e l l s , , , r u l t u red k i n f ib rob las t r . a r r ie r den t i f i ca r ionnd pre-

natal diagnosis are available.

FABBER ISEASE. his is an aulosomal recessive isorder thatresults from the deficiency of the lysosomal enzyme ceramidase

and the accumulation of ceramide in various tissues, especiallyrhe joints. Symptoms can begin as early as the 1sr yr of life withpainful jornt srvellingand nodule formation (Fig. 85-18), whichrs sometimesdiagnosedas rheumatoid arrhrit is. As che diseaseprogresses, nodule or granulomatous formation on the vocalcords can lead to hoarsenessand breathing difficulties; failure tothrive is common, In some patients, moderate central nervoussystemdysfuncnon s presenr seeTable 86-16).Parientsmay dreof recurrent pneumonias in their leens; there is currently no spe-cific therap,v-The diagnosrs of this disorder should be suspectedin patienrs who have nodule formacion over the loints but noother lindings of rheumatojd arthritis. In such patrenrs, cerami-

dase activrt,vshould be determined in cultr-rredskin fibroblasts orwhite blood cel ls. Carrier deteccion and Drenatal diaqnosis areavailable.

WOIMANDISEASENDCHOI.ESTEROLSTERTOBAGEISEASE(CESD). hese are autosomal recessive ysosomal storage diseasesthat resulr from the deficiency of acid lipase and the accumula-non of cholesterol estersand triglycerides in hrstiocytrc foan cellsof most visceral organs. The gene for lysosomal acid lipase is onchromosome10 (10q24-q25). (/olmandiseases !he more severeclnical phenotlpe and is a fatal disorder of infanc,v.The clinicalfeatures of che disease become apDarert in the 1st rvk of life andinclude failure to thrive, relentliis vomiting, abdominal distention, steatorrhea,and hepatosplenomegaly see Table 86-16).

Figurc 86-18, Forerrm of an 18 rno old girl wich Farber disease.Note tpainful joint sweiling and the nodule formarion. The infanr rvassuspecte

having rheumatoid arthritis

There usr.rally s hyperliprdemia. Hepatic dysfunction and Iibrsis ma,v occur. Calcification of the adrenal glands is pathognmonic for the disorder. Death usuallv occurs wirhin 5 mo.

Cholesterol ester storase disease s a less severe disorder thmay not be dragnosed un;il adulrhood. Hepatomegaly can be tonly detecrable abnormaliq., but af fected individuals are at snificant risk for premature atherosclerosis. Adrenal calcilicatiois not a feature.

Diagnosis and carrier identification are based on measuriacid lipase actrvity rn leukocyresor cultured skin fibroblasts. Prnaral diagnos is depends on measunng decreasedeozyme levels

cultured chorionic villi or amniocytes. There is no speci6c heraavailable for either disorder, although pharmacologic agents suppress cholesterol synrhesrs, rn combination lvith cholestyrmine and diet modilication, have been used in patients with chlesterolescer toragedisease se eChapter 86.3).

Charrow J, Andenon HC, Kaplan P, et al, Enzyme replacemenr herapy a

monitorins for children wirh rvpe r Caucher d,sease:Consensus ecomendationsI Pediatr 2004;144:112 120.

Clark JTR: Naiiarive revier': Fabry disease.An lflten Med 2007;14

425433.

Desnick Rl, Brady R, Barranser J, er al: Iiabry disease,an under recogr z

multi systemic disorder: Experc recommendadans or diagnosis, mana

ment, and enzvme replacemenr therapy. Arz lnten Med 2003.13

t38-345.Elstein D, Abrahamov A. Hadas Hrlpern I, et al: Cauchcr's lisea,\e. dn

2001;358:324 37

Escolar ML, Poe N{D, ProvenzaleJM, et aL:Trarsplantarion of umbilicafcoblood in babies with inhntile Krabbet disease. N Ehgl I M

2005i20:2069-2080.

Johnsor V/G: The clinicat specrrum of hexosamrnidase eiciency diseaNewolosy 1981i3r tl4 53 1456.

Kaplan B And€rson HC, Kacena KA, YeeJD: rhe clinicaLand dcnograph

characrerisrics f nonncuronpathicGaucherdisease n 887 children ar dianosis Arch Pedidtl A.lolesc Med 20O6;16U603-608

Meikle PI, Ranien E. SimonsenH, et al, Nervborn screening or lvs(xomsrorage disorders: Clnical evalDation of a rrvo tier straregl Pedidr2004i114:909-916

Mistry PK, Abraharnov A: A practicalapproach ro diagnosisand manasem

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SchuchmanEH, Desnjck RJ, Types A and B Niemann Pick drsease n Scriver

CR. BeaudetAL, Sty rWS.er al leds)tThe Metabolic and Mole.ulat Bases

of lnherited Dsease, 8rh ed. New York, Mccraw Hill, 2001

Wilcox wR, BanjkazemiM, Guffon N, et al: Long rerm safetvand efficacvcf

enzyme replacement therapy for Fabry djsease. Am I Hun Cenel

20O4t7 ;65-74.

Chaplert r oelects r Metabolism l Carbohydrates 6

Carbohydrate synthesis and degradation provide the ener

required for mosr metabolic processes.The importanr carboh

drates include three monosaccharides-glucose, galactose, afructose-and a polysaccharide, glycogen. The relevant br

chemical pathways of these carbohydrates are shown in Figu

87-1. G|,rcose s the principal substrare of energy melabolism,

conrinuous source of glucose from dietary mtake, Sluconeogesrs, and glvcogenolvsis of glycogen maintarns normal blo

glucose levels. Metabolism of glucose generates adenos

triphosphate (ATP) via glycolysis (conversion of glucose or glyc

gerr o pyruvate), mitochondrral oxrdative phosphorylation (co

version of pyruvate to carbon dioxide and water), or bot

Dietary sources of glucose come from ingesting polysaccharid

primarrlv starch and disaccharides, including lacrose, maltos

and sucrose. Oral intake of elucose s rntermirtent and unreliab

Glucose made de novo from amino acids , primarily alanine (g

coneogenesis) contribures to maintarning the euglycemic sta

but this process requires time to be acrive. The breakdown hepatic glycogen provides the rapid release of glucose, whi

mainrains a constanc blood glucos€ concentratlon. Glycogen

also the primarv stored energy source rn muscle, providin

glucose for musc le activity during exercise. Galactose and fru

!ose are monosaccharides rhat provide fuel for cellular metab

lism; their role is less significanc than chat of glucose. Galacto

rs derived rom lactose galacrose glucose),which rs found

milk and milk pruducrs.Calactose s an imporrant energl 'our

rn rnfanrs, but i t is 1st merabolized ro glucose. Galactose (exog

nous or endogenously synthesized rom glucose) s also an impo

tant component for cenain glycolipids, glycoprotetns, a

glycosaminoglycans . The dietary sources of fructose are sucro

(fructose + glucose, sorbirol) and fructose itself, lvhich is fou

in fruits, vegetables,and honey.

Defects in glycogen metabolism rypically cause an accumution of glycogen in the tissues,hence rhe name g/lcogen stora

disease Table 87-1). Defects in gluconeogenesisor rhe glycoly

pathway, includng galacrose and fruccose metabolism, do n

resulc n an accumulation of glycogen (see Table 87-1). T

defects n pyruvare rnetabohsm in rhe parhv-ay of rhe conversi

of pyrr-:vate to carbon dioxide and water via mrtochondr

oxidarive phosphorylarion are more often associated rvirh lac

acidosisand some issueglycogenaccumulation.

87.1 Gr-vcocrr ToRAGETSEASESPriya .KishnanindYuan-Tsonghen

The disorders of glycogen metabolism, the glvcogen storage deases (GSDs). result from de6ciencies of various enzymes

transport proleins in the pachways of glycogen metabolism (

Fig. 87-1).The glycogen ound in thesedisorders s abnorma

quanrrq; quality, or borh. GSDs are calegonzed by numeric ryin accordance with the chronologrc order in which these en

matic defects lvere identified. This numeric classification is s

widely used, at leasr up ro number VlL The gJycogenstorage d

eases can also be class i6ed bv organ inr.olvement and clinic

manifestations into liver and muscle glycogenoses (see Ta

87-rJ.There are more than 12 forms of gl,vcogenoses,lucose

phosphatase eficiency type l), lysosomal acid cr-glucosideficiency type Il), debrancherdeliciency type III), and liv

86.5 Muc0LlPt0osEs.ar$aret . McGovernandRobert. Desnick

I-cell disease mucolipidosis II [MLl!) and pseudo-Hurler poly-

dystrophy (mucolipidosis III IML-IU) are biochemically related'

rare autosomal recessive disorders that share some clinical fea-

activities. The enzyme that catalyzes the lst step, the UDP-N-

enzymatic levels n cultured skin fibroblasts. Direct measuremenc

of the phosphotransferase accivitv is possible. Prenatal diagnosis

and carrier identificaoon studies are available for both disorders

by measurenent of lysosomal enzymaric activities rn cultured

cells. Neonatal screening by tandem mass spectroscopy may

detect -cell disease.

l-CEtt DISEASE. his disorder shares many of the clinical mani-

festations of Hurler syndrome, although there is no mucopolysac-

chariduriaand the presentadon s earlier seeTable 86-16).Some

parienls ave clinical features evident ar birth, including coarse

facial fe ures, craoiofacral abnormalities, restricted joint move-

ment, and hypotonia. Nonimmune h1'dropsmay be present n the

fetus. The remainder of patients present in the 1sr yr wich severe

psychomotor retardation, coarse facial features, and skeletal

manrfestations that include kyphoscoliosrs and a lumbar gibbus.

Parients may also have congeniral dislocation of t he hips, inguinal

hernias, and gingival hypenrophy. Progressive, severe psy-

chomotor retardation leads to death in earlt' childhood No

lreatment is available.

PSEUD0-HURtEFP0tYDYSTR0PHY- seudo-Hr-rrlerpolydystrophy

is a less severe disorder than I-cell disease,with later onset and

survival to adulchood reported. Affected children may present

around the age of 4 or 5 yr wich joint stiffness and short starure.

ings include corneal clouding, retinopathy, and astigmatism;

visual complaints are uflcommon (see Table 85-15). Some

patients have learning disabilities or mefltal retardation. Treat-

menr, which should include orthopedrc care, is symptomaric.



\

Debrancher

./'o*' Galactos€

l l - - -__-_-- . - - - , - -_-_-- -

1-P Uridvl Enslerase

t+ Phosphohexoseisomerase

{otc-o ase

Glucose Fruclose_1,6+J phosphotrucbkrnaseotpnospna€se r

F-1,.6-P, F-1-P<- Fructl l

Aldoiase 5.\G lyceraldehyde 'l Aldolaser - '

Glyceraldehyde-3-P- Dihydrcxyacelone-P

tlPhosphotrioseisomerase

ll Glyceraldehyde-3-Pehydrooenas€

l,3.Bisphosphoglycerale

f{ ehosphostycerate inase

3-Phosphogiycerate

llPhosphoglycerate utase

2-Phosphoglycerat€

1+ Enoiase

Phospho€nolpyruvale

I Pyruvate imse

I Lactaledehydrog€nas€Pytvale . . _ Laclale----Z'-\-

GSa=z csb

UDP-Glc

6m r PABTXT Metabolic iseases

phosphorylase kinase deficiency (t-'-pe X) are the most common

that rypicallv presenr n early childhood; myophosphorylase de6-

ciency (type V, McArdle disease) s the most common in adoles-

cenrs and adults. The frequenc,vof all forms of GSD is =1/20,000

live births.

TIVERTYCOGENOSES

The GSDs rhat principally affect the liver include glucose-5-phospharase deficiency (type I), dehranching enzvme deficiency(type Ill), branching enzvme deliciency (t,vpe V), liver phospho-

rvlase delicienc,v t),pe VI), phosphorylase kinase deficiency (type

IX, tbrmerly rermed GSD VIa), glycogen s,vnrherasedelicienc,v(type 0), and glucose transporter-2 defect. Because heparic car-

boh,vdrare merabohsm is responsible for plasma glucose home-

oscasis, rhis group of disorders typically causes fasting

hypogl,vcemiaand hepatomegalv. Some(rvpe III, tvpe IV, tvpe IX)

caD be associaredu.ith crrrhosis- Other organs can also be

fiBure E7 t- Parhlvav elated ogen storagedlseases nd galacto

tructose disorders GSa, aclivegen synrhetase;CSb, inactLvefl,vsvntherase;Pa! actLvephospho

Pb, nactive phosphorylase; 'aI.

phorylase a phosphatase;Pb(a.

phosphorylase kinase;PbKb, in

phosphor,vlase kinase; G, gly

rhe primer for glrogen synrhesi

uridine diphospharc; CLUT-2, g

rransporrer 2; NADA,'ADH, nnamide-adenrnedrnucleotide (

fied from Beauder AR: Gly

slorage disease n IsselbacherKl

lcdsl Haltison s PtinctpLes f In

Medi.ine, 13th ed. \ew

McGraw-Hill, 1994 Rcprcduce

permission ot The McGrar

Companies.)

involved and may manifest as renal dvsfunction in type Imyopathy (skeletal and/or cardiomyopathy) rn types Ill an

as rvell as in some rare forms of phosphorylase kinase deficr

TYPE GLYCOGENTORAGEISEASEGLUCOSE,6"PHO

0RTRANSL0CASEEFICIENCY,ONGIEBKEISEASEI.vpei . causedhv rhe absence r deficiencroi gluco'e-o-ph,r'ph

activity in the liver, kidney, and intestinal mucosa. It cadivided inro trvo subtypes: type Ia, in vr'hich the gluco

phosphataseenzyme is defeccive;and rype Ib, in u'hich a tra

case that transports glucose-5-phosphate across the microsomembrane is defeccive.The defects in both tvpe la and rvp

lead to inadequate hepatic conversion of glucose 6 phospha

glucosechroughnormal glycogenolysis nd gluconeogenes

make affected individuals susceptible o fastrng h,vpogl,vcem

Tvoe I GSD is an autosomal recessivedisorder. The srruc

gene or git cose 6 phosphatase s located on chromosome 17

th e gene for rranslocase s on chromosome 11q23. Com

mutarions responsible for the disease are koown. Carrier d



Chapter8 7 D e fe c ts n M et a bo l is m f C a .b o hv d ra t es

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f ion and Prendlll (Li3Bn()srs1r c Lr()ssrble'rfh rhe I)N'\_l- 'ased

il theueonatalperiud virh hr prri: lvccmia rld acuc acidosisr he v

an.l proruherantabdomen Lrat ; .1ue o nlassive cpatomegelt:

rhc krdrevs ere also eniargcd, rrlcfcJs the spLeen nd heart are

norma .

Th c Lriochemical allrnarks of rhe discascerc hypoglvce

lacnc acrrlosrs, hypcr rriccnria. ,urci hvperlipicJerlia. Fl-

gLycernrand acricaci. losis aLr levelopeffer shorr ast.Hy

ur ceLria s prcscnr n voung children;guLrr arclv clcvelops e

f.Lrbertr.Dcspitc rnerked hepatoLregaLy,hc 1it,cr ransanr

letcl. er c usuall,v orLn.rlor onlr slighdv clcvarcd. ntenur

dilrr hea nra,v c.Llr tthe Llecherrisrns urrknorvn) liasy bru

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e.ihesion.



6lN r PARTX MetabolicDis€ases

The plasma may be "milkv" in appearance as a result of a strik-ing elevauon of rrrglyceride evels. Cholesterol and phospholipids

are also elevated, but less promrnently. The lipid abnormaliryresembles type IV hyperlipidernia and is characterized byincreased levels of very low density Lpoprorein, low-densitylipoprorein, and a unique apolipoprotein profile consisting of

increased levels of apo B, C, and E, wirh relatrvely normal orreduced levels of apo A and D, The histologic appearance of theIiver is characterized by a universal distention of heparocytes byglycogen and far. The lipid vacuoles are particularll' large and

prominent. There is litde associared ibrosis,All these findings apply to both rype Ia and wpe Ib GSD, but

type Ib has addrtronal features of recurrent bacterial inlecrionsfrom neutropenia and impaired neutrophil funcrion. Oral andintestinal mucosal ulcerarron and inflammatory bowel diseasearecommon. Excepronal casesof rype lb wrthour neutropeniaan dtype Ia with neulropenra have been reported.

Although tvpe I GSD affects rnarnly the liver, multiple organsystems are involved. Pubert,v is often delayed. Virruallv allfemales haye ultrasound lindrngs consiscent with polycystic

ovaies; other features of polycystic ovary syndrome (acne, hir-sutism) are not seen. It is uncerrain whether rhis affects long-

term ovularion and fertilicy. There have been mutiple reports of

successfulpregnancy in adult rvomen with GSD I. Symptoms ofgout usually srart around pubertl' from long-term hyperuricemia.

Secondary co the hpid abnormalities, there is an increased nsk ofpancreatitis. The dyslipidemia, together with elevatederyrhrocyceaggregation, predlsposes these parients to atherosclerosls. Pre-mature arherosclerosis has rtot yec been clearly documented

except for rare cases. rnpaired platelet aggregation and increasedanrioxidatrve defense o prevent lipid peroxrdation may function

as a Drotective mechanism to helo reduce the risk of atheroscle-

rosis, Frequent fractures and radiographic evidence of osteopenia

are common; bone mineral content is reduced even in prepuber-

tal patiencs.

By the 2nd or 3rd decade of life, mosr patienrs wirh rype I GSDexhibit hepatic adenomas that can hemorrhage and, in somecases,become malignant, Pulmonary hypertension has been seenin some lons term survivors of the drsease.

Renal disiase is another complication, and most pacients with

type I GSD l,/ho are >20 yr of age have proteinuria. Many alsohave hypertension, renal stones, nephrocalcinosis, and alteredcreatimne clearance. Glomerular hyperfiltrarion, increased renalplasma flov; and microalbuminuria are often found in the early

stagesof renal dysfunction and carl occur before the onset of pro

teinuria. ln younger patienls, hyperfiltration and hyperperfusion

may be the only signs of renal abnormalities. With the advance-

men! of reflal disease, focal segmental glomerulosclerosis and

interstitial fibrosis become evident. In some patierrtsj renal func-

cion has detenorated and progressed o failure, requiring dialvsis

and transplancerion. Other renal abnormalities include amyloi-

dosis, a Fanconr-like syndrome, hypocitraruria, hypercalciuria,

and a distal renal rubular acidification defect.Diagnosis.The diagnosis of rype I GSD rs suspectedon the basis

of clinical presentacron and the laboratory findings of hypo-

glycemia, lactrc acidosis, hyperuricemia, and hyperlipidemia.Neutropenia is noted in GSD Ib pacienrs, typically after the 1st2-3 yr of lile- Administracron of glucagon or epinephrine resultsin litde or no rrse n blood glucose evel, buc the lactare level risessignificantly. Before rhe glucose-6-phosphatase and glucose-5-phosphate rranslocase genes were cloned, a definitive diagnosisrequired a liver biopsy. Gene-based mutation analvsis now pro-

vides a floninvasive $'ay of diagnosis for mosr patients with typesIa and Ib disease.

Taealmenl. Treatment is desrgned to maintain normal bloodglucose levels and is achieved by continuous nasogastric infusion

of glucose or oral administration of uncooked cornstarch. Naso-gasrnc drip feeding can be introduced in early infancy from rherime oi diaenosis. It can consist of an elemental enteral formula

or containonly glucose r aglucose olvmer o providesuffrcglucose o maintain normoglycemia urrng the night. Freqfeedingswith high-carbohydrateontentaregiveoduring he d

Uncooked ornsrarch ctsasa slow-releaseorm of elucosecan be ntroduced r a doqe f t.6 g/kgevery hr foi rnfantyr of age.The response f young nfants s variable.As the cgrows older, the corns tarch egrmencan be chaoged o ev6 hr at a doseof 1.75-2.5g/kg of body werght,Becauserucand galactoseannotbe converted irectly o glucosen GSD I, these ugars re restrictedn the diet. Sucrosetablesugar,

sugar, rher ngredients),ructose fruit, juice,high fructoses;rrup), actose dairv foods),and sorbitol shouldbe avoidelimited, Due to thesedietary resrrictions, iraminsand minesuchas calcium and viramin D may be deficientand supplemration is required to preveflt nutritional deficiencies.Dietherapy mproveshyperuricemia, yperhpidemia, ndrenal ution, slowing he developmenr f renal ailure.Thrs herapy ahowever, o normalze bloodurrc acidand ipids evels omplein some ndividuals,despitegood metabolic control, especafter pubeny,. he control of hyperuricemia an be further amenredby the use of allopurinol, a xanthine oxidase nhibiThe hyperlipidemiacan be reducedwith lipid-lowering drsuch as HMG-CoA reductasenhibitors and fibrate(seeCha861.Mic roa lbuminur ia .near lynd ica to rf rena l ys funcrrype disease,s treatedwith angiorensrn-convertingnz

(ACE) inhibitors. Citrate supplementscan be beneficialparienrs with hypocitraturia by preventing or amelioranephrocalcinosrsnd development f urinary calculi.

In patientswith r1'pe b GSD, granulocrte and granulocmacrophage olony-+timulating actorsare successfuln corring the neutropenia,decreasing he number and severirbacterial nfections, and improving the chronic inflammaboweldisease.

Orthotopic liver transplaltation is a potential cure of typGSD, but the inherenrshort- and long-termcornplicarionsethis as a treatm€nrof last resort, usually or patientswith limalignancn muhiple liver adenomas,merabolicderangemrefractory !o medical management, nd/or liver failure. Laadenomas >2cm) that are rapidly increasing n size andnumbermay requirepartial hepatic esecuon.Smalleradeno

(<2 cm) can be trearedwirh percutaneous thanol njectiontranscatheter rterial embolizatron.

Beforeany surgical rocedure,he bleeding rarusmust be euated and good meraboliccontrol established. rolongedbleing times can be normalizedby the use of intensive nlraven

glucosenfusion Ior 2448 hr beforesurgery.Useof l-deami8-o-argininevasopressinDDAVP)can reducebleeding omcations. Lactated inger solution should be avoided becaucontains actateand no glucose,Glucose evelsshould be matained in the normal range hroughout surgerywith the use107o dextrose.

Prognosis. reviously,many patientswith rype GSD died young age, and the prognosiswas guarded or chosewho svived.The ong-rerm omplications ccurmostly n adultsu'hdisease as not adequatelyreatedduring childhood.Early d

nosis and effectiveEeatmenthave moroved he outcome: edi*ease nd lormationof heparic denomas rL hporenriafor malignantrransformation emaln serious omplications.

TYPEII GIYCOGEN TOBAGE ISEASEDEBRANCHEREFICIEtlMlT DEXTBINOSIS).ype III GSD is causedby a deficiencglycogendebranching enzyme activity. Debranching enzytogetherwith phosphorylase,s responsibleor completededationofglycogen. (hen debranchrngnzyme s defective, lygen breakdown s incompleteand an abnormal glycogenwshort outer branchchainsand resemblineimit dextrin acculares. Deficiencyoi glycogendebranlhing enzvme cahepatomegaly,hypoglycemia,short stature, variable skemyopathy, and variable cardiomyopathy.The disorder usu



involves both liver and muscle and is termed tvpe IIIa GSD. In

=157. of patients, the disease appears to involve only liver and

Droaressiveweaknes. and waslinS. Myopathy does no t follow

any-parricularpatrern of involvementlboth proximal and distal

-uril"t ,t" involved. Electromyography reveals a widespread

mvopathyi nerve conduction srudiesmay be abnormal. Venrric-

ular'hypenrophy is a frequent finding, but overt cardrac dv s

funcdon is rare. Hepatic symptoms in some patients may be so

mild that rhe diagnosis is not made until adulthood, when che

develoPmenr n a pati€nt wrrh tvpe IIIb glycogen

nt has debrancherdeficrencv n livs but normal

d, he had hepatomegalv, vpogtvcemia, nd growth

he no lonsef bad h€patomegalvor hvpoglvcemia'

s normal He had lro muscleweakn€ssor atroph,vi

this is in contrast to rvpe IIIa pari€nts, n whom a progressivemvopathv rs

ChaDter7 r Dolectsn Metabolism l Ca.bohydroles

patients show symptoms and signsof neuromuscular disease.T

initial diasnosis has been confused with Charcor-Marie-Too

disease.Polycystic ovaries are common; fertilrt,v,however, is

reouceo.

Hypoglycemra and hyperliprdemia are common. In contras

rype I GSD, elevation of liver transaminase levels and fas

ketosis are Drominent, but blood lactate and uric acid conc

trations are usuallv normal. Serum creatine kinase levels can

useful to identify patients with rnuscle nvolvemenr; normal le

do nor rule out muscle enzyme deficiency.The adminrstration

glucagon 2 hr after acarbohydrare meal provokes a nor

increase n blood glucose; after an overnrgh! fast, glucagon m

provoke no change in blood glucose level.

Diagnosis.The hisrologic appearance of the liver is charac

has been seen n some patienrs with GSD lII.

Parienrswith mvopathy and liver symptoms have a general

enzyme defect (type IIla). The deficient enzyme activity can

demonsrrated not only in liver and muscle, buc also in o

tissues such as heart, erythrocl/tes, and cultured 6brobla

n btype asslgnmenr in the maioricy of patienrs.

Dietary management is less demanding than in

I nts do not need to restnct dietary inrake of fruc

rhan recommendinga high-protein diet and an exerciseplogr

Liver transplantation has been performed in pariencs with

stage cirrhosis and/or hepatic carcinoma.

TYPEV GLYCOGEl{TOBAGEISEASEBRANCHINGNZYMECIENCY,MYLOPECTIN0SIS,8 ANDERSENlSEASEl eficof branching enzyme activity results n accumulatior of afl ab

mal glycogen with poor solubiliry. The disease s referred t

type IV GSD or amylopectinosis because he abnormal glyco

has fewer branch points, more q. 1-4 linked glucose u

and longer ourer chains, resulting in a structure resemb

amvloDectln-TyF IV GSD is an autosomal recessivedisorder The glvco

branching enzyme gene is located on chromosome 3p21. M

tions responsible for rype IV GSD have been identified, and

characterization in indrvidual patients can be useful in predic

the clinical outcome. Some mutations are associacedwith a g

mosr common and classic form is characterized by progre

cirrhosis of the Lver and is manifested in the 1st 18 mo of lif

hepatosplenomegaly and failure to rhrive. The cirrhosis

gresses o portal hypertension, ascites' esophageal varices,

liver failure that usually leads to death b-v -51'r of age.

patients survive without progression of liver disease

A neuromuscular form of the disease has been repo

Patients may present at brrth wirh sevete hypotonia, mu

atrophn and neuronal involvement with death in the neo

period; others may present in late childhood wirh myopath



606 PARTX Melaholiciseases

cardiomyopalhy;or presentas adults with diffuse central andperipheralnervoussystem ysfunctionaccompanied y accumu-lation of polyglucosanbody drseasen the nervoussystem so-calledadult polyglucosan ody disease). or adult polyglucosandisease,eukocyte r nervebiopsy s neededo establish hediag-nosisbecausehe branchingenzyme eficiencys lrrmted o thosettssues.

Diagnosi$. issuedeposrionof amylopectinJikematerialscanbe demonsrratedn liver, heart, muscle,skin, inrestine,brain,spinalcord, and perrpheral erve.The hepatichistologic indingsare characterized y micronodular cirrhosis and fa inrly srainedbasophilic nclusionsn thehepatocl.res.he nclusions onsistofcoarsely lumped, toredmarerial hat is periodicacid-Schiffpos-itive and parcially resistant to diastase digestion. Electronmrcroscopy hows,n addition o theconventional and p glyco-gen parcicles, ccumulationo{ the fibrillar aggregationshat aretypical of amylopectin.The drstirct staining propertiesof thecytoplasmic nclusions, s well as electronmicroscopic indings,could be diagnostrc. owever,polysaccharidosesirh histologicfeatures emrniscent f type IV disease, ut without enzymaciccorrelation,havebeenobseryed. he definitivediagnosisestsonthe demonstration f the deficientbranchingenzymeactivity inliver, mu..1., cultured skin fibroblasts,or leukocytes.Prenataldiagnosis spossible y measunng he enzyme ctivity n culturedamniocytes r chorionicvilli.

Treatnent, here s no specificreacmentor type V GSD.Livertransplantation as beenperformed or patientswith progressrve

hepatic ailure, but becauser is a multisystem isorder nvolvingmany organ systems,he long-term success f liver transplanta-tion is unknown.

TYPEVI GTYCOGENTORAGEISEASEI.IVER HOSPHORYTASEDEFIGIENCY,ERS ISEASE).here are few patientswith docu-mented llver phosphorylasedefcrency.Such patients have abenrgn ourseand presentwith hepatomegaly nd growth retar-dation in early childhood. Hypoglycemia,hyperliprdemia, ndhyperketosis re usuallymrld if present. actrcacid and uric acidlevels are normal. The heart and skeletal muscles are notinvolved. The hepatomegalyand growh retardation rmprovewith age and usually disappeararound puberty.Treatment s

svmptomatic.A high-carbohydrate iet and frequent eedingareefiectire n preventing ypoglycemia; osrpalients equirenospecific reatment.GSD VI is an autosomalrecessive isease.Diagnosis estson elzyme analysis f the liver biopsy.The liverphosphorvlase ene (PYGL) is on chromosome74q21-22 andhas 20 exons.Many mutationsare known in this gene,a splicesite mutation in intron 13 has been dentified n the Mennonitepopulatlon.

TYPEX GI.YCOGENTOBAGEISEASEPHOSPHORYTASEII{ASECYl.This disorder epresents heterogeneousroup ofoses, Phosphorylase, he rate-limiting enzyme of

glycogenolysis,s activatedby a cascade f enzymaric eactions

kinase. he latterenzyme as ou r subunicsn, p, 16), eachencodedb;' differentgenes n differentchromosomes nd differ-entially expressedn various issues. his cascade f reactions sstimulared rimanly by glucagon.This glycogenosisould be heresult of any enzymedefciency along thrs pathlvay; the mostcommon s the deficiency f phosphorylase inase.

The numenc classiflcarion f phosphorylase inasedefrciencyis confusing, anging rom rypeVIa to VIII to IX. It is advisableto refrain from sucha designation nd to classify he variousdis-ordersaccording o organ nvolvement nd mode of inheritance.

X-tlNKEDUVEBPHOSPHOBYLASEINASE EFIGIENGYlinkedliver phosphorylase rnasedeficiency s the most common form

of liverglycogenoses.n additron o live! enzyme ctivitycanbedelicient n erythrocytes nd eukocyces;t is normal n muT1'pically, 1-5 yr old presentswith growth retardarionanrncrdentalindingof hepatomegaiy. holesterol, nglycerideliver enzymes remildly elevated. etosismay occurafrer asLactateand uric acid evelsare normal. Hypoglycemia s mipresent.The responsen blood glucose o glucagon s norHepatomegaly nd abnormalbloodchemistries raduallybenormal with age.Most adulcsachreve normal 6nal heighare usually asymptomaricdespite a persistentphospho

kinase deficiency. iver histologic appeatance howsglycodistendedhepatocltes.The accumulatedglycogen p partrosette orm) hasa fra;,'ed r burstappearancend s ess omthan the glycogenseen rn type I or type III GSD. Fibseptal formation and low-grade rnflammatory changesbe oresenc.

fhe strucruralgene or the common iver soform of rhepphorylase inase ubunit, iver crsubunrt s ort he X chromo(rrl- at XpZZ.2).Mutations of this geneare known.

AUTOSOMALIVERANOMUSGTEHOSPHORYTASEINASEGlEilCYSeveral atientshavebeen eportedwith phosphorkinasede6ciencyn liver andblood cellsand an autosomalmof inheritance.As with the X-linked form, heparomegalgrowth retardationapparent n eadychildhood are rhe pred

inant symptoms.Somepatientsalso exhibit musclehypotI(/hen measured n a few cases, educedactivity of the enha sbeen emonstratedn muscle.Murations ausine uto:ll y rransminedrverand rnut.|"nhosphorvlaseinaiedeficare for-rndn the autosomalp subunitgeneof rhe PK gene cmosome 6q12-q13).

AUT0SOMAI-IVEBPH0SPH0RYLASEINASEDEFICIENCform of phosphorylase inasedeliciency s due to mutarrothe testis/liversoformof rhe7 subunit of the gene TL, PHKIn contrast o the benign ourseof XJinked phosphorylaserdefrciency,atienrswich mutatronsn the PHKG2 genehavemsevere phenotypes wrth recurrent hypoglycemia and odevelopa progressiveiver cirrhosis.PHKG2 maps ro chrosome16p12.1 and many disease-causingutationsare kn

IOr tirls gene

ilUSCtE-SPECltlC PH0SPH0RYLASE INASE DEFICIENCYA casesof phosphorylase krnase deficiency restricted ro muscleknown. Patients, both male and female, present either wmuscle cramps and myoglobrnuria with exercise or withgressive muscl€ weakness and atrophy. Phosphorylase kinactivit't is decreased n muscle but normal in liver and blood cThere is no hepatomegaly or cardiomegaly. The structural gfor muscle specifrc form q subunlt (crM) is located at XqMr-rtationsof this genehave been ound in male patients with disorder. The gene for muscle l subunit (1M, PHKG1) is on cmosome 7p12 (29). No mutations in this genehave been reposo far

PH0SPHORYI-ASEINASE EFICIENCYlMlTEDT0 HEABT.patients resentwith cardiomyopathyn infancyand rapprogresso heart ailureand death.Phosphorylaseinaseciency is demonstrated in the heart with normal enz_vme ctirn skeletal muscle and liver.

Diagnosis. Definitive diagnosis of phosphorylase kinase dciency requires demonstration of the enzymatic defecr n affetissues.Phosphorylase kinase can be measured in leukocyteserythrocytes, but because the enzyme has many isozymes,diagnosis can be missed withour studies of l iver, muscle, or htn certain rnstances,

Tteatment.The treatment for liver phosphorylase kinase dciency includes a hrgh-carbohydrate diet and frequent feeding



lase kinase deficiency other than healt transplafltation.

ctYcOcEN SYIIIThErASE EFlCltttloYGSD0}. Deficiency of hepacic

glycogen synthetase eads o a marked decreaseof glycogen srored

in the li"er The patients Present in infancy with early-morning

(before eating breakfast) drowsiness, pallor, emesis, and fatrgueand sometimis convulsions associated with hypogll'cemia and

cated on chromosome 12p72.2-fteatmett

consists of frequenr

eals, rich in prorein, and nighttime supplementation wich

uncooked cornstarch.

HEPATIC GIYCOGEI{OSISWITII RENAT FAIIICONI SYNDROIIIE

and small meals with an adequate caloric intake may Implove

grol\,'th.

MUSCTETYCOGEI{OSES

Chapter? Detects[ Mel.bolistnf Calbohydrates6

theseatter enzyme eficiencresan alsobeassocrated ith a copensaced emolysis,suggestinga more generalizeddefectglucosemetabolism.

WPE l GtYCOGEl{TORAGEISEASEtYS0S0MAtACID r1,4-G

C0SIDASEEFICIEI{CY,OMPE ISEASE}.ompedisease, referred o as GSD type II or acid maltasedeficiency,s caus

This enzymedefect esults n lysosomalglycogenaccumulat

in multiple tissuesand cell types, with cardiac, skeletal, a

smoothmuscle ellsbeing he most serrously ffected. he dise

is characterized y accumulationof glvcogen n lysosomesopposed to its accumulation rn cyroplasm in the orhglycogenoses.

Pompediseases an aurosom recessive isorderwith an rn

denceof =1/40,000 ive births. he gene or acrdq-glucosid

rson chromosome-q25.2. Multiptepathogenic utations a

been dentifred hat could be helpful in delineatingchephetypes. n sitemutation IVS1-13T-"G), omonly see enrsof caucasian escent.

Clinicat e disorder ncompa\ses range

appearance," eeding difficultres, macroglossia, epatomegand a hypertrophiccardiomvopachyollowed by dea from cdiorespiratory ailure or respiratory nfectronusuall by 1yr age.Juvenileand adult-onsetdisease late-onsetorms) is chacterized y a lack or absence f severe ardiac nvolvement

The clinicalpicture s dominatedby slowly progressive roxim

muscleweaknesswith truncal involvementand gteater nvolment of the lower limbs than the upper imbs. The pelvicgird

paraspinalmuscles, nd diaphragrnare the musclegroupsm

seriously ffected.With disease rogressiol,patlentsbecome ofined cowheelchairs nd requireartrficialventilation.The init

sympromsn

somepatientsmay be espiratorynsufficiencyma

ifestedby somnolence,mornrflgheadache, rthopnea,and extional dyspnea, which eventually lead to sleep-drsordbreathingand respiratory ailure.Respiratory ailurers the caof significantmorbrdrtyand mortality in this form of the diseThe ageof deathvaries rom early childhood o late adulthodependingon the rate of disease rogression nd the ex tenresDiratorvmuscle nvolvement.

laborrtoryFindings, hesencludeelevatedevelsof setumcatine kinase,aspartate mrnotransferase,nd lacratedehydronase. In the infanrile form a chest x-ray showing mascardiomegalys requently he 1st symptomdetected. lectrodiographic indings nclude a high-voltageQRS complex anshortenedPR interval. Echocardiographyeveals hickeningboth ventricles nd/or he ntraventricular eptumand/or eft vricular outflow tract obstruction.Musclebropsy hows heprence of vacuoles thac stain positively for glycogen; aphosphatase s increased,presumably from a compensaincrease f lysosomal nzymes. lectfonmi(ro\copy re\eglycogenaccumulationwithin the membranous ac and in cytoplasm.Electrornyographyevealsmyoparhic eatureswexcessive lectrical rrirability of muscle rbers and pseudootonrcdischarges. erumcreatinekrnase s not alwayselevain adultpatients.Depending n the muscle ampled r testedmusclehrsrologicappeara[ceon electromyographymay not

abnormal. c is prudent o examine he affectedmuscle.nosrs of Pomid cr-elucosiskin fibrobla



6mr PARTX Metabolicisaasas

dried blood spots, eukocyces, r blood mononuclear ellsusngmahose,glycogen, r 4-methylumbelliferyl-a-D-glucopyranoside(4MUG) as a substrare,Deficrencys usually more seyeren rheinfantile form than rn the juvenile and adult forms. The skrnfibroblastassay s usuallypreferred o musclebiopsybecausetis less nvasiveprocedurewith rhe advantage f maintainingace line for future use and providing information on residualenzyme activit)'. Blood-basedassayshave the dvantageoI arapid turn-around ime. A musclebiopsycan yi d faster esultsand provide addrtronalnformation aboutglycogen ontentand

site ofglycogen

storagewichin and outside the lysosomes fmuscle ells.A mayor imitarion of a musclebropsy n late-onsetpatients s the variablepathologyand glycogenaccumulation ndifferentmuscles nd withrn muscle6bers;musclehistologyandElycogen ontentcanvary depending n the siteof muscle ropsy.There is also a risk from anesthesia. renatal diagnosisusingamniocytesor chorionic villi is available n the fatal infantileform.

Treatmentoptions were once imited to supportiveor care. Clinical trials of enzyme eplacementherapy(E beenpromisingand ERT with myozyme s availablefor treatmentof Pompedisease. ecombinant cid cr-glucosidaseis capableof improving cardiacand skeletalmuscle unctions(Frg.87-3). For patientswith the late-onset orm of rhe disease,a high protein diet may be beneficial.Nocturnal ventilatory

support, when rndicated, hould be used. t has beenshown toimprove he quality of life and is parricularlybeneficial uring aperiodof respiratorydecompensation.

GIYCOGEI{IOBAGE ISEASES IMICKING YPERINOPHTCAR-DI0MY0PATHY.eficrencies f lysosomal-associatedembraneprotern 2 (LAMP2, also called Danon disease)and AMP-activatedproteinkinasey2 (PRKAG2) esult n accumulation fglycogenn the hean and skeletalmuscle.Thesepatientspresenrprimarily as a hypenrophiccardiomyopathy, ur can be distin-guished rom the usual c sesof hypertrophiccardiomyopathydue to defecrsn sarcome prorein genes y their electrophvsio-logic abnormalities,particularly ventricular pre-excitationandconduction defects.The onset of cardiac symproms, ncludingchestpairi, palpitation, syncope,and cardiac arrest,can occlrr

between he agesof 8 and 15 yr fo r LAMP2 defrciency',othan the averageage for patients u'ith PRKAG2 defiwhich is 33 yr, The prognosis or LAMP2 deficiency swith progressiveend-stageheart failure early in aduhCardiomyopathydue to PRKAG mutations s comparibllong-term survival, although some patients may necethe implantarion of a pacemakerand aggressive ontarrhythmias.

TYPEV GIYCOGEflTORAGEISEASEMUSGTEHOSPHO

DEFICIENCY,CARDTEISEASE).his rscaused y rhe defiof musclephosphorylase crivity. Lack of this enzymemuscle ATP generationby glycogenolysis,esults in glyaccumulation, nd rs he prototypeof muscle nergydisorddefrciency f myophosphorylasempairs he cleavage f glmolecules rom the straighrchainof glycogen.

erancewith muscle ramps/pain.wo rypesof acLiviryecause ymptoms:brief exercise f grear ntensirysuch assing or carryingheavy oads;and less ntensebut sustainediry suchas climbingstarrsor walking uphill. Moderateexsuch as walking on level ground, can be performed bypatients or long periods.Many patientsexpetience chaistic "secondwind" phenomenon. f they slow down o

brieflyat the lst appearancef muscle ain. rheycan eexercisewrth more ease, Due to the underlying myothese patientsmay be at risk for statin-inducedmyositrhabdomyolysis.

About half repon burgundy-colored rine afrerexerciseis the consequencef exercise-induced yoglobinuriasecoto rhabdomyolysis.ntensemyoglobinuriaafter vigorousexmay causeacute enal failure. In rare cases, lecromyogfindingsmay suggest n inflammatorymyopathy and thenosis anbe confused irh polymyosiris.

The levelof serum creatinekinase s usuallyele.\'atedand increasesmore after exercise.Exercisealso increaslevelsof blood ammonia, nosine,hypoxanrhine,and uricThe latterabnormalities reattlbuted to acceleratedecycmuscle urinenucleorideswing o insufficient TPprodu

Pre-treatment Post-treatment

Fisure 87-3. Chestx-rav and musclehistotogy indan infanrile-onsetPompe diseaseparient before fnafter fEl enzyme eplacement herapy.Nore rhe de

in heart sizeand musle slycosenwirh rhe rherapy.i6ed Irom Amalfitano A, Beneur AR, Mone R?,Recombinant human acid alpha-glucosidase etherapy' for Lnfannle gtycogea storage disease yResults of a phase VII cljnical trial, Genet2001i3:132-138.)



Type V GSD is an aulosomal ecessive isorder.The gene or

muscle hosphorylasePYGM)hasbeenmapped o chromosome

described,rcise est offers a rapid diagnostic

sc mecabolicmYoPathY. ack of an

in s and exaggerated lood ammoniaelevations ndicatemuscleglycogenosis nd suggest defect n

the conversronof muscleglycogenor glucose o lactate. The

abnormal ischemrcexercise esponses not limrted to type V

GSD. Other muscle defects in glycogenolysisor glycolysis

producesimilar results deficiencies f musclephosphofrr-rctoki-

nase, phosphoglycerate inase, phosPhoglyceratemutase, or

lactatedehydrogenase).Phosphorusi"gn.tr. t".onuttc" imaging(31PMRI) allows for

rhe nonrnvasive valuationof musclemetabolism Patientswith

typeV GSDhaveno decreasen incracellular H and haveexces-

sive reduction n phosph<xrearinen responseo exerciseThe

diagnosis houldbi confirmedby enzymatic valuation f muscle.

A cbmmonnonsensemutation R49X in exon 1 is found rn 907"

of white patients,and a deletionof a singlecodon n exon 17 is

found in 51% ofJapanese atrenrs.Other commonmutatrons nwhrres G204Sn exon5 and K542T in exon 14 ) makeDNA-

baseddragnosis nd carrier tesring or McArdle disease ossrble

fbr the 2 populations.Treatmeni. voidance f strenuous xelcise levents he svmp-

toms;however,egularand moderate xercises recommendedo

improve exercisecapacity.Sucrosegiven before exetcisecan

-"ik"d1y i-ptou. tolerancen these atients.A high-prorein ier

may ncreasemuscle ndurance ndcreatine upplement asbeen

shown o improvemuscle unction n someparients. ongeviry s

not generallyaffected.

TYPE II GTYCOGENTORAGEISEASEMUSCTEHOSPHOFRUC-

TOKINASEEFIGIENGYABUT ISEASEI.ype VII GSD rs caused

sible n is population.Clinic Manile$tations, ix features f rypeVII are distrncrive:(1) Exercise ntolerance,usually evidenr n childhood, is more

severehan in typeV disease ndmay be associated ith nausea,

vomiting, and severemuscle ain; vigorousexercise auses evele

m.,scle tamps and myoglobinurra (2) A compensated emoly-

sis occursas evidenced y an rncreasedevel of serumbilirubin

Chaptei7r D.lectsn Metaholismf Calbohydiat

because lucose nhibits lipolysis and rhus deprivesmuscfatty acrdand ketonesubstrates.n contrast,parientswirhV drseaseanmerabolize lood-borne lucose erived rom eliver glycogenolysis ! exogenous lucose; ndeed,glucose

sion mprovesexerciseolerance n type V pattents. 6) Thno sDontaneousecond-wind henomenon ecause f the in

ity to metabolizeblood glucose.Two rare rype VII variants occur. One variant prese

infancy with hypotonia and limb weakness nd proceed

rapidlv progressivemyopathy rhat leadsco death by 4 yr o

The other variant presents n adults and is characterizeslowly progressive,ixed muscleweakness ather than crand myoglobinuria.

Diagnosis. o establisha diagnosis,a biochemicalor hchemrcal emonstrarion f the enzymaric efecr n the musrequired.The absence f rhe M isoenzyme f phosphofrunase an alsobe demonstratedn blood cellsand fibroblas

Trcatment.here s no specific featment,Avoidance l scous exercise s advrsable o prevent acute attacks of m

crampsand myoglobinuria.

OTHER USCI.E TYCOGEI{OSESITHMUSCTE NERGYMMENI Six additional defects in enzymes-phosphoglykinase,phosphoglyceratemutase, actate dehl'drogenasetose-1,6-biphosphateldolaseA, musclepyruvatekinase,a

enolase in the pathway of the terminal glycolysis-symptoms nd signs f muscle nergympairmentsimilar o of typesV and MI GSD.The failure of blood actate o incln responseo €xercises a usefuldiagnostic esrand can bero differentiatemuscle glycogenosesrom disorders of mecabolism, uch as carnrtinepalmitoyl transferaseI defi

and very long chain acyl-CoAdehydrogena deficiency,walso causemusclecrampsand myoglobinur Musclegly

levels an be normal in the disordersaffecting erminal gly

sis and assaying he muscleenzymeacrivity ts needed o mdefinirediagnosis. here is no specifrc reatment, voidanstrenuous rercisepreventsacuteattacksof musclecrampmyoglobinuria.Avoidanceof drugs suchas statins,and mnant hypenhermiaprecaulions or patientsundergoingansia should be followed.

87.2. DEFEGISNGATACTOSEETABOTISMPriyaS.Kishnani ndYuan-Tsonghen

Milk and dairy products ontain actose, hemajor dietarysof galactose. he metabolismof galactose roduces uel foh-rlarmetabolism hrough its conversion o glucose-L-pho(seeTable 87-1). Galactose lso playsan important roleformation of galactosides, hich includeglycoproteins,iprds, and glycosaminoglycans. alactosemia enotesrhvated evel of galactose n the blood and is found in 3 dinborn errors of salactosemetabolismdefecriven 1 of rh

lowing enzyrnes:alacrose-1-phosphateridyl transferasetokinase, and uridine diphosphategalacrose-4-epimeraterrngalactosemia, lthoughadequate or the deficienciesof thesedisorders, enerally esignareshe transferaseefr

GAIACTOSE-1-PHOSPHATEBIDYTTBANSFERASEEIIC

GAIACT0SEMIA,wo forms of the deficiency xisr: nfantcomplete r nearcomplete eficiency f theenzyme classic

tosemia)and those with partial transferase eficiencyCgalactosemias a seriousdiseasewith onserof symptomcallv bv the 2nd half of rhe 1st wk of !fe, The incide1i50,0d0.The newborn nfant receives igh amountsof la(up to 40% in breastmilk and certain ormulas),which co



610 PABT r MetabolicDiseases

of eqLralparrs of glucose and galactose. firhout the transferaseenzyme, the infant is unable ro metabolize galacrose- -phosphate,

the accumulation of which results in injury ro krdne_v, iver,and brain. This injurv may begin prenatally in the affecred fetusby transplacental galactose derived from the diet of the her-efozygous mother or bv endogenous producrion of galactose rnffre lerus.

Clinical Manilsslations. The diagnosrs of uridyl transferasede6-ciency should be considered in newborn or young infants wirhany of the following fearures: aundrce, hepatomegaly, vomrting,

hypoglycemia, convulsions, lethargn irritabilirl, feeding dif6cul-tres, poor weight gain or failure to regain birth weight,aminoacidurla, nuclear cataracts, vitreous hemorrbage, hepaticfaiLure, liver cirrhosis, ascites, splenomegaly',or mental retarda-rion. Symptoms are milder and improve when milk is temporar-ily withdrar,r.n and replaced by intravenous or lactose-freenutrition, Patients wirh galacrosemia are at increased risk forEscberichia coli neonatal epsis ; the onset of sepsisoften precedes

the diagnos is of galactosemia.Death from liver and kidney failureand sepsis may follow within days. \X/hen che diagnosis is normade at hitth, damage ro the liver (cirrhosis) and brain (mental

retardatron) becomcs ncreasingly severeand irreversible.Partial translerase deficiency is generally asympromatic. ft is

more frequen! than classic gaLacrosemia and rs diagnosed innervborn screening because of moderatell' elevated blood galac-tose and./or ow rransferaseactivit-v'.Clalactosemiashould be

con-sidered for the newborn or young infant who is not rhriving orwho has any of the preceding 6ndings, Light and electronmicroscopy of hepatic tissue reveals farty rnfiltrarion, che orma-tion of pseudoacini, and eventual macronodular cirrhosis. Thesechanges are consistent with a metabolic disease but do noc indi,cate the Dreciseenzvmatrc defect.

Diagnosis. he prehminary diagnosisof galactosemias madebv demonstrating a reducing subsrance n severalurirte specimenscollected while the patien! is receiving human mrlk, cow's milk,or any other formula containing lactose, The reducing substancefound rn urine by Clinitest (glucose, galactose, others) can beidentilied by chromarography or bv an enzymatic test specific forgalactose. Galacrosuria is present, provided che lasr milk feeddoes nor dare back more chan a fer,,'hours and rhe cbild is norvomiting excessively. Chnistix urine test results are negarivebecause he res t matenals rely on the action of glucose oxidase,t'hich is specific for glucose afld is nonreactive with galactose.

O$.ing to a proximal renal tubular syndrome, however, theacurely rll babv may also excrere glucose together with amino

acids. Because galacrose is injurious to persons with galacto-

semra, diagnostic challenge tests dependent on administeringgalacrose orally or intravenously should noc be used. Directenzvme assay using erythroc,vtes establishes the diagnosis. Oneneeds to confirm that the Danent did not receive a blood trans-Iusron before the collection of the blood sample, as a diagnosiscould be mrssed. Deficient activit,' of galactose-l-phosphare

uridyl cransferase s demonstrable in hemolysatesof eryrhrocytes,which also exhibit increased concentratrons of salactose-1phlsphate.

Genetics. Transferase deiciency galacrosemla rs an autosomalrecessivedisorder. There are several enzymatrc variants of galac-tosemia. Tbe f)uarte variant, a single amino acid substitution(N314D), has drminished ed cell enzymeactrvirybu t usuallynoclinical significance. Some Afrrcan-American pacienrshave mildersymptoms despice he abselce of measurable rransferaseactivityin erythrocytes; these parienrs retain 107o enzyme activity in Jiver

and inrestinal mLrcosa,.,vhereas os t white parients have nodetectable activity in any of rhese issues. n African-Americans,

62% of allelesare represenred y cheS135L mutation, a mura-tion tha! is responsible for a milder diseasecourse. In the whitepopulation, 70% of alleles are represenred b,v the Ql88R andK285N missensemutations an d are associatedwich severedisease.Carrier tescingand prenatal diagnosis can be pertbrmed

by drrect enzyme analysis of amniocytes or chorionic vil li; rescirn a[5o be DNA basrd.

Trealrnent and Prognosis. Because of newborn screening galacrosemia.parienrr ar e berng identrf ied and rreared iaVa r iuus m i l k suh l i ru r ( \ a re a ra i lab le (ca .e in hyd ro lysso,vbean-based ormula). Elimination of galactose from the dreverses growrh failure and renal and hepatrc dysfunctioCataracts regress,and most parients have no impairment of esrght. Early diagnosis and treatment have improved the prognsis of galactosemia; howeve! on long-term follor-up, patie

still manifest ovarlan failure wich primary or secondarv arnenrhea, decreasedbone mineral densit,v,deveJopmenral delali alearning disabilities that increase n severit,v virh age. Most milest speech disorders, whereas a smaller number demonsrrpoor growth and impaired moror function and balance (r,r,'i

wrthout overt araxia). The relative control of galactosephosphate levels does not alwa,vs correlate with long teoutcome, eadingco he belief hat orher faccors, uchas clevagalactitol, decreased uridine diphosphate galactose (UDP-gal

tose, a donor for galactolipids and proteins), and endogenogalactose production may be responsible.

GALACT0KINASE EfICIENCYThe deficient enzvme is ealactonase. rhrch normallv caralyzes he phosphorvlaiionof

'g.rlacr

The principal metabolites accumulated are galactose and gala

tol. Tu'o geneshave been reported to encode galactokinase: Gchromosome 1r-q24 arrd. GK2 on chromosome 15. Cataraare usually the sole manifestation of galactokinase deficienpseudotumor cerebri is a rare complicarion. The affected infais othenvise asymptomacic. Heterozygore carriers may be at rfor presenile cataraccs.Affected patienrs have an increased cocentration of blood galaccose evels, provided they have been a lactose-containing formula. The diagnosis is made by demostraung an absence of galactokinase activiry in erylhrocytes fbroblasrs. Transferase acrivrty is normal. Treatment is dietarescriccionof galactose.

URIDINEDIPH0SPHATE AtACT0SE-4-EPIMERASEEtICIENCY.abnormalJy accumulated merabolites are simrlar ro those n tranferase

deficrency; ho.w'ever, here is also an increase in celluUDP-galactose. There are 2 drstinct forms of epimerase deciency. The 1st is benign form discovered incidentally throuneonatal screening programs. Affected persons are healthy ar.ithout problems; the enzvme deficiency is limlted to leukocyand eryrhrocytes- No rreatmenr is required. The 2nd formepimerase deficrency s severe, and climcal manifestations reseble transferasedeficiencl r.r'ith he additional symptoms of h;rpconia and nerve deafness. The enzyme defciency is generaliz

and clnical symptoms respond ro restdction of dietary galactoAlthough thrs form of galacrosemia s rare, it rnust be considein a symptomatic patient wirh measurable galatose-1-phospha

who has normal transferase activity. Diagnosis is conlirmedthe assayof epimerase n erythrocytes.

Patients wrth rhe severe form of eDimerasedeficiencv cannsynthesize alactose rom glucosean d ar e galactosedependBecause alactose s an essentral omponent of manv nervosystem structural proteins, patienrs are placed on a galactorestricted diet rather rhan a ealactose free diet.

Infants with the mild {orm of epimerase deficrency have nrequ r redfea tment .t j * adv isab le, ' f o l l ow u r ine pec im ensreducing substances and exc lude aminoaciduria within a feweeks of diagnosis while the infant is still on lactose-containiformuia.

The gene for UDP-galactose-4-epimerase s located on chrmosome I at 1p36. Carrier detecrion is possible by measuremeof eprmeraseactivity in the er)'throcyles. Prenatal diagnosis frh e severe orm ui eprmerase e6.iencl. using an enzymeassof cultured amniotic fluid cells. is oossrble.



87.3 DEFECTSNFBUCTOSEETAEOLISMPriya .KishnanindYuan-Tsonghen

DIFICIENCYTTRUCTOKINASEESSENTIATRBENIGN BUCTO-SURI cyof fruccokinasesnot associatedith anyclin-rcal ons. ft is an accidentalinding usuallymade

becauseheasvmptomaticatient's rine ontains reducingub-

stance. No treatment is neiessaty and the prognosis is excellent

Inheritance is autosomal recessive with an incidence of

1/120,000. The gene encoding fructokinase is locared on chro-

mosome2p23.3.

Fructokinase catalyzes the 1st step of metabolism of dietary

fructose: conversion of frucrose to fructose 1-phosphate (seeFig

87-1). Without this enzyme, ingested fructose is not metabolized.

Its level is increased in the blood, and it is excreted in urine

because here is practically no renal threshold for fructose. CIin-

itesr resLrlts eveil the urinary-reducing substance,which can be

identilied as fructose by chromatography.

DEFICIENCY OF FRUCTOSE.I,6.8ISPHOSPHATETDOTASE

5 uctute'The true incidence of hereditarY

f unknown but maY be as high as

Chapler 7 . D.lects n Metaholism f Calbohydiates

An intravenous fructose tolerance tesc, admrnisceredwith gr

caution! is 1 step in facilitating diagnosis. The fructose challe

will cause a rapid fall, lst of serum phosphate and then of blo

glucose,and a subsequentncreasen uric acid and magnes-A n,rral rolerance e*i should not be perfurmed becau:epati

can become acutely ill. Definitive diagnosis is made by assa

fruccaldolase B activiry in the liver' Gene-baseddiagnosis is av

able for most patients with thrs disease;a common mutation (s

sticution of Pro for Ala ar position 149) accounts for 537. of H

alleles worldwide.

Treament Treatment consistsof the complete elimination o

sources of sucrose, rucrose, and sorbirol from the diet. Ic may

difficult because these sugars are widely used additives, fou

even in most medicinal preparations Wirh tleatment, l

and kidney dysfuncrion inproves, and catch-up in grorwh

common. Intellectual development is usually unimpaired. As

patient matures, symptoms becom milder evell after fluct

ingesrion; he long-termprognosis1 good. Because f volun

diilary avoidanceof suciose,affec d patientshave lew de

canes.

87.4. DEFEcrsN INTERi|EDIARYARB0HYDRMETABoUsMss0ctATED|TH Acrlc cto0st

PriyaS.KishnanindYuan-TsonghenLactic acrdosrs ccurswirh defects f carbohydratemetabochacnrerferewith the conversion f pyruvate o glucose ia

respirarory haindefeccs,ndpyruvate arboxylase e6ciencdrsordersn the pathway of pyruvaremetabolism ausing a

acidosis,Lactic acrdosis an also occur in defectsof fatty oxrdacion, rganicacrdurias se eChapters856, 85.10,

86.1),or biotin util izadondiseases.hesedisorders re e

distinguishable by the presenceof abnormal acylcarnprofiles and amino acids in the blood and unusual org

acids in the urine, Blood laccate,pyruvate, and acv lcarnprofiles and lhe presence f theseunusual urine organic a

ihould be determined n infants and children with unexpla

acidosis,especially f there is an increaseof aoion gap

Chapter 5) .Lactic acidosisunrelated ro an enzYmaticdefect occu

dosis s shown n Figure87-5

DISORDERSFGLUCONEOGENESIS

DEFICIENCYF GTUCOSE-G.PHOSPHATASEWP E I GTYCGSD is the only glycogenosis sacidosis.The chronic metabolic

lien!s to osteoPenia; fter proloted wirh hypoglycemias a life-th

ening ondition se eChapter 7.1).



612 r PABT r MetabolicDis€as€s

dehydrogeMse'

El active

Acetyl-coA\-> Cilicacid ycle

\______: "_ r ,H:U

I'igurc 87-1. Enzvmatic reachonsof carbohydrate metabolsn, deliciencies f u'hich can gjve rise ro lactic acidosrs,pvruvate elevarions,or hypoglycemiapvruvaredehydrogenase onplex comprises, n addition to Er, Fr, and E:, an exfia lipoate containingprorein (nor shown), calledprotein X, and p_vruvar

orogenasenospnarase.

fBt CTOSE-1,5-DIPHOSPHATASEEFICIENCYruccose- 6 diphos-

pharase efieiencl mpairs rhe formarion ol glucose ro m al l glu-

cooeogenic precursors, including dietary fructose. Hypoglycemia

occurs when glycogen reservesare limited or exhausted. The clin-ical manifestations are characterzed by life-rhreatening episodesof acidosis, hypoglycemia, hyperventilation, convulsions, andcoma. ln about 7. of che cases, he deficiency presents n the 1stwk of life. In infants and srnall children, episodes are triggeredb1' febflle inlections and gastroenterrtis if oral ibod inrakedecreases.The frequency of the attacks decreaseswith age. Lab-orarory lindings include low blood glucose, bigh lactate and uricacid lerrls. and metabolic acidosrs. n contrast to bereditary fruc-rose intolerance, rhere is r-rsuallyno averslon to s\{'eers; renalrubular and liver functions are normal.

The dragnosiss established y demonstratingan enzymedefi-

ciency in erther liver or intestrnal biopsl', The enzyme defect canalso be demonsrrated in leukocytes in some cases. The gene

eodrng or frucro.e-1. 6dipho'phata'e rs ocatedon chromosom.9q22; mutarions are characteriz-edmaking carrier detection andprenatal diagnosis possible. Treatment of acute attacks consistsof correction of hypoglycemia and acidosis bv inrravenousglucose infusion; the response is usually rapid. Avoidance offasting, aggressivemanagemenr of infections and reslriclion offructose and sucrose from the diet can Dreve[r further eDisodes.For l, 'ng-1er6preventionof hyp'glycemia. a slowll rele.: ied ar-bohydrate such as cornslarch is useful. Panents who survivechildhood develop normallv.

PHOSPHOENOTPY8UVATEARBOXYKINASEPEPCK} EFIGIENCYPEPCK s a key enzyme n gluconeogenesis.t catalyzes hecon-versionof oxaloacetate o phosphoenolpyruvateseeFrg.87-4).PEPCKdefrciencys both a mitochondrialenzl'me eficiency nda cytosolicenzyme eficiency, flcoded y 2 distinctgenes.

The disease as been eportedJnonly a few cases. he clinicalfeatutesare heterogeneous,ith hypoglyc€mia,accicacidemia,hepatomegaly, ypotonra, der.elopmental eJay,and farlure cothrive as the major manifestations. here may be multisysceminvoLvemenc,wlth neuromuscular deficrts, hepatocellulardamage, enal dysfunction,and cardiomyopathy. he dragnosisis based n the reducedacrivityof PEPCK n liver,6broblasrs, r

lymphocytes.Fibroblastsand lymphocytesare not suirabldiagnosinghe cl,tosolic orm of PEPCKdeficiency ecausetissuespossessorly mirochondrial PEPCK. To avoid hglycemia,patientsshould be treated virh slow-releasearbdratessuchas cornstarchand fascing houldbe avoided.

DISORDEBSFPYRUVATEETABOTISM

Pyruvate is formed from glucose and other monosaccharfrom lacrate, and from alanine. It rs metabolized through 4 menzyme sysrems: lactate dehydrogenase, alanine aminouaferase, pyruvate carboxylase, and pyruvare dchydrogecomplex. De6crency of the N{ subunit of lactate dehydrogecauses exercise intolerance and myoglobinuria (see Cha87.1). Genetic deliciency of alanine aminotransferase hasbeen reported in humans.

PYBUVATE EHYDR0GENASE0MPL€XDEFICIENCY fter entethe mitochondria.pyruvafe s converted nt o acetylcoenz\m(acetyl CoA) by the pyruvate dehydrogenase complex (PDH

*'hich catalyzes the oxrdation of pyruvate to acetl'l CoA, .rv

then enters the tricarboxylic acid cycle for ATP production.

complex comprlses 5 components: E1, an cr-keto acid deboxylase; E2, a dihydrolipoyl transacylase; E1, a dihydrolipdehydrogenase; protein X, an extra lipoate-conraining prot

and pyruvate dehydrogenasephosphatase. The most commoa defect in the Er (seeFiE- 87-4).Deficiencv of the pvruvate dehydrogenasecomplex is the m

common of the disorders leadine ro lacric acidemia and cennerrr'ous system dysfunction. Tlie cettttrl nervous syscem funccion s because he brain obtains irs energy primaril l, fr

oxrdation of glucose. Brarn acetyl CoA is synthesrzed neexclusively from pyruvate-

The E, defects are caused by mutations in the genecodingE1a subunit, which is XJinked. Although X-Lnked, i ts deficieis a problem in both males and females, even thor.rghonlyo allele n femalescarriesa mutatiorr.

ClinicalManilestations.he disease as a r,r. ideoectrumof \entations rom the most severeneonataloresenrariono a m



FanyAcld OxidationOetects

Chapter , I Dof.crs o lo|lholi lm ol Carbohydrates

Metabolic cidosis

Skin ash/Alopecia

lncreased

3 HydroxyButyraie:Acetoacetale

Propbnic acidemh l

MEthylmalonic cidomb iOtherorganic ac*furia i

BiotinidassHolocarborylase

Eynlhetasedslicbncy

Diabetesmellitus

Normal02saturation

Normalo low3 HydroxyButyratelAcetoacoialeyp€rglycemia

NormalGlycemiaNo Ketosis

late-onset orm. The neonatal onset is associatedwith lethal lactic

acidosis, white matter cystic lesions, agenesisof the corpus cal-

losum, and the most severeenzyme deficiency. nfantile onset can

be lethal or associatedwith psychomotor retardation and chronic

drogenaseomplex,but also n thecr-keto lutarateand brancchainketo acid dehydrogenaseomplexes. yruvate ehydrasephosphatase eficiency as also been eported.TheseoPDHC defectshave clinical manifestationswithin the varspectrumassociated ith PDHC deficiency ue o E' deficie

TrestnentThe general rognosis s poor except n rare cawhich mutation is associated ith altered affinity for thiapyrophosphate,which may respond o thiamine supplemtion. Because arbohydrates an agglavateactic acidosis, keenicdiet is recommended. he diet has been ound to lowe6lood lactate evel,but limited or no long-termbenefit s sepotential reatmentstrategy s to maintain anyresidualPDHits active orm by dichloroacetate,n inhibitor of Er kinase

UrineOrganic cidsplEsmaacylcamitineprofi19

Decr€aa€dor normalpyruvaieincreased aclale/pyruvalo alio

Multisyslem nvohEment"RaggedRed Fibei

in musde biopsy

FiBure 87-5. Algorithm of the drflerentiaj diagnosjsof lactic acidosis.



614 PABT r MebbolicDiso.so6

eficial effects n controlling postprandial actic acidosisn somepatientshave beenshom,

DEFICIENCYFPYBUVAIEABBOXYTASE-vruvate arboxylasesa mirochondrial.biotin-conraining tuyme essential n theprocess f gluconeogenesis;t catalyzes he conversionof pyru-vate o oxaloacetate. he enzymes also essentialor Krebscyclefunction as a providerof oxaloacetate nd rs nvolved n lipoge-neslsand formation of nonessential mino acids.Clinical rnani-festationsof this deficielcy have varied from neonatal severe

lactic acidosisaccompanied y hyperammonemia, itrulhnemia,and hyperlysinemiatypeB) to late-onsetmild to moderate acticacidosis nddevelopmental elay typeA).In both types,patientswho survivedusually had severe sychomotor etardationwithseizures, pasticicy, nd microcephal,v.omepatientshavepatho-Iogic changesn the brainstemand basal ganglia hat resembleLeigh disease. he clnical severityappears o correlatewrth thelevelof the residualenzyme ctivity.A "benign" form of PC defr-ciency charactenzed y recurrentattacks of lacric acidosisandmild neurologicdeficits as alsobeendescribed. aboratory ind-ingsare characterized y elevated evelsof blood lactate,pyru-vate, alanine, and ketonuria. In the case of type B, bloodammonia, citrulline, and lysine evelsare also elevated,whichmight suggest primary defectof the ureacycle.The mechanismis likely causedby depletronof oxaloacetate,which leads to

reducedevelsof aspartate, substrate or argininosuccinateyn-rhetasen the ureacycle seeChapter85.11).Trearmentconsistsof avoidanceof fasring,and eatinga carbohydratemeal beforebedtime,During acuteepisodes f lactic acidosis, atrents houldreceivecontrnuous ntravenousglucose.Aspartate and citratesupplements estore he metabolic abnormalities;whether thisfieatmentcan prevent he neurologicdeficits s not known. Livertransplantation asbeenattempted;ts benefit emainsunknown,Diagnosis f pyruvatecarboxylase eficiencys madeby themea-surementof enzymeactivity n liver or cultured skin frbroblastsand musr be differentiated rom holocarboxylase ynthetase rbiotinidasede6ciency.

DCFICIEI'ICYFPYRUVATEARBOXYI.ASEECOIIOARYO DEFI-CIENCYOF HOTOCARBOXYIASEYNIfiETASE R BIOTIT{IDASE.

Deficiencyof either holocarboxylase ynthecaseHCS) or bio-tinidase,whrchare enzymes f biot in metabolism, esult n mul-ciple carboxylasedefrciency pyruvate carboxylaseand otherbrotin-requiringcarboxylases nd metabolic reactions)and inclinical manifestations ssociated ith the resDectiveeficiencies.as well as ra'h, iacricacrdosis.nd alopeciJse ealsoChaprer85.6). The courseof HCS or biotinidasedeficiency an be pro-tracted,with intermitten!exacerbation f chronic acticacidosis,failure to thrive, seizules,and hypotonia leading to spasticity!lethargy,coma, and death. Late-onsetmilder forms have alsobeen reported, Laboratory findings include metabolic acidosisand abnormalorganicacids n theurine. n HCS deficiency, iotinconcentrationsn plasmaand urinearenormal. Diagnosis an bemade n skin libroblastsor lymphocytes y assay or HCS activ-ity, and in the caseof biotnidase, n the serumby a screening

blood spot. Treatment consistsof biotin supplementation, -20 mg/day,and rsgenerally ffectivef treatment s startedbeforethe developmentof brain damage.Parients dentifred hroughnewbornscreening nd trearedwrth biotin have emained symp-tomatic.

Both enzymedefciencies re autosomal ecessiveraits. HCSand biorinidaseare locatedon chromosome2'1q22and 3p25,respectively. thnic-specific utations n the HCSgenehavebeenidentified.Two commonmutations del7lrns3 nd R538C) n thebiotinidase eneaccount or 52lo ol all mutant alleles n symp-tomaucparen15 irh biorinidaseeficiency.

MrTocHoNoRtAr ESPTRAToRYHATNEFECTSoX|DATTVEHoS-PHORYIAflONISEASE).he mitochondrial esoiratory haincat-

alyzes heoxidation of fuel molecules nd transfershe electto molecularoxygenwith concomitantenergy ransductionATP (oxidativephosphorylation). he respiracory hainprodAT? fiom nicotnamide-adenine inucleorideNADH) or FADand ncludes5 specific omplexesl: NADH-coenzymeQ redtase; I: succinate-<oenzyme reductase; II: coenzymeQcytochromeQ reductase;V cltochromeC oxidase;V: ATP srhase).Each compJex s composedof 4-35 individual prota[d, wrth the exceptionof complex I (which is encoded oby nucleargenes),s encodedby nuclearor mitochondrial D

(inheritedonly from the mother by mitochondrial nhertanDefects n any of these omplexes r assembly ystems rodchronic actic acidosis resumably ue o a change f redoxswrth increased oncentrations f NADH. In contrast ro PDor pyruvatecarboxylase e6ciency',keletalmuscleand hearusually nvolved n rhe espiratory hain disorders; nd n mubiopsy,"raggedred fibers" (rndicatingmitochondrialproliftion) are often see[ (seeFig.87-5). Because f rhe ubiquinatureof oxidativephosphorylation,a defectof the mitochdrial respiratorychain accounts or a vast arrayof clinical mifestations nd should be consideredn patients n all agegropresenting with multisystem involvement. Some dencieresemble eighdisease, hereas therscausenfantilemyopatsuchasMELAS (mitochondrialmyopathy, ncephalopathy,aacidosis, nd strokelikeepisodes),MERRF (myoclonusepile

with ragged ed frbers),and Kearns-Sa1re;rrdrome (exteophthalmoplegia,acidosis, retinal degeneration,heart blomyopathy,and high cerebrospinallr.rid rorein) [Table87-2alsoChapters 98.2an d610.4].Diagnosisequires easureof enzyme ctivitiesn tissues r analysis f mitochondrialD(mtDNA) mutation, or both (Fig. 87-5). Analysis of oxidaphosphorylationcomplexes -IV from inraccmitochondrialated from fresh skeletalmuscle s the most sensitive ssamitochondrialdisorders.Specific riteria may assist n makindiagnosis Table87-3). Treatment emains argely symptomand does not significantlyaller the outcomeof disease.Spatients,however,appear o respond o cofactor supplemtypicallycoenzymeQ10 plusL-carnitineat pharmacologic o

TEIGHOISEASESUBAGUTEEGROTIZTNGIICEPHALOMY

THY).Leigh diseases a heterogenous er:rologicdiseaseremainsa neuropathologic escription haracterized y demnation, gliosis,necrosis, elativeneuronalsparing,and capilproliferation in specific brain regrons. n decreasing rdeseverity, he affectedareasare he basalganglia,brainsrembellum, and celebralcortex (seeChapter 598). The classicpse ation is of an infant who presentswith centralhyporodevelopmental egression r arrest, and signsof brainstembasal ganglia involvement.The clinical presentation s higvariable.Diagnosiss usuallyconfrrmedby radiologicor palogic evidence f symmetric esionsaffecting he basalganbrainstem,and subthalamicnuclei. Patientswith Leigh dishave defects in several enzyme complexes.Dysfunctioncl.tochrome C oxidase (complex IV) is the mogt commoreported defect, followed by NADH--coenzvmeQ reduc

(complex ), PDHC, and pyruvatecarboxylase.Mutations nnuclearSURF1gene,which encodes factor involved n the genesrs f clrochromeC oxidaseand mitochondrialDNA mutions in the ATPase6 coding region, are common molecfindings n patientswith Leigh disease.

87.5. DEFEGTSNPENTOSEETABOTTSMPriya .KishnanindYuan-Tsonghen

Abour 90% of glucosemetabolism n the body is via thecolytic pathway, with the remaining 10% via the hex



Chapter7 . Deleclsn Metabolisml Carbohydrates

(IAIITDITETIONSN

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616 PARTX Metabolic isEosos

Figure 87-6. Murations jn the human mitochondial genome hat are known to causedisease.Disorders har are {requentlyor prominenlty associated ith

tions in a parricular geneare shown in 6old. Diseases ue Eomutations $at imparr mitochondrial prorein synthesis re sholvn h rl&e. Diseases ue to

tions in prot€in-coding genesare shown in raL ECM, encephalomyopathyiFBSN, amilial brlateralstnatal necrosisiLHON, l,eber hereditary optic neuro

LS, LeiSh syndJonq MELAS, rnirochondrial encephalomyopathr lacrc acidosis, and srrokelike episodes;MERR4 myoclonic €pilepsy with ragged-red

tvlll-S, maternally nherited Leigh syndrome; NARB neuropathy,ataxia, and retinrtis pigmentosa;PEO, prog€ssive external ophthalmopl€giaiPPK,palmo

tar keratoderma; and SIDS, sudden infant dearh syndrome. (From DiMauro S, Schon EA: Mirochondrial respirarory-chain disesses.N Engl J2003;348:2656-2668. Copyright @ 2003 MassachusettsMedical Societt All flghts reserved.)

monophosphatepathway. The hexose monophosphateshunrleads o formationof pentoses, swell asprovidingNADH. Oneof the metabolites s ribose-5-phosphate, hich is used n thebioslnthesis of ribonucleotides and deoxTribonucleotides.Through the transketolaseand cransaldolase eactions, thepentose phosphatescan be converted back ro fructose-6-phosphateand Blucose-6-phosphate.

ESSEIIflAL EIIITOSUBIA.ssential entosurias a benigndisorderencountered rincipally n Ashkenazi ewsand is an autosomal

trair, The urine contains L-xylulose, which is excreteincreased mounts because f a block in the conversionoxylulose o xylitol due to rylitol dehydrogenaseeficienccondition is usually discovered ccidentally n a urine tesreduci[g substances;o treatment s required.

IWt SAIO0|ASEDERGIEXCY.o date, only 2 pati€ntsreported;1 presentedwith liver cirrhosisand hepatosplenaly in early nfancyand rhe other presented ith severe eohepatopathy and cardiomyopathy,Biochemical abnorma



revealedelevatedevelsof arabitol, ribitol, and eythrirol in the

urine. Enzyme assay n the lymphoblasts/fibroblastsemon-strared ow transaldolasectivity,which was confirmedby muta-trons n the transaldolase ene.

RIBOSE-5-PHOSPHATES0MEBASE €FlClEt{CY nly I casehas

been eported.The affectedmale had psychomotor etardationfrom early n li fe and developed pilepsyar 4 yr of age.There-after, a slow neurologicregression eveloped,with prominent

cerebellar taxia,somespasricity, ptic atropht and a mild sen-sorimotorneuropathy.MRI of the brain at ages11yt and 74 yr

showed extensiveabnormalitiesof the cerebralwhite rnatterProton magneticresonance pecffoscopy MRS) of the brainrevealed levatedevelsof ribitol andD-arabitol.Thesepentitols

were also increasedn urine and plasmasimilar ro the patient

found in transaldolase eficiency.Enzyme assays n culturedfibroblastsshoweddeficient ibose-5-phosphatesomerase ctiv-iry which was confirmedby a molecularstudy.

Amatnrano A, Bengur AR, Morse RP, €t al: Recombinanthuman acid alpha

glucosidase nzyne cherapy or infanrile glycogen storagedisease ype Il:

Resulrsof a phaseVII clinical vial. Genet Med 2001;3:132-138.

Arad M, Maron BJ, Gorham JM, er al: Glycogen storage dis€asepresentlng

as hypertrophic cardiomyop thy. N Ensl J Me.l 20O5352:362-372BachrachBE, gehstein DA, Otbo Melander M, et al: Glycogensynrhase efi-

ciency(glycogenstoragedis€ase ype O) presentingwrth hyperglycemiaand

glucosuria: Report of rhree new mutarions..l Pedatr Z0n2;1401781-783

Bosch AM, GroorenhuisMA, Bakker HD, er al: Living wrh classicalgalac-

rosemiai Heal${elrt€d qualiry of life consequences. Pel,dtli.s

2004;1I3:e423€428.

Chamoles NA, Niizawa G, BlancoM, et a| Glycogenstoragedisease ype II:

Enzymat,cscreenins n dried blood spors on fiher paper, CIn Arn Acta

20A347:97-s1tJ2.

Ch€n YT: Glycogenstorasediseases.n krjver CR, BeaudetAL, Sly WS' Valle

D leds). The Metabolic and Molecular Bases of lnherited Disease, 8rh ed.

New York, Mccraw-Hill, 2001, pp 1521 1551.

Cnmi M, Papadlnitrious A, Galbiati S, er al: A new mitochondrial DNA

muracion r ND3 genecaustngsevereLeis.hsyndrornewjth early lerhality

Pediatl Res 2004;5 S:842-846.

D€ Menleir L: D€Iecrsof pyruvate merabolisrnand the Rrebs cycle.J Child

Ne/rol 2002j17(Suppl3):l526-iS34.

Den Boer MEJ, Dronisi-Mci C, Chakrapani A, et al: Mitochondrial trifunc'

lional protein d€fici€ncy:A xvere fany acid oxidation disorder wrth cardiac

and neurologic nvolvement.I Pediatr 2003.742:68a489.

DiMauro S, Schon EA: Mitochondrial respirarory-chaindiseases.N Engi /Med 2003 348:26 6:2668

Elpeleg O: Inherited mitochondrial DNA depletion. Pedia, Res

2003;54:153-159.Franco LM, Krishnamurrhy V, Bali D, €t al, Heparocellujar carcinoma in

glycogen storage disease rype la: A case series. lftheit Metab Dis

200Ji28:153-162.

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neonaral rnirochondrial cytaparhies: A study of 57 parients.Pedhttics

2O05t116:1170-1777 .

Haller RG, VissingJ: No spotrraneous econdwind in musclephosphofruc-

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Holton JB, WaherJH,Tyfield IA, a al: Galacrosemia.n ScriverCM, Beauder

AL, Sly wS, ValleD (eds):TheMetabolic and Molecular Basesof lnherited

Diiersd, 8rh ed. New York, Mccrrw-Hill, 2001, pp 1551-1J87

Huck lH, VerhoevenNM, StruysEA, er al: Ribose-s-phosphatesomerase e6-

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a slowly progressive leukoencephalopathy: Am J Huft Genet

2004'74:745-751.

Hunrsman RJ, Sinclair DB, BhargavaR, Chan A: Atypical presentatioflsof

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K,shnani PS, HowelL RR: Pornpedis€ase n irfants and children. I Pediarl

2004;144:Sl5-S43-

LivingstoneC,.\l Riyalri S,Wilkins P,FernsGA: McArdle's dneasediagnosed

followrns statin inducedmyositis. Affi Clin Biocben 20O4i41tJ38-340.

ScasliaR Toqbin JA, Craieehr0q, ec al: Clinical spectrum, morbidity, and

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Chapte.07 r Dol.cls ir Mdabolisn ol Carbohydrates

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rn liver rnicochondrial resprratory chain disorders. ,f Pediatr 200

4t4417.

ShenJJ,ChenYT: Molecular characrerization fglycogen storagedisea

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Shoffn€rJM: Oxidarive phosphorylationdiseases.n ScDverCR, Beau

Sly wS, Valle D (edt:

"r€Metabolic and Molecutu Basesof tnh

Diseds?, rh ed, New York, Mcc.aw-H'll, 2001, pp 2367 2423.

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Van den Hout JMP,KamphovenJHJ,Winkel LPF,et a| Long-term ntra

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Zeviad M, Di Donaro S: Ifrcochondridl disorders. Brain 200

21s31172.

87.6. DISORDERSFGTYGOPROTEINEGRAOAAND TRUCTUREMargaretM. McGovern n

Robert . OesnickThe disordersof glycoproteindegradation nd structure nseveralysosomal torage iseaseshat result rom defectscoproteindegradation, nd the congenitaldisorders f glyctein (CDGs), which are pathophysiologically unreGlycoproteins remacromoleculeshat arecomposed f oligcharidechains inked to a peptidebackbone.They are ssized by 2 pathways: he glycosyltransferaseath\ray, ws''nthesizes ligosacchandesinked O-glycosidically o or lhreonine r€sidues;and the dolchol, lipid-linked patwhich synthesizes ligosaccharidesinked N-glycosidicaaspafaSrne.

The glycoprotein ysosomalstoragediseasesesult fromdeficiencyof the enzymes hat normally participare in

degradationof oligosaccharidesnd include sialidosis, asialidosis, aspartylglucosaminuria,and c-mannosidossome nstances!he underlyingabnormality hat leads o gprotein accumulationalso results n abnormal degradacofher c)asses f macromoleculeshat cortain similar oligcharide inkages,suchas certainglycolipidsand proteoglIn these nstances,he underlyingenz)'matic eficiency esthe accumulationof borh glycoproteinsand glycolipidsclassiEcation f these ypesof disordersas liprdosesor gproteinoses s dependenton the nature of the predomistoredsubstance.n general,he glycoproteindlsorders reacterizedby autosomal ecessivenheritanceand a progrdisease oursewith clinical features hat resemble hosesthe mucooolvsaccharidoses.



618 r PARTX MelabolicDiseEse$

SlALlD0SlS ND GAIACTOS|AI|D0SlS.ialidosis s an aurosomalrecessivedisorder that resuks from the orimarv deficiencv of neu-ram ni dase ue ro murarions n thegene har encodes hi sprorein.which is locared on chromosome 10. In conrrast. salacrosialido-' i s sdue o thede f i c ienc ) l2 t ysos , 'm a lenzyme . .eu ram rn ida reand p-galactosidase.The loss of these enz_ymaoc criv ities resultsfrom mutations in a gene ocated on chromosome 20 tbat encodesprotective protein/cathepsin A (PPCA), which funcrions to stabi-lize rhese eozymatic activiries. Neuraminidase normally cleavesterminal sialyl linkages of several oligosaccharides and glycopro

teins. Its deficiency results in rhe accumularion of oligosaccha-r ide ( , . l nd rhe u r ina r t e \ c r . t i on o f s ia l i c ac id re rm ina loligosaccharides and sialylglycopeptrdes. Examrnation of tissuesfrom affected individuals reveals pachologic srorage of substratein many rissues ncluding liver, bone marrow, and brain.

The clinical phenotype associated with neuraminidase defi-ciency s vanable and includes type I sialidosis which usually pre-sents n the 2nd decade of life with mvoclonus and the oresence. , f a ehe r ry cd sp , , r . hese a r ien r r p i ra l l y eome o j t t en lon

secondary o gait disturbances,myoclonus,or visual complaints.In contrast, type II sialidosis occurs as congenital, infanr e, and

;uvenile forms, The congenital and infantile forms result from iso-lated neuraminidase de6ciencn t'hereas the juvenile form resultsfrom boch neuraminidase and B-galactosidase deliciency. Thecongenital type II disease is characterized bv hydrops fetalis,

neonatal ascites, hepacosplenomegaln stippling oi the epiphyses,periosteal cloaking, and srillbirth or death in infancy. The type IIinfantile form presents n the lst,vr of life with dysosrosis mulri-plex, moderate mental recardation, visceromegall, corneal clouding, cherr ;r red spot , and seizures. The juvenile type II form ofsialidosis, which is somerimes designatedgalactosialidosrs, has avariable age of onsec ranging from infancy to adulthood. Ininfanc;i tbe phenotvpe is similar co thar of GMr gangliosidosis,u.ich edema, ascites, skeleral dysplasia, and cherrv red spot.Parienrs virh laler-onsetdisease ave dvsostosismulriolex. vis-

ie rom ega l l .m en r , r l e ra rd . l i on . y m orph ism . o rnea l loud ing ,progressive neurologic dererioranon, and bilateral cherry redspots. No specific therapv exists ior any form of rhe disease,although s tudies in animal models have demonstrated improve-ment in the phenotypeafter bone marrow rransplantacion. he

diagnosisof sialidosisan d galactosralidosiss achieved by thedemonstration of che specific enzymatic deficiency. Prenacaldiag-nosis using cultured amnioric cells is also possible.

ASPARTYLGIUC0SAMI|'IUR|AAGU). This is a rare autosomalrecessive ysosomal storage disorder, except in Finland, where thecarrier frequency is estimaced at l/36. The drsorder results fromthe deficient activity of aspartylglucosaminidase and rhe subsequent accumulation of aspartylglucosamine, particuLarly in theliver, spleen, and rhyroid. The gene for the enzyme has been ocal-ized to tbe Longarm of chromosome 4 and the cDNA has beencloned and sequenced. n the Finnish population, a single muta-oo n in th e gene (C153S) accounts for most mutaor alleles,rvhereasoutside of Finland, a large number of privare mulationshave been described- Affected individuals with AGU typicallv

present in the 1sc 1r of life w-ith recurrenr infecrions, drarrhea,and hernras.Coarseoingof the faciesan d short stature usuallydevelop later, Other features include jornt laxity, macroglossia,hoarse voice, crystal-like Lensopacities, hypotonia, and spascic-iry. Psychomocor der.elopmenr is usually near normal untrl theage of 5 when a decline rs noted. Behavioral abnormalities aretypical and lQ values in affected adults are usually <40. Survivalto aduLthood s common, with most earlv deathsarcributable opneumoniJ or o ther pu lmonarv cau .es . DeEn i r r ve iagnns isrequires measuremencof the enzyme in peripheral blood leukocytes. Molecular diagnosrsby analysisof DNA for the C163Smutation is possible or Finnish patien!s.Severalparientshaveundergone allogeneic bone marrotr,' cransplants, but rhisapproach has not been proven effective and no specific treatment

rs available. PrenataLdiagnosrs by the determinatron of the leof asparcylglucosaminidase n cultured amniocyres or chorionvilli has been reported.

aS-MANNOSIDOSIS.hi s autosomal recessivedisorder resufrom the delicient acnvity of q-mannosidase and rhe accr.rmtion of mannose-rich compounds. The gene encoding the enzyhas been localized o chromosome 19p13.2-q12, although tcDNA has not been cloned. Affected patjents wich rhis drsord

drsplay clinical heterogeneicy.There rs a severe nfantile form,type I disease, nd a milder juvenilevarianr, type II disease.parients have psychomotor retardation, facial coarsening, adysosrosismultiplex. The infantile iorm of the disorder, hou'evis characterized by more rapid mental deteriorarion, with deaoccurring betrl,'eenhe agesof 3 and 10 yr. Parienrs.rvich he infatile form also have more severe skelecal involvement ahepatosplenomegaly. The juvenile drsorder is characterized onser of symptoms rn earll' childhood or adolescencewirh mildsomanc features and survival to adulthood. Hearins loss. destrur i ve , , ynov i t i s , an i \ ropen ra . nd .pa . r i . pa r rp leg ia ave bcreported in type II patients, No specific therapv exists for the dorder The diagnosis is made b1' the dernonstrarion of the decieocy of q-mannosidase actrvity in white blood cel ls or culturefibroblasts, and prenaral diagnosis has also been achieved.

CONGENITAL ISORDEBS f GLYG0SYLATI0NCDGS). hese areheterogenous group of aurosomal recessivedisorders tbac resfrom defects rn tbe processing and svnthesis of the carbohydramoiety of glycoprotetns.

There are at least 22 jdentiliable disorders; rype Ia is the mocommon (Table 87-4). One main group includes those rvdefects in biosynthesis or transfer of sugar chains from a lipihnked oligosaccharide precursor to a nerv protein in rhe endpLasmic eticulum (group Ia to IL). Group II (I la ro IIf) characcerjzed by defects in N linked sugar chain Golgi proceing. Undefined disorders are cemporarily assigned o group X.

A distinctive brochemrcal marker of che disorder r s the preence of carbohydrare deficient transferrin in serum and cebrospinal fluid. The most consisrent clinical t-eatures of t

disorder include psychomocor retardarion, which varies in sevity, and facial d1'smorphic fearures that rnclude a prominent )aand ears and inverted nipples. l'requenc neurologic Endings infancy include cerebellar atrophy lFiS. 87-7), hypotonia, weaness, hyperreflexia, and strokelike episodes,

In chrldhood, ataxia, muscle atrophl, decreaseddeep cendreflexes, toe r',alking, and continued strokelike episodes aobserved. The latcer events may be related to coagulopathjcharacterized by reduced factor XI, protein C, and ancithrombIII. Strabismus is a consistenr finding and retinitis pigmenrosacommon. Growth failure, liver dyslunction, retinal degeneratioand skeletal abnormalities have also been described. The skelefeatures can include contractures, kyphoscoliosis, and peccuscainatun, all of which ma y be secondary o rhe neurologiceifeof the disorder Pericardral effusion in older patienrs and hvoe

t roph icobs r rucL rv ra rd rom yupa rh tn rhe n lanra l " o occu iTransferrin studies ha.'e also revealed rhar infantile olivooon

tinecerebellar trophy is e revcre form ol LDC. Lrpudv'rropu'ith prominent fat pads on the buttocks is a dishnchve featurThe disorder should be considered in patients u.ith mental retadation, cerebellar hypoplasia, heparic dysfunction, and episodscrokelike pisodes, nd in parienrswith vari ous combrnationsrhe features detailed in the previous paragraph. The diagnosis cabe confirmed by analysis of the transferrin patrern by rsoelecrfocusing. Although prenatal diagnosis by analysis of transferrhas been attempted, rt has not proven reliable. Trcatment of thedisorders rs symptomaric, except for CDGIb. whrch respondsoral mannose (100-150 mgikgiday ever,v 4 6 hr), and possibCDGIIc, whrch may respond to oral fucose (25 mg/kg/day nd)



chapter 7 r Defectsr l{otEholism f carbohydrdes



622 " PARTX MetabolicDiseases

MPS-I MPS-tlPahcnts vrrhv in(nrs rr ,pes i mucopolrsrceharoscs :

r l i scasc.( l r |l VI : Nlrr)t . ru\ I t rnrv rs€; rse.t yr

MPS-|il tvtPs-tv MPs-vlHurlcr (hsers. . r fi I l : Llurrrr dis. isc. 1l yri l l l i S.rnl i ppo disersc, ! r: lV: Nlor.

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i,tAqav 60i05,tAl ioq {

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s,[At,i, )ti ,F,A. lt 9

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Vfi st rlRX flya roxdd5eeioenry AR

,4rid q: c .l Hurle'henoipewith arkei orneal0udqbut ornr,rlnteqefire;tld l] at qa r:0i nrne l"l,A(ridprirterd ?vererpE55ionndlffercfitfarn,e5 4 sulfden'atdre

litI5L irhsel6il5iJlq7111 tbf)ingfmmeGlf)dopr0mlCl'rno?h,Jn,erJs du!.ni nlrrnuloq'i.! tsgLliLlroni&\! 5,;Ar,(yHlALl )1) PErrtiola, d55e5.o ]ir,hphenotlpe |]yailmnca5et r

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HurlerDisease. hi s fbrm of MPS I (lvlPs -H) rs a severe, ro -

arrery narrowing. Obstructive airway isease, nocably during

sleep, may necessicate racheotomy Ob ructive air',vav disease,

respiratory infection. and cardrac compl atiols are the common

causes f death.

Most chrldren$'tth Hurler s)'rdrome acquireonlv limited lan-

'r.r'irhdentigerous cysts,

Chapler 8 | Mucopolysaccharidoses

HurlerscheieDisease. he clinrcalphenotypeof NIPS IVS

incermediace ecweenHurLer and Scheiediseases nd is char

rerized by progressive somalic in\.olvemenr, including d,vsost

mult iplex with litr le or no intellectuaIdysfunction.The onse

symproms s usuallvobserved etrveen and 8 vr of age;surv

ro adulrhood s common. Cardiac nvolvemeotan d upper airu

obstrucrioncontribute ro cli nical morbidicy.Somepariencs a

spondylolischesis,vhich nay cause ord comptession.

Scheie0isease.N{PS -S s a comparativelymild disorderch

accerized v jornr stiffness, ort ic vah'e disease, ornealcloudi

and mrld dysostosismultiplex. Onset of signiGcant ymptomusually after the age of 5 vr, rvith diagnosis made betu'een 10 a

20 vr of age. Patients with Scherediseasehave normal rntellige

and srature but har.e significant joint and ocular involvement

carpal runnel syndrome ofren develops. Ophthalmic featu

include corneal clouding, glaucoma, and retinal degenera

Obstruccive airway disease, ausing sleepapnea) developsrn so

patients, necessrtating tracheotomy. Aortic valfe disease(L ,mmon nd ha r requ i red a lve ep lacementn somepa t ien

MUCOPOLYSACCHARIDOSISl. Hunter dis€ase MP S II) i s an

linked disorder caused by che de6cienc,vof iduronate 2-sulfat(tDS). Th e gene encoding DS is mapped o Xq2ll. Point mu

tionsof rhe DS genehavebeenderecredn abouc807o of patie

wirh \4PS IL Major delerions or reatrangements of the IDS ghave been found in the resr; these are usuallv associaredwlth

more severeclinical phenotype (seeFig. 88-2). Hunter dise

manifestsalmoscexclusrvely n males; t ha s beenobserved

ferv fernales and this is explained by skeu'ed rnactivarion of

X chromosomecarrying the normal gene.

\.larked molecular hecerogeneiw explains the rvrde clini

spectrum oi Hunrer disease.Paciencs'rth severeMPS II have f

I r ist 'c88. ] 'D-v5ostosismuhiplex.A,sanl i l ippodiseasc,4l r:TC, Hurler discase, 8 mo:.nterior supetx)r ypoptasia f l - -1 resul t rngn hooL-shaped ppearance



624 r PABTX MetabolicDiseases

cFigurc 88-4. Dysosrosismu[iplex. A, Mucopolysaccharidos,s MPS) I'H, 10 yr. The inferior porrions of the jlia are hypoplastic with resufting liac flar

shatlo{' ace|abular ossae.The femorat necksar€ in valgus position. B, MPS I-H, 4 yr . Metacarpalsand phalangesare abnormally shorr, wide, and defo

uith proxlmal pointing of the rnetacarpalsand bullet shap€dphalanges.Bone trabeculation s coarseand the cortices are thin. C, MPS l-S, 13 yr . The c

bonesare smalJ eading o a V-shapedconfguration of rhe digits. The short tubular bonesare well rnodeled.Flexion of the middte and dLstalphalanges I

causedbv ioint concractures.

B

tures simllar to those of Hurler disease xcept or rhe lack ofcorneal clouding and t}le somewhat slower progressionofsomatlc and CNS deterioration, Coarse acial features,short

staturerdysostosismultiplex, )oint sriffness, nd menral etarda-tion manifestbetween and 4 yr of age. Groupedskin papulesare present n somepatients.ExtensiveMongolian spots havebeenobservedn African and Asian patientssincebirth and maybe an early marker oI the disease.Gastrointestinal toragemayproduce chronic diarrhea. Communicatilg hydrocephalus ndspasticparaplegiamay developdue to thickenedmeninges. nseverelyaffectedpatienls,exrensive! lowly progressive euro-logic involvement recedes eath,which usuallyoccursbetween10 and 15yr of age,

Patientswith the mild form havea prolonged ife span,minimalCNS nvolvement, nd slow progression f somaticdereriorationwirh preservation f intelligence n adult life. Survival o ages65 ar'd 87yr has been reported; some palients had children ,Somatic features are Hurler-like but milder wi th a greatly

reduced ate of progression.Adult height may exceed150cm,Airway involvemen!,valvular cardiac disease, eating impair-ment, carpal tunnel syndrorne,and joint stiffnessare commonand can result n significant ossof function n both the mild andsevele orms.

MUCOPOLYSACCHARID0SISll. Sanfilippo iseaseMPS II) makesup a generically eterogeneousut clinically sirnilar group of 4recognizedypes.Each ype s caused y a differentenzyme e6-ciency nvolved n thedegradation f heparan ulfate see ig. 88-1), Mutatlons havebeen ound in all the MPS III disorders orwhrch the senes ave been solated.

Phenotypic ariation exists n MPS III patientsbut to a ldegree han m other MPS disorders.Patrenrswith Sanfidrseaseare characterizedby slowly progressive, evere

involvementwith mild somatic disease.Such disoroportirnvolvemenrf the CNS s unique o MPS ll, Onsettf clifeatures suallyoccursbetrveen ar'd, yr in a child who pouslyappeared ormal.Presentingeaturesncludedelayedopment, hyperactivity with aggressivebehavior, coarsehirsutism, leep isorders, nd mild hepatosplenomegalyse88-2),Delays n diagnosis f MPS II arecommondue o thephysical eatures,hyperactivity,and slowly progressive elogic disease. evere eurologjc ereriorarion ccurs n patientsby 5-10 yr of age, accompanied y rapid deteriorof socialand adaptiveskills. Severe ehaviorproblemssucsleepdisturbance, ncontrolledhyperactivity, emper antrdestructive ehavior,and physicalaggression re common.found mental retardationand behaviorproblemsoften occpatientswith normalphysical trength,making managemen

ticularlv difficult.

MUCOPOIYSACCHABID0SISV Morquio disease(MPS IVcaused y a deficiency f N-acetylgalactosamine-5-sulfataIV-A) or of p-galactosidaseMPS V-B). Both resuft n the dtive degradarion f keratansulfate.The geneencodingN-acgalactosamine-5-sulfatases on chromosome 16q24.3 andgeneencodingp-galactosidase, lBl, on chromosome p2:p-galactosidaseatalyzesGNogangliosiden addition to kersulfare,and mos! mutarionsof GlBl result n generalized



intelligence.MPS IV-A is usuallymore severe han MPS lV B,

*ith idult heightsof <125cm in the former and >150 cm in the

latter.There s considerable ariability of expressionn both sub-

rypes, owever.heappearancefgenua alga. yphosis. rorvthriiardaLion it h shorr runkan dneck, ndwaddling ar twnh a

tendency o fall are early symptomsof MPS IV (seeFig. 88-2)

Extra skeletalmanifestationsncludemild corneal louding,small

MUCOPOTYSACCHARIDOSISl Maroteaux-Lamy drsease N{PS

VI) is caused y mutations f rhe,4RSB en eon chromosome5q11-13 encodingN-acetylgalactosamine-4ulfatase arylsulfa-

taseB). It is characterizedy severeo mild somatrcnvolvemenr,

as seen n MPS I, but with preservationof intelligence The

somatic nvolvemenr f the severe orm of IVIPS l is character-

ized by cornealclouding, coarse aci features, ornt stiffness,

valvular eart isease,ornmunicating drocephalus,nddysos-

rosismultiplex se e rg. 8-21.n the severe.,rm.growthcan be

norma l o r rhe s t fewyears l ' l iFe u t seemsi r tua l lyo srop

after aee5-8 yr The mrld to intermediateorms of Nlaroteaux

Lamy Jiseasern be easily onfusedwirh Scheie yndrome,Spinal

cord compressionrom chickening f the dura in the upper cer-

vical canalwith resultantmyelopathv s a flequentoccutrencen

palienrswirh IVIPS l.

MUC0P0LYSACCHABID0SISll Slysyndrome MPSVll) is caused

by mutatrons f the GUSB en eocacedn chromosomeq21.11.

Mutations esuk n a deficiencyf p-glucuronidase,ntracellular

srorageof glycosaminoglycanragmentsand a very wide range

of clinical nr.olvement. he most severeotm Presenls s lelhal

nonimmune eralhydropsand may be detectedn uteroby ultra

dysostosismultiplex but normal incelligence nd usual cleal

corneae. hey may be found incidentallyon the bastsof bloodsmear hat showscoarsegranulocvtic nclusrons.

MUC0P0LYSACCHABIDOSISX.The disorders caused ;ra muca'

acetabulae ere rheonly radiographic indings.

ChspterSS Mucopolysaccharidos

DIAGI{OSISNDDIFFERE]IITIATIAGl{OSIS

Radiographs f chesr, pine,pelvis,and handsar usefulcodearlv igns f dysostosrsultiplex se e igs. 8-3 nd 88-4)quantitativespot tescs or increased rrnary GAG excretio

ably be diagnosed n serum using monoclonal antibodkeratansulfate.Any indivrdualwho is suspected f an MPorder basedon clinical features, adiographic esults,or uGAG screeningests houldhavea definitivediagnosis stabby enzyme assay,Serum, leukocytes,or cultured fibroare usedas the tissuesource or measuring ysosomalen(see Table 88-2). Prenatal diagnosis s available fomucopolysaccharidosesnd is carriedout on culturedcellsamniotic luid or chorionicvillus biopsy.Measurement f Gin amniotic fluid is unreliable.Carrier testing n Huntedrome,an X{inked disordeq equiresanalysis f 1DSgenthe specificmutation or chromosome t.angementn the funder consideration s known. Molecular analysis n Pawith other mucopolysaccharidosesr rn known carriers ea specrficationale.Attemptsare beingmade o developmetor routrnenewDornscreenlng-

Mucolipidoses nd oligosaccharidosesanifesrwith theclinical and radiographic eatures s mucopolysaccharidoChapters 6,4an d 86.5). n these onditions,he urinarytion of glycosaminoglycanss not elevated.Hurler-hke acirures, oint contracture!. ysostosismulriplex,and elurinary GAG excretiondilferentate the mucopolysacchafrom other neurodegenerativend dwarfing conditions.

TBEATMEI{T

Bone marrow transDlantarion from related or unrelated dor cord blood transplantation results in significant c

improvement of somatic drsease n MPS I, II, and Vl, C

effects include increased life expecta[cy, resolution or imp

ment of growth failure, heparosplenomegaln joint stiffness,

appearance, pebbly skin changes in MPS II, obstructive

apnea, heart disease,communicaring hydrocephalus, and h

loss. Enzyme activity in serum and urinary GAG excretion

malize. Transplantation does not significant ly improve the

ropsychologic ouccome of MPS patients if there is irnp

mentation at the time of transplaoration. This is true for M

H, II, and III. Patients with MPS I who have undergone

plantation befbre 24mo of age and with a baseline m

derrelopment ndex >70 have improved long-rerm or:rcome

transplantation in MPS Il may have the same effect. Tran

tarion in MPS VI stabili zes or improves cardiac manifestaposlure, and joinr mobility, Stem cell transplantalion do

correct skeletal and ocular anomabes; they have to be t

with appropriare orthopedic and ophthalmologic proce

Cord blood lransplantalion is the therapy of choice in ch

with MPS I-H, and possibly MPS lI, before the age of 2 y

transplantation-related dearh or primary graft failure,

occurs in =307o of the patients, must be weighed against

therapeutlc optlons.

Enzyme replacement uslng recomblnant enzymes is app

for patrents with MPS I, MPS II, and MPS VI. It re

organomegaln ameliorates rate of grouth and joint mobiliry

reduces rhe number of episodes of sleep apnea and urinary



626 PABT r Metrbolic iseos.s

excretion.The €nzymes o not cross he blood-brainbarrieranddo not prevent deterioration of neurocognitive nvolvemeot.Consequently, rhis therapy is the domain for patients withmild centralnervous nvolvement.To stabilize€xtlaneuralman-ifestations,t is also ecommendedn young patientsbeforestemcell transplantation.The combination ol enzyrne eplacementtherapy and stem cell transplan tationmay oIf€r the best reat-m€f,t. Recombinart iduroflate-2-sulfatasemeliorates he non-newologic manifestations f Hunter disease, nd recombinantN-Ac-gal4-suUataseas beensuccessfullyested n patientswith

MPS VI.Prirnary prevention through Beneticcourseling and tertiafy

preyention o avoidor treat complications emains he mainstayof supportivepediaric care,Multidisciplinary attention o respi-ratory and cardioyascular omplicatiofls,hearing loss, carpaltunnel syndrome,spinal cord compression, ydrocephalus, ndotherproblems angreatly mprove hequaliryof life for patientsand theL families (Tabte88-3). The progressive atureof clini-cal involvementn MPSpatientsdictates he need or sp€cializedand coordinatedevaluation.

Allen JL: Treatmenr of respiratory syst€m(not just lung) abnormaljtiesmucopofysaccharidosis I. J Ped.iatr 20n4;144:561-562.

BeesleyCE" Meaney CA, Greenland G, et al: Mucational aralysis of mucopolysaccharidosis ype I families: Frequ€ncy of known mu[arjoidentincation of 17 norel mulacions and in viro expression of misse

muratioff, Hrrtt Genzt 2O0(;1O9:5Q3-511.

BroadheadDM, Kirk JM, Burt d er al: Full expressionof Hunrer's diseas

a femalewith an X-chromomme deletion eading to non-random rnact

ti,on. CIin Gerret 1986i30:392-39 8.

Cheng Y, V€rp MS, (nui€l I Hibbard JU: Mucopolysaccharidosisy?e all

a cause of recu-trena non-immune hydrops fetalis. J Pettwt M

2003i31:535-537,

Fuller M, Rozaklis T, Ramsay SI. et al: Disease-specinc markers for

mucopolysaccharidoces. PeAafi Res 2004\561733-738.

Grewal SS,Wnn R, Abdenur JE, et al: Safery and effrcacy of enzyme repla

menr rherapy in combitration with hematopoietic stem cell transplantatioin Hr:rlet syndrome. Genet Med 2005;7t1,43-146.

Harmatz P, Ging[ani R, Schwartz I, et al: Enzyme replacemenr thera

for mucopolysaccharidosis M: A phase 3, randomized, double-blinplacebo-concrolled, multinational study of recombrnant humanacetylgalactosamin€+sulfatase (recombrnant human arylsulfatase B

RHASB) and fofLow-on, openlabel extension study, J Pediafi 2006;14533-539.

Harmarz 4 Whitley CV, Waber L, et aJ: Enzyme replecemeot rherapy

mucopolysaccharidosis VI (Maroteaux-lffy syr.&ome). I Pedi

2004;144574-580,

Hershkovitz E, Young Er Cmper A, et al: Bone marrow transpLantatior Maroteaux-Lei$y syndrome.J b herit Metab Dis 1,999t22r5}4z

Ito K, Ochiai T, Suzuki H, et al: The effect of haematopoieticsrem cell traplant on papuleswith

'pebbly'app€rence in Hunter's syndrome. BrJ D

matot 2004;15 1 207 271,

Meilde PJ, Ranien E, SkLmonsen , et al: Newbom screening or lysoso

srorage disordersr Clinical evaluetion of a two-trer stategy. Ped.iat2004i714:9O9-914.

Muenzer J: The rnucopolysaccharidoses: heterogeneous roup of disordwith variablepediatric prcse$tations./ Pedidt200444:527-533.

on J, Crowhursr J, Carey B, Greed L: Incidence of rhe mucopolysa

charidoses n V€srern Australia, An J Med Genet A 2003;123A:31

313.Ochiai I lto K Okada T, et aL Significanc€ f ext€nsiveMonBolian spors

Hunter's syndrome.8r / Defltutol 2003t148t1173-1178.

Robeftson SB Idug GL, Roge6 JG: Cerebrospinal luid shunts n the ma

agement of behavioural problems in Sanflippo syndrome (MPS I )

Pediatr 1998\157 953-65 5.SouillecG, Guffon N, Maire I, et al: Ourcome of 27 patienrswith Hurle

syndrome ransplanted rom eirher elatedor unrelat€dhaemaropoietic t

cell sources.Bonc Marrolr Traflsplant2003;37:1105-1117.

Saba SL, Escolar MI. Po€ vt er al: Cord-bJood ransplanrs tom unrela

dono$ in pati€$ts with Hurler's syndrome. Nea, Engl I Med 2004135

1960-1969.

Tomatsu S, Okamura K, Tak€rani T, et al: Development and testrng of n

screening method for kelatan sulJate in mucopolysaccharidosis IVA. Pel,d

Res 2004;55 592-597Triggs-RaineB, Salo TJ, Zh^nE 4 et ^L Mutations in HYAU, a member

a taademly distibured mubigene femily €ncoding disparate hyaluronid

activities, cause a newly describ€d ysosomal disorder, mucopolysacch

dosis IX. Pnc Ndt Acad Sei U S A 199996:62964300 .

VeJlodi A, Young E, Cooper A" et a| lrcng-term follow-up following bo

marrow transpfantatiotr for Hunler dtsease. J Inheit Meab D

1999i221638-548.

Vihox \(R: Lysoeomal storage disc,rders: The need for beBer pedianic reco

nrtion and comprehursive czre. J Pediav 20041,144: S3-S14.

WrairlJE, Clarke LA, BeckM: Enzyme epLac€menth€rapy or mucoFolys

charidosis I: A randomized, double-blinded, placebo-controlledrnLrlttional study of recombiaant human o-jduronidase \LaronidaseJ. J Ped.

2004j144:581-588.



The inherited disorders of purine and pyrimidrne metabolism

Purines are involved rn all biologic processes;all cells require

a balanced supply of purines for growrh and survival. They

orovide th e ptimary sourceof cellularenergy hrough adenosine

irrphosphate ATI-) and. Logetherwirh pyrimidines' proride rhe

source or the RNA and DNA that stores, tlanscribes, and trans-

lates qenetic information. Purines provide the basic coenzymes

(NAD-, NADH) for metabolic regulation and play a ma,or role

in sisnal transduction (GTl cAMP, cGMP) Metabolically active

nucliotides are formed from heterocyclic nitrogen-contarning

Urlc acid is not a specific drseasemarkeq so the cause of its ele-

vation mus! be determined- The level of uric acid present at any

time depeflds or the size of the purine nucleotide pool, which rs

derived from de novo purine synthesis, catabolisrn of tissue

nuclerc acids, and increased rurnover of preformed purines. Uric

acid is poorly solubl€ and must be excteted continuously to avoid

ro{ic accumulations in the body. Its renal excretion involves lhe

following components: (1) glomerular filtration, (2) reabsorption

in rhe proximal coavoluted cubule, (3) secretion near the lermF

Chaptoi 9 r Diso.doFof Puiine nd Pyrimidinolelabolism.

nus of rhe proximal tubule, and (4) limited reabsorption

these secretory sites. Thus, renal loss of uric acid is resu

renal rube excretion and ls a function of serum ull acid

centration and a homeostatic mechanism to avoid hyperurice

Because renal rubule excretion is greater in chrldren tha

adults, serum uric acid leve.lsare a less reliable indicator of

acid production in children than in adults, and conseque

measurement of the level in urine may be required to determ

excessiveproduction. Clearance of a smaller portion of uric

is via the gastrointestinal tract (biliary and intestinal secret

Owing to poor solubrlrty of uric acid under rrormal circstances,uric acid is near the maximal tolerable limrts, and s

alteratrons n production or solubility or changes n secret ion

result in high serum levels. In renal nsufficiency, urate excre

is increased by residual nephrons an by the gastrointestinal tr

lncreased production of uric acid is found in malignancv; R

syndrome; Down syndrome; psoriasis; sickle cell anemia; c

otic congenital hearr disease; pancreatic enzyme rePlacem

glycogen storage disease ypes I, I[, IV, and V1 hereditary f

lose ifltolerance; acyl coenzyme A dehydrogenasedeficrency

eout.The metabolism of both purines and pyrirnidines can

drvided into two biosynthetic parhways and a catabolic pathw

The 1sr, the de novo parhway, involves a multrstep biosynth

of phosphorylated ring structures from precursors such as C

glycine, an glutamne. Pr-rrineand pyrimidine nucleolidesproduced om nbose-S-phosphate or carbamyl phosph

respectively.The second, a single-step salvage pathwav, reco

purine and pyrimidine basesderived from eicher dietary intak

th e cataboLcpathway {seeFigs. 89-1, 89-2, and 89-3). n rh

novo pathway, the nucleosides guaoosrner adenosifle, cylid

uridine, and thymidine are formed by' che addition of nos

phosphate to the purine basesguanine or adenine' and to

pyrimrdine bases cytosine, uracil, and thymine. The phosph

Iation of these nucleosides produces monophosphale, dip

phate, and triphosphate nucleotides. Under usual crrcumsta

the salvagepathway predomrnates over the biosynthetic path

Synthesis is most active in trssues with high rates of cel

turnover, such as gut epithelium, skin, and bone marrow.

Phosphoribosylpyrophosphate(PRPP)synthetase

o ol l lP-O-P-O

OH O

l ' ' tsurc 1) . Ea r v xeps rn hebiosln the ' rs frhe purine ring.

Phosphoribosyl--pyrophosphate

(PRPP)

c

c

OHIc\

N/

N

cH <-nr Num€rouseactions

Inosin€-5rphosphate(lnosiniccid,MP)

D-ribose hosphate

5-Phosphoribosylamine



628 PART I Motabolic iseases

DNAsynthesis - dGTP

+I

RN A I

Feedbackinh ib i t i on - - - - -

De novo---> synthesis

DN AdATP-----t- synthesis

I

II RN A

Feedbackinhibit ion

synthesis -

Guanosine

II{o

GT P

tAdenosineeaminase

deficiency

q F- Adenosine

--------->synthesis

Adenine hosphoribtransteraseef cienc

ATP

1Inosiniccid

(rMP)

IY

-+ -----+ --_-r- Adenylicacic

Hypoxanthine-guanrnePRPP

lransferase

Hypoxanlhineriboside(lnosine)

+ PRPP + PRPP

NH ,t -

Adenine

+ Phosphoribosyl--pyrophosphatePRP

tI

II

Hypoxanthine

_lXanthine xidaseT

I

o Y oI

Ribose-s-phosphateA

H

Xanthine

Figurc89-2.Parhwaysn purinemerabolismndsaLvaBe.

third pathway is catabolism.The end product of the catabolcpathwayof thepurines s uric acid,whereas atabolism f pyrim-idinesproduces itric acid cycle ntermediates. nly a small rac-tion of the purines turned over each day are degradedandexcreted.

lnborn errors n the synthesis f purinenucleotidesnclude: 1)phosphoribosylpyrophosphatesynthetase superactivi!y, (2)adenylosuccinaseefrciencnand (3) 5-amino-4-imizolecarbox-amide (AICA) riboside deficiency AICA-ribosiduria).Disordersresulting from abnormalities n purine catabolism ncluder(4)muscleadenosinemonophosphate AMP) deaminase eficiencn(5) adenosine eaminase eficrency,6) purine nucleoside hos-phorylase eficiency, nd (7) xanthineoxidoreductase eficiency.

Disorders esulting rom the purine salvage athway ncluder 8)hypoxanthine-guanine hosphoribosyltransferaseHPRT) deli-ciency, and (9) adenine phosphoribosyltransferaseAPRT)Genclency,

Inborn errors of pyrimidine metabolism nclude disordersofp1'rimidine ynthesis nd of pyrimidine nucleotidedegradation.Disorders nclude: (1) hereditary orotic aciduria {uridinemonophosphace ynrhasedeficiency), (2) dihydropyrimidinedehydrogenaseDPD)defrciencl',3) dihydropyrimidinaseDPH)deficiencS 4) p-ureidopropionase eficiency, 5) UMPH-1 defi-ciency (previously pyrimidine S'-nucleoridase eficiency),(5)pyrimidine nucleosidedeplerion and overactivecytosolic 5rnucleotidase,7) thymidinekinase2 defrciency,nd (8) thymidinephosphorylase efi iency.

H

Uric acid

GOUT

Gout presentswith hyperuricemia,uric acid nephrolithiand acute inflammatory arthritis. Gouty arthritis is duemonosodiumurace rystaldepositshat result n nflammatiojoints and surrounding issues.The presentation s most cmonly monoarticulai, ypically n the metatarsophalangeaoof the big toe.Tophi,deposrts f monosodium ratecryscals,occur over poirits of insertionof tendonsar the elbows, knand feet or over the helix of the ears.Primarygout, ordinaoccurring n middle-agedmen, results rom overproductiouric acid,decreasedenalexcretionof uric acid,or both. The b

chernical tiologyof gout is unknown for most of thoseaffecand it is consideredo be a polygenic rait. When hyperuriceand gout occur n childhood, t is mostoften secondary out,result of another drsorder n which there s raprd tissue bredort'n or cellular urnover eading o increased roducriodecreased xcretion of uric acid. Gout occurs n any condithat leads o reduced learance f unc acid: during therapymalignancy or wrth dehydration, actic acidosis,ketoacidstarvation, diuretic therapy, and renal shutdown. Excespurine,alcohol,or carbohydratengestionmay ncrease ric atevels,

Gout is associated ith hereditarydisorders n rhreediffeenzyme isorders har result n hyperuricemia. hese ncludesevere orm of HPRT deficiency(Lesch-Nyhandisease)



Chapter 9 r oisoiders l Purin.andPydmidineMet.bolisn r

cooHI

NH, CH,t - t -c-:o-Hc-cooH

NH

/*Carbamyl-L-aspartaie

OH

Nz"'cH.--------->

| |-

O:C.rr.,C$!O"

UMPSynthase(Orotidyliccid

, decarboxylase)+1f-

Feedback

inhibiiionor

rcpress|on

Iriboss hosphate

orotidine-5honophosphale (OMP)

OHI

*zc-c"t t l

O:C\N,,-C-cooH

Dihydrooroticacid

. , \ n u

co2+ I ll- vn

Iribose hosphate

uridine '-monophosPhateUlvlP)

IY

Orotic cid

UTP RNACTP l--------+anddCTPI DNAdTTP synthesis

Figure 89-3. Pathways n pyrimidine biosynthesrs.

diminished renal excretion of urate. Glycogen storage disease

types III, Y nd VII are associated with exercise-inducedhyper-

uricemia, th consequenceof rapid ATP urilization and failure to

regenerate t effectively during exercise(seeChapter 87 1). Auto-

somal dominant iuvenile hyperuricemia, goury arthritis,

ulin-associated kidney disease IJAKD) has beenproposed. Unlike

the three inhented purine disorders that are X-linked and the

recessively nherited glycogen storage disease, hese are autoso-mal dominant conditions. Familial iuvenile gout or familial juve-

nephropa hy.

Treatmentof hypenricemia nvolves he combinarionof aurinal (a xanthine oxidase nhibitor) to decrease ric acidduction.probenecido increase ric acidclearancen thosenormal rinal function, alkalinizationof the urine to increa

solubiliw of uric acid. and increased luid intake to reducconcentrationof uric acid.A low-purine diet, weight reduand reducedalcohol nrake are recommended.

ABiIOBMALIIIESNPURII{EATVAGE

LESCH-NYHANISEASElJ{D}.This is a rare Xiinked disordpurine metabolism that results from HPRT deficiencyenzymes normallypresentn eachcell n the bodn but its hiconcentrations n the brain,especiallyn the basalganglia.ical manifestationsnclude hyperuricemia,ntellectualdisadystonic movement disorder that may be accompanichoreoathetosisnd spasticiry, ysarthricspeech, ndcornp

self-biting,usuallybeginningwith the eruption of teeth,There are severalclinical presentations f HPRT delicHPRT levelsare related o the extentof motor symptoms,presencer absence f self-injury, ndpossibly o the evelofnitive function. The majority of individuals with classichave ow or undetectableevels f the HPRT enzyme. artiaciency n HPRT (Kelley-Seegmilleryndrome)with >1.5-2enzyme s associated ith hyperuricemia nd variableneurodysfuncrion neurologicHPRT deliciency).HPRT defrcienclevels 87o eads o a severeorm o{ gout,with apparently ocerebral unctioning HPRl-relaredhyperuricemia) lthougnidve deficitsmay occur.Qualitarivelysimilar cognitive dorofileshavebeen eported n both LND and variant casesints produced sco.is that are intermediateberween ho



630 PARTX Mdabolic Diseases

patients u'lth LND and normal controls oo nearly everv neu-

ropsychologic measure tested.

Genetics. The H?RT gene has been localized ro the long arm

of the X chromosome (q26-q27). The complete amino acrd

sequence for HPRT is known (=a4 kb; 9 exons). The drsorder

appears in males; occurrence rn lemales is excremelv rare and

ascribed to nonrandom lnactivation of the normal X chromo-

some. Absence r.:f HPRT prevents che normal merabolism ofhl.poxanthine resulting in excessive uric acid producrion andrnanifestations of gout, necessltating specilic drug treatmenr

(allopurinol). Because of the enzyme deficiency, hypoxanthineaccumulates n the cerebrospinal fluid, but uric acid does not; uric

acid rs not produced in the brain and does nol cross the blood-brain barrier, The behavior drsorder is no! caused by hyper-

uricemia or excess hypoxanthine because patients with partial

HPRT deliciencl rhe variant$ with hyperuricemia, do not selfi-

injure and infants having isolared hyperuricemia from birth do

not develop self-iniurious behavior-

The prevalence of the classic Lesch-Nyhan disease has been

estimatedar 1/100,000 co 1/380,000. The rncidenceof partial

variants ls no! known. Those with classic LND rarely surwive hetr d decadebecau"eof renal or respirator) compromise.Th e l i ie

span rnay be normal for patiertts with partial HPRT deficiency

without severe enal involvement.

Parhology.No specific brain abnormality rs documented after

detailed histopathology and elecrron mrcroscopy of affected brainregrons.Magnetic resonance maging has docunenred reductions

in the volume of basal ganglia nuclei. Abnormalities in neuro-

transmitter metabolism have been idenri6ed in three autopsied

cases.All three patients had very low HPRT levels (<1ol" rn stri-

atal tjssue and 1-2Y" of control n thalamus and cortex). There

was a functional loss of 65-90% of che nigrostriatal and

mesolimbic dopamine terminals, although the cells of origin rn

rhe substantia nigra did not show dopamine reduccion. The brain

regions primarily involved were the caudare ntrcleus, putamen,

and nucleus accumbens. It is proposed chat the neurochemical

changes ma,v be linked to functional abnormalities, possrbly

resulting from a djminution of arborization or branching of den-

drites rarher than cell loss. A neurotransmitter abnormalrty i s

demonsrrared by changes in cerebral spinal flurd neurotransmit-

ters and their metabolites, and confrrmed bv posrtron emissiontomography scans o[ dopamine {unction. Reductions in vrvo in

the presynapric dopamine transporrer have been documented in

rhe caudatean d putamen of six individuals.

The mechanism whereby HPRT leads to the neurologic and

behavroral symptoms is unknown. Borh hypoxanthine and

guanine metabolism is affected; guanosine triphosphate {GTP)and adenosinehave substantial effects on neural tissues. There is

a functional link betra'eenpurine nucleotrdes and the dopamine

system that involves guanine, the precursor of GTP Dopamine

brnding to its receptor results in either an activatron (Dr

receptor) or an inhrbition (D2 receptor) of adenylcyclase. Both

receptor effects are medrated by G proreins (CTP-binding

proteins) dependenc on guanosine diphosphate (GDP) in the

GDP/GTP exchange or cellular activation. Dopamrne and adeno-

sine s,vstemsare also linked through the role of adenosine as aneuroprotective agent ln preventi[g neurotoxiciry Adenosrne

asonists mimic the biochemical and behavioral actions of

d6pamine antagonrsts, whereas adenosine receptor antagonists

act as funcrional dopamine agonist s. Dopamine reduction in

brain is documented in HPRT deficienr strains of mutant mice.

Clinical Mani{estati0ns. At birrh, infants wirh LND have no

apparent neurologic dysfunction. A fter several months, develop

mental delan intellectual disabilicy, and neurologic s igns become

apparenl.Before he ageof 4 mo. hyporonia. ecurrentvomiting.

and difficulty r,'ith secretions may be nored. By =8-12 mo,

extrapyramidal signs appear, prirnarily dystonic movemenrs. In

some cases!spastrcity may become apparent at this time or, in

some instalcest later in life.

Cognirive function is usually reported to be in che nild-moderate range of rntellectual disability, alchough some indruals test ln che low normal range. Because est scores mayinfluenced by drfficultv m tesdng rhe sub,ects owing to t

movement disorder and dysarthric speech, overall inrelligemay be underestimated.

The age of onset of self-injury may be as early as 1 vr aoccasionally, as late as rhe teens. Self-injury occurs, althoughsensory modalities, including pain, are intact- The self inluriobehar.ior usually begins with sel{-biring, although other patte

of self-injunous [rehavior emerge wrth time. Most charactercalln the fingers, mourh, and buccal mucosa are mutilated. Sbiting is intense and causes issue damage and may result ln amputation of fingers and substanrial loss of rissue around lips (Frg. 89-4). Extraction ol primary reerhmay be required.biting parrern can be asymmetric, with preferentral mutilation

the left or righr side of rhe bodl'. The cype of behavior is dif

ent from rhar seen in other intellecrual disability slrndroinvolving self-rnjury; self-hitting and head banging are the m

common initial presenrations n other s)'ndromes.The inrensi rthe self-injurious behavior generally requires chat the parient

restrained.When restrajnts are removed, the individual rvitl LN

may appear erfified, and stereot)?icalll' placea 6nger in chemouThe patient may ask for restraints to prevent elbow movemwhen the resrraintsare placed or replaced, he patrent may app

telaxed and better humored. Dysarthlc speech may cause rnpe$onal commumcation problems; chehigher-functioning childcan express hemselves ully and participate in verbal rherap1.

The self-mutilation presenrsas a compulsive behavior thatchild tries to conrrol bur frequently is unable to resis t. Older rn

viduals may enlist the help of others and notify them when t

are comfortable enough ro have restuaints removed. In so

instances, the behavior may lead to deliberate self-harm. In

viduals with LND may also show compulsive aggressron

inflict injur,v to others through pinching, grabbing, or hittingby using verbal fotms of aggressron.Afterwards thev may ap

ogize, stating that rheir behavior was out of their concrol. Or

maladaptive behaviors include head or lrrnb banging, eye pokiand psvchogeoic vomiting.

Diagflosis.The presenceof dystonia along wirh self-mutilat

of the mouth and frngers suggests Lesch-Nyhan disease. Wpartial HPRT deficiency', ecognition is linked to either hypuricemia alone or hyperuricemia and a dystofllc movemenr

order. Serum levels of uric acid >4-5 ms uric acid/dl- anurine uric acrdrcreatininr atro oi 3:4 or more are highly sugtive of HPRT deficrenc%particularl)' when associatedwirh n

rologic symptoms. The defininve diagnosis requires an analof che HPRT enzyme. This is assayed n an erythrocyte lys

Individuals wrth classicLND have near 07o enzvme activity a

rhosew iLhp . r r l i J l a r ian rshuw va lues etween . iq . and 60

The intact cell HPRT assal' rn skin fibroblasts offers a good c

relation benveen enzyme acrivity and the severity of the diseM-olecular cchniqr-resre used br genesequencrng nd rhe d

trfrcatton ot catflers,Di{ferential diagnosis includes other causes of i nfanhle hy

tonra and dystonia. Children with LND are often initially increctly diagnosed as having athetoid cerebral palsy. !' hendiagnosis of cerebral palsy is suspected n an infanr with a normprenatal, perinatal, and postnatal course, LND should be c

sidered. Patial HPRT deliciency may be associated u.ith ac

renal failure in infancy; therefore, clinical awareness of par

HPRT deficiency i5 of parricular importance.

An understanding of che molecular disorder has led to ef

tive drug treatrnent for uric acrd accumulation and anhritic toprenal srones, and neuroparhy. Reduction rn uric acid alone d

not rnfluence the neurologic and behavioral aspects of LN

Despire rreatment from birth for uric acid elevation, behavroand neurologic sydptoms are unaffected. The most srgmfic

complications of LND are renal farlure and self-mutilatxrn-



Figurc 89-4. SelI-iniurv in Lesch-

Nyhan disease. issuedamaBe o the

lip 1Al and fineers fBl was selfinflicr€d. Managernent o{ rhis

problem requires covering any dan-

gerous porcions of rhe wheelchair in

combinarion with Protectrveresuaints fcl. (From VisserJL Bar

PR, Jinah HA: Lesch-Nyhandisease

and the basalganglia.BlaillRes Rer

2000;32:449a7)

ChoDter9 Diso.d€FofPuiineendPyrimidino otabolism

alone, usingoperalt conditioning approaches, ave nor pro

ro be an adequate eneral r€atment.Altl,ough behavioralpcedureshave had some selecti*'e uccessn reducingself-injgeneralization outside the experimental setting limits tapproachand palientsunder stressmay revert o their previself-injunous ehavior.Behavioral pproachesmay also ocusreducing the self-injuriousbehavior rhrough the treatmen

phobic anxiety associatedwith berngunrestrained,The rn

common techniquesare systematicdesensitization, xtinctand differentral rernforcementof other (competing)behavStressmanagement as been ecommendedo assistpatieDtdevelop noreeffecrive opingmechanisms.ndividualswith LNdo not respond o contingentelectricshock or sirnilar averbehavioralmeasures. n increasen self-injurynay be obsewhen aversivemechods re utilized.

Restrainr day and night) and dentalprocedures te commmeans o preventself-injury.The time in restraints s linkedthe ageof onsetof self-injury.Childrenwith LND canparticipin makingdecisionsegarding estrairtsand he typeof restraThe time n resrraintsmay potentiallybereducedwrth systembehavior reatment rograms.Many patientshave eethextracro prevent self-injury. Others use a protective mouth gudesigned y a dennst.Most parentssuggesthat stress educand awareness f the patient's ne€dsare the mosc effectivreducing elf-injury.Positrve ehavioral echniques f rernfor

lppropriate behavior are rated effectiveby almost half of taml11es,

ADENINEPHOSPHORIBOSYTTRANSFERASEAPRTIDCFICAPRI a purine alvagenzyme,atalyzeshe synthesisf Afromadenine nd5-phosphoribosyl-1-pyrophosphatePP-nP),The absencef this enzymeesultsn the nabihty o utadenine and accumulated adenine being oxidized by xanth

dehydrogenase co 2,8-dihydroxyadenine, which is extrem

Treabnent.Medical management of this disorder focuseson the

ble. Self-mutilation is reduced through behavior management and

the use of restraints, removal of reeth, or boch. Injection of borulism toxin into the masseter muscles was useful in one patient.

Pharmacologic approacbes to dectease anxiety and spasticity

rvith medication have mixed results. Drug cherapy focuses on

svmptomaricmanagementof antrcrpatoryanxiery,mood srabil-

irarion, and reduction of self-iniuriousbehavior.Diazepamma y

be helpful for anxiety symptoms' and calbamazePine ol

gabapentin for mood srabilization.Each of these medications

may educe self-injuriousbehavior by helprng o reduceanriery

and srabilize mood.

the birth of an unaffected male infant.

Both the motivation for self-injury and its biologic basis must

be addressed n creatment programs. Yet behavioral techniques



GPI PABT r Metabolic iseases

rnsoluble.APRT deficrency s presenr from birth, becomingapparentas early as 5 mo and as ate as the 7rh decade.Genet-ics:The disorder s anautosomal ecessiverait with considerableclinical heterogeneicy.he AIDRT ene s locatedon chromosome16 q(16q24.3) nd encompasses.8 kb of genomrc NA , Thereis an APRT knockout mousemodel that replicares he diseaseprocess.Clinical manifestationsnclude urinary calculus orma-tion rvichcrystalluria,urinary tract infecrions,hemaruria, enalcoLic, ysuria,and acute enal ailLrte. he presence f brownishsporson the infant'sdiaper or of yellorv-browncrystals n the

urine is suggestive f the diagnosis, aboratory indings:Urinarylevels f adenine, hydroxyadenine,nd 2,8-dihydroxyadenineare elevated,vhereas lasmauric ac id rs normal.The deficiencymav be complete type ) or pardal (type I); rhepartial deficiencyis reported n Japan.The diagnosiss madebasedon che evelofresidualenzyme n erythrocyte ysates.The renal calcuJi,com-posedof 2,8-dihydroxyadenine,re radiolucent,soft, and easilycrushed. Thesestones are not distineuishable rom uric acid\tone\ hv routine esrsbur requirehigh-pressureiquid chromatographv HPLC), ultravroletor infrared radiation detection,mass pectroscopyMS),x-ray crysrallography,r capillaryelec-trophoresis or diagnosis, articularly o distinguish rom stonesin HPRT defrciency.

Treatment ncludes igh fluid intake,dietarvpurineresrnction,and allopunnol,which inhibits the conversionof adenine o irs

metaboltes,urther ,8-dihydroxyadeninexcrerion,nd uftherstone formation. Alkahnization of tbe urine is ro be avoided,because,nJike hat of uric acid, he solubiJity f 2,8-dihydrox-

,vadenrne oes not increase up to a pH of 9. Shock-wavelithotnpsy has been reported to be successful. he prognosisdepends n renal function at the rime of diagnosis.Early treatment is critical rn the preventionof stonesbecause evere enalinsuffrciencymay accompanvate recognrtron.

DISORDEBSINKEDOPURINEUCTEOTIDESYNTHESIS

PHOSPHORIBOSYTPYBOPHOSPHATEPBPPISYNTHSTASEUPEB-AGTIVITY.RPPs a substratenvolvedn the synlhesisf essen-trallyall nucleotidesnd rnportant n rhe egulation f rhedenovoparh!{'aysf purineand pyrirnidine ucleotide vnthesis.This enzymeroduces RPProm rjbose-S-phosphatend ATIasshownn Figures 9-1and89-2-PRPPs he 1scntermediarycompound in the de novo synchesis f purine nucleotides rhat lead!o the formatron of inosine monophosphace. Superactivrty of theenzyme results in an increasedgeneration of PRPP BecausePRPPamidotransferase, the 1st enz;.me of the de novo pathwan rs notphvsiologically saturated by PRPP, the synrhesis of purinenucleorides increases,and, consequently, the production of uricacid is increased. PRPP s;rnthetasesuperactlvity is one of the fewhereditar;,''djsorders in which there is enhancement of the acrrv-rty oi an enzyme.

Genetics: Phosphoribosylpyrophosphare synthetase (PRS)

superactivity is inherited as an X-linked rrait and presencswithtwo clinical phenotypes with varying degrees of severicl'. Threedrstinct PRS cDNAs have been cloned and sequenced.Two forrnsare X lrnked to Xq22-924 ar'd,Xp22.2-p,22.3 (escapesX inacri-vation), respectively,and are widely expressed; he third maps tohuman chromosome 7 and appears to be transcribed only in rhetestes.Even though the defect is X linked rt should be consideredin a child or voung adult of either sex with hyperuricemra and/orhyperuricosuria and normal HPRT acrivrty in lysed red cells.Clinical manifestatioos in the more severe vDe in affected hem-izygousmales rncludr signsof uric acid overproductron har ar eapparent n infancy or early childhood, neurodevelopmental

ior have been described.Heterozygous emale rriersalsodevelopgout and hearing mpairment.The la juvenearlv adult onset ype s found in maleswho show gour oac iduro l i rh ia r rsur no neuro log ic : igns .mechan i .moneurologicsymptoms s unknown. Laboratory findings: Buric acid may be two to three times normal values,anurinary excretion of uric acid is increased.The diagrequires nzyme nalysis f erythrocytes nd cultured6brob

This disorder must be drffe rentiated rom partial HPRTciency nvolving he salvage arhwanwhich also esulrs nr:ologicHPRT deficiencyor hyperuricemiawithout neurleatures,

Treatment s wirh allopurinol,which nhrbitsxanthineoxithe ast enzymeof the purine catabolicpathwav.Uric acrdduction is reducedand is replacedby hypoxanthine,whimore soluble, han xanthine. The initial dose of allopuri10-20 mg/kgl24hr in children and is adjusted ro mainormal unc acid evels n plasma.Occasionalln anthinecmay form. Consequently, low-purine diet (one free of omeats,dried beans,and sardines), igh llurd intake,and alkrzahonof the urine ro establish urinary pH of 6.0-6.5 rses.ar).Thesemea'urt's onrrol rhe hypiruricemia nd neuropathybut do not affect he neurologicsymptoms- h

no known treatmenr or the neurologiccomplications.

ADENYT0SUCCINATEYASEADSt)DEFICIENCY.his s an iired deficiency f de novo purine synthesisn humans.Adesucclnaseyase s an enzyme hat catalyzes wo pathwaysrovo synthesis ndpurinenucleotide ecycling. hese re heversion of succinvlaminoimidazolecarboxamide rib(SAICAR) rnto aminormidazole arboxamrde botide (AICin the de novo synthesis f purine nucleotides, nd the cosion of adenylosuccinareS-AMP) nro adenosinemonophare (AMP); the latter is the 2nd step in the conversiinosinemonophosphatellvlP)rnto AMP in the purinenuclecycle.ADSLdeEciencyesults n rhe accumulationn urine,

brospinal luid, and, ro a smaller extent, n plasma,of SAribosideSAICAT) nd succrnyladenosineS-Ado), ephoslated derivatives f SAICAR and S-AMP, espectivel)'. enThrs is an autosomal recessive isorder; the gene hasmapped o chromosome2q13.1-q13.2nd =20genemutahavebeen dentified. aboratory nvestigationshor,r,.he prein urine and cerebrospinalluid of succinylpurines, hicharemally undetectable.

Clinical manifestarionsncludevarying degrees f psychror retardation, generallyaccompaniedby a seizure disand/or aulistic ike behaviors poor eye contacr and repebehaviors).Neonaral seizuresand a severe nfantile eoiencephalopathyreoften he lsLmanifestarionsf thi. disOthers demonstratemoderate o severe ntellectual drsa50metimess.ociared irh growth erardarionnd mu,ele

ronia.One reportedcase, girl, tested n rhe mild rangeof ilectual disability.The form with prolound inrellectualdisahasbeendesignatedype , the variant casewirh mild intelledisabrliryas ype II. Other patientshavean intermediate lisymptompattern with moderatelydelayedpsychomotordopment,seizures, tereorypies,nd agiration,Pathology:CTMRI of the brain may show hypocrophyor hypoplasiaocerebellum, articularly hevermis, t is proposed hat rarherbeingcausedby purine nucleotidedeficiency,he symptomdue co the neurotoxic effectsof accumulating uccinylpurThe ratio of S-Ado/SAICAT asbeen inked ro phenotypeity suggestinghat SAICATs the more toxic compoundandS-Ado might be neuroprorective, he laboratory diagnobased n the presencen urine and cerebrospinalluid of SA



and S-Ado; both are usually undetectable. No successtul tfeat-

ment has beendemonstrared for this disorder Prenatal diagnosis

has been reporced, Systematic screening lvrth the Brarcon-Mar-

shall test isiuggested in infancsan d children with unexplarned

psychomotor retardation and/or seizure disorders

5-AMlt{0-4-lMl0Az0tf ARB0xAMIDEAICA) IB0SIDEEFICIENCY

by chebifunctionalenzymeAICAR transformylase/llvlPycLohv-

diolase (ATIC). The transformylases deficienr n fibroblasts n

this disorder.Genetics: hts is an inborn error of purine biosyn-

thesis aused y amurationof ATIC geneeffectingAICAR trans-

form'la'eactrvitl. n a reported ase, ICAR ran'formyla'e aspro found lye6c ienr ,herea .he MP cyc lohydro laseeve l a t

407" of no.-"I. Clinical features:The disorder s describedn a

der No successfulreatment s described.

OISOROERSESUTTINGROMBiIORMATITIESNPURIiIEATAEOTISM

MYOADENYTATE EAMII{ASEOEFICIENCYMUSCtE AOENOSINE

MOItI0PH0SPHATEEAMlf{ASED€FlClEf{GY). yoadenvlare deam-

inase rs a muscle-specific isoenzyme of AMP deaminase that is

active in skeletal muscle. Dunng exercise! lhe deamination of

AMP leads to increased levels of IMP and ammonia in propor-

ical manifestarions are, most commonly, isolated muscle

weakness, fatrgue, m,valgrasafter moderate to-vtgorous exerclse'

or cramps.Myalgias may be assocrared it h an increased erum

creatinekinase evel and derecrabLelecrromyelographic bnor-

tion durrns muscle contraction. lt is unclear how individuals mal'

carry the Jencit and be asymptomatic. n addit ion to muscledys-

function, a mutation of liver AMP deaminasehas been proposed

as a cause of pflmarv gout, leading to overproductron of uric acid.

The inherited form of rhe disorder is an autosomal recessrve

vart. AMP-DI, the gene responsible for encoding muscle AMP

deaminase, s located on the short arm of chromosome 1

(1p13 2l). Population rudres eveal that chis mutanc allele s

found at high frequenc in Caucasian popLrlations. The disorder

Chapter9r Disordersl Purinr ndPyrinidine etEbolis

mav be screenedor by performing he orearm schemic xtest.The normal elevationof venous lasmaammoniaaftercise hat s seen n normalsubjectss absent n AMP deam

deliciency. he 6nal diagnosrss made by histochemicalchemrcal ssays f a musclebiops,v. he primary fotm is dguishedby the linding of enzyme evels<2% $,'ith ittle immunoprecipirable nzyme.Affe ed individualsare adviexercisewith caution to prevenr habdomyolysts nd mybinuria-Although rhereare no documelted ully effectivements, ir has been proposed thac enhancing the ra

replenishment f the ATP pool might be beneficial.Usinrationale, reatmentwirh ribose(2-60 gl24 hr orall,v,n d

doses) r xylirol, whrch s converred o nbose,has been epto improve endurance nd musclestrength n somecasesineffecciven others, Geneticapproachesma-vbe leasiblefuture for inherited cases,whereas reatmentof the Lrndcondition s essentialn secondatvascs.

A0EN0SINEEAMINASEEFICIENCYeeChapter 25.1

PURllttEUCtEoSIDEH0SPHoRYIASEEFICIENCYeeCht25 2.

XANTHII{EOXIDOREDUCTASEEFICIEiICY EREOITARYANUBIAAI0tYBDEt{UM 0FACTOBEFICIENCYanthine oxductase XOR) is the catalyLc enzyme n che rnal step purrnecatabolicpathwayand oxideshypoxanthine o xaandxanthrne o uric acid.Because OR exisrs n rwo formsthine dehydrogenase nd xanthine oxidase, the deficiealso referred to as xanchine debydrogenase/xanrhrne(XDHD(O) deficiency. anthrne, he rmmediate recursoroacid, rs esssoluble han uric acid n urine and de6ciencyenzymeresults rn xanthinuria. Xanrhine oxidoreductascienc-vmay occur n ao isolated orm {xanrhinuria ype l)combined orm involvingxanthineoxidoreductase eficienaldehydeoxidasedeficiency xanthinuria rype Il), or in a

bined orm with deficrency f xanthineoxidoreduccase,ldoxidase,and sulfite oxidase(molybdenumcofacror defrcThe isolated orm resul ts n an alrnost otal reDlacemenac idbv h lpoxanrh inend anth rne .a t ien rs anox id izurinol ro oxypr:rinalvia aldehyde xidase.Parientswith thlared orm are usuallyasymptomaricr havemild symhowe,.er,enal stones, ften nor visibleon radiography, refor renaldamage nd may appear t any age.Crystallinthine deposrtsn musclemay resut in musc le ain ollowingtion. Rarely,xanthine sloneshar.ebeen eported as a reallopurinol administrarion.n rype I, the clinicalpresentsimilar to rype . Type l patienrsare deficient n borh oxand cannot metabolizeallopurinol. Molybdenum cofactociency failure o s)'nthesizehe molybdenumcofacror) nall three molybdoenzymes nd, like isolatedsr.rlfite xidas

ciency, esults n neonatal eediogproblems,

neonatalseincreased r decreased uscle one,ocular ensdislocationintellecrualisabilicy,nd death n earlychildhood.

The inherirance f types and II is autosomal ecesshumanXOR gene s ocatedon chromosome p22. n bothof the deEciency,he diagnosiss madeby measuring lasmcenrrations f uric acid;plasmauric acid s lorv (<1 rng/dxanthine s elevatedn plasma nd urine.Urinary uric areduced, being replacedbv xanthrne and hypoxanthimoLybdenum ofacrordeliciency, here s, rn addrtion,ansive excretionof sulfiteand other sulfur-containingmetabEnzyme iagnostic easuremen!equireseyunal r l iverbecause hese re the only human tissueshat containapble amountsof xanthineoxidoreducrase. ulfiteoxidasea



63{ r PARTX MelabolicDise8ses

mol,vbdenum cofactor can be measured in liver and libroblasrs.Although rhe isolated deficiency is generally benign! treatmentwith a low purine dret and increased fluid intake are recom-mended. Allopurinol has been recommended for chosewith residual xanthine oxidoreductase activiry It completell blocks theconversion of hypoxanthine into the far less soluble xanrhrne.The prognosis for molybdenum cofactor deficiency rs very poor,

DISORDERSFPYRIMIDINEETABOTISM

The pyrimidines afe the burlding blocks of DNA and RNA andinvolved n the formarion of coenz,vmes,as active inlermediaresin carbohydrareand phospholipid metabolism,glucuronidationin decoxification processes, and glycocylation of proreins andlipids. Pvrimidine synrhesis drffers from thac of purines in thatthe single pynmrdine ring is 1st assembled and then linked toribose phosphate to form uridine 5rmonophosphate (UN{P), Thepyrimrdines uracil and thymine are degraded in four steps, asshown in Figure 89-3. Eight disorders of pyrimidine metabolismare revrewed-Purine metabolsm has an easily measurableen dpomt in uric

acid;however,

there is no equrvalen! compound inpvrimidine metabolism. The 1st defect, heredrtary orotic aciduria,is in the de novo synthetic pathwal whereas the other disordersinvolve overacrivitl' (in one syndrome) or defec ts in rhe pvriml-

dine degradation pathway. Degradation disorders may presenrasanemra, neurologic disorders, or rnultisystem mitochondrial drs-orders. The 1st three steps of the degradacion parhways forthymine and uracil make use of the same enzymes (DPD, DPH,and UP). These three steps result in the corversion inco p alaninefrom uracil. There rs ncreasing evidence chatpyrimidrnes play animportant role in the regulation of the nervous system. Reducedproduction of the neurottansmitter function of p-alanine ishypothesized to produce clinical symptoms. Clinicalll., theserare disorders may be overlooked because symptoms are norhrghly specrfic; however, chey should be considered as possiblecauses

of anemia and neurologic diseaseand are a conrraindica-tion for treatment of cancer patients with certain pyrimidine

analogs.

HEBEDITARYROTIC CIDURIAURIOII\IE ONOPHOSPHATEYN .THASETYPE1 DEFIGIENCY).hrs is a disorder of pyrimidine syn-thesis assocrated v,ith deficient acrivity of the last two enzymesof the de novo pyrimidine synrhetic pathway, ororare phosphor!bosyluansferase (OPRT) and orotidine--5!monophosphate decar-boxylase (ODC). The ac tivities of rhese two enzvmes reside rnseparate domains to a single polypepride coded by a single gene.This bifuncrional protein, r.rridine5'-monophosphate (UMP) syn-lhase, catalyzes the two step conversion of orocrc acid co UMP,via orotidine monophosphate (OMP). Hereditary

orotic acidunaresults in the excessiveaccumulation of orotic acid. Genetics: Thisdisorder is autosomal recessive. Two functional domains areencoded on a single gene. The gene for UMP synthase s locatedon the long arm of chromosome 3 (3q13). Genecic metabolicdefects that nvolve four of rhe six enzymes associared with theurea cycle mav result in orotic acrduria secondary ro PP-ribose-Pdepletion resulring from a substantial increased lux rhrough thede novo pathwal', Clinically, patients with hereditary oroticaciduria (UMP synthas€ type 1 defciency) have a macrocytichypochromic megablastic anemia lhat ls unresponsive to theusual forms ol rherapy (iron, folic acid, and B1r) and may haveleukopenia. Onset is usually rn the 1st months of life. Untreated,

rhis disorder can lead to developmencaldrsabilirl', intellectual dability, failure to chrive, cardiac disease,strabismus, crysrallurand occasional urereric obstruction. Renal unction is eeneranormal. Heterozygolesmar' havemild orotr aciduriabuf ar. n

pharmacologic agents (5-azauridine,allopurinol) produce sondary ororic aciduria and orotidrnuria by specilically inhibiciODC. Orotic aciduria rnay also occur in association with penteral nutritionr essenrial amino acid deficrency, and R e sy

drome, The enz\mat rc de fe . t m ay be dem ons t ra red l r "lvmphoblasrs, erythrocytes, leukoc,r'tes,and cultured skin fibrolasts. A carrier detection test is available, as s prenaral diagn' is. ln OD( deficiencl rUVP synrhase yp 2 deficiencyl, clinical symptoms show neurologic abnormaliti u'ithout megloblastic anemia, In reported cases,both orotid una and oroaciduria were found.

impror.ement and reduction in orotic acid excrerion. Lifelot f ea rm en t\ requ i red . rac i l i s ne f f e r r i vee iause , n i kepu r inpy r im id ine a lvage ccu rs r rhe nuc leos ideu r id ine l . ve l . llong-cerm prognosis in uncomplicated cases is good; howev

DIHYDIOPYRIMIOII{EEHYDROGINASEDPD)DETICIENCYPcatalyzes the initial and rate-hmiting step in the degradationthe pyrimidine basesuracil and thiamine. DPD has been idenfied in most tissues, rvith the highest acrrvrty being in lymphq'tes. Genetics: DPD deficiency s an autosomal recessivedisordmapping to chromosome 1p22 wirh ac leasr 32 pol,vmorphismdetected. It is estimated tbat the frequency of the heterozygomay be as high as 3%. The clinical manifestations in childremay rncLudeseizure disorder, inrellectual disabilit_v.and motdelay. Lrs. frequenrar e grourh rerardation,microcephalv.autisrrc-like behavior and ocular anomalies. Others do noc shodevelopmental abnormalities but may have milder neurolog

symptoms and language disorder. In most cases, here is an initiperrod of normal psychornotor developmenr, followedsubsequent developmental delays. Sympcoms may be linkedaltered uracil, chymine, and p-alanine homeostasis. DPD is thinitial and rateimiting enzyme in the catabolism of the neoplatic drug S-fluorouracil (5 FU), being responsible for u07o of catabolism. Patients wrrh a partial deliciency of this enzymare at risk for developing a severe s-Fu-associared toxici adult paciencs,neurotoxlclty (headache.somnolence, visua lsions, and memory impairment) linked ro pyrimidinemia after FU treacmenr for cancer is reported in prevrously healtrndividuals.

Prenatal diagnosis has been reported. Laboratory findingDPD deficiency s characterized by a varrable phenocypeand dianosed by che accumulation of thramine and uracil in urinplasma,

and cerebrospinal fluid and no activit], in fibroblastDiagnostic tests use high-pressure liquid chromatograph(HPLC) or gas chromatography-mass spectroscopv (GC-MS

Alternarively, DPD defciency mav be conlirmed by measuring thenzyme in cultured fibroblasrs and leukoblasts. Uric acid levehave been reporred to be normal. BecauseB-alanine is a strutural analog of y amioobutl.ric acid (GABA) and glycine, it hbeen proposed rhat it na1' affect inhibirorl.neurotransmissionThere is no established treatment for this disorder: Datienrs rviseizures o rerpond to annconvulsanLmedirations. arienrs rrDPD deliciency should not be given 5-FU, and thrs deficienshould be suspected when neurologrc symptoms emerge aftcancer rreatment wlth 5-FU,



DIHYDBOPYBIMIDINASEDPH}DEFICIENCYDIHYDROPYRIMIDIN-

maDDedo chromosome q22 ln one studn therewas no signif-

icani differetrcen residualactivirv betweenmutationsobserved

in symptomaric nd asympromaticndividuals.Populationpreva-

lenie in a Japanese ample s 0.1% Clinical manifestationsnthree unrelatadaffectedcasesncludesetzures ith dysmorphrc

testswith uracil, dihydrouracil, thymine, and drhydrothymine

havebeenused o differentiacehis disorder rornDPD deliciency-

Io symptomatic casesi teatment with p-alanine has been

attemDt;d with equivocal results. Although ir has not been

reported, nc.eased ensitiviryo fluorouracil s expected ecause

of its role in pyrimidinemecabolism.

N-CABBAMYt-g-AMlN0AclDuRlA(DEHCIE -URElD0Pfio"

PIONASE).he pyrimrdinebases racil and aredegraded

via rhe consecutive ctionof threeenzym anineand p

aminoisobutyric acid, respectively. he chird enzyme in the

patiway is p-ureidopropionaseUP) and its deficiencyeads co

N carbamyl-p-amino ciduria.Urinary analysisn a reported ase

showedelevatedevels f N-carbamyl-p-alaninend N-carbamylp-aminoisoburyric cid,The enzymes expressednlf in the iver

andno activrtyof p-ureidopropionases derectedn a iver biopsy.

Genetics: luorescencen situ hybridization ocalized he human

treatment or UP deficiency.

URlDlt{E 0N0PH0SPHATEYDR0LASEDEFICIENCYPYRlMlDll' lE

5'-l{UCtE0TIDASEEFICIENCY).rythrocvte aturationsaccom-paniedby RNA degradation nd he release f mononucleotides,

PyrimidineSlnucleotidases tbe 1st degradative nzymeof the

pyrimidinesalvage ycleand catalyzeshe hydrolysisof pyrimi-

dine Srnucleotides o the correspondingnucleosides. nzymedeficiencv esults n the accumulationof high levelsof cytidine

and urid'inenucleotides n the erythroc;tes of those affected,

which results, n turn, in hemolysis.Defi encyof pyrimidine 5:

nucleotidases atleast n par! compensate n vivo by othernucle-

osidasesor perhaps other nucleotide metabohc pathways.

Genetics: his s an aurosomalecessiveisorder nvolvrnga gene

Chapter 9 r Disorders f Plrin. .nd PyrinidineMetoboliEm

pvrimidine S'-nucleocidase and assessmentof lead levels sh

te included whenever rhe hemolltic anemia, p,vrirnidrne

nucleotidase deficiencn and basophilic strpplng are fo

rogerher. Diagnosrs requires demonstration of a complete

ciencv of the major isoenzymeuridrne monophosphate hydrol

1. The enzyme defect should be suspected in parients w

nonspherocytic hemolytic anemia with basophilic stipplng

anemia is usually moderate, and transfusions are rarely neces

There is no specific treatment. Splenecromv has not prove

be an effective treatment. Lead-induced acquired pyrimid

S'-nucleotidase delicienc;; is treatable, unlikeche conge

deficiency.

PYflMTDINE{UCTEOSIDEEPTETIONNDOVERACTIVEYTO5,-NUCLE0TIDASE.yrimidineucleosideepletion ndover

tion in the activiry of pyrimidine S'-nucleoridase in fibrobl

with both purine and yrimidine substrates. nvestigarion in

tured fibroblasts der ed from these patients showed no

incorporation of purine bases into nucleorides but decre

incorDoration of uridine and orotrc acid. Clinical manifestat

include developmenLal elay. serzures. taxia. recurrent in

tions, severe anguage deficit, hyperactivity! short atcention sand agg ssive behavior appearing in the 1st feu' yr of

Affected atients show electroencephalogram (EEG) abnorm

ties. Metabolic testing is normal except for persisrent hypour

suria. It is proposed that increased catabolic activiry

decreased pyrimrdrne salvage cause a deficiency of pyrimid

nucleotides. Treatment is with oral uridine, based on its ef

on reversing rncreased nucleotide catabolism. AII repo

patients rreated wich uridrne show improved speech and be

ior. decreased seizure activitv with disconrinuation of se

medications, and decreased requeocy of infections.

THYMIDtNEPH0SPHORYLASECFICIENCY hymidine phosph

lase catalyzes the conversion of thymidine to thymine.enzyme is also known as platelet-derived endothelial cell gro

factor due to its angiogenic or "gliostatin" properties, indica

its inhibitory effects on glial cel l proliferarion. Ic has been im

cated in mitochondlal nucleoside metabolism. Plasma thvmi

level is increased>20-fold in paciencs ompared to controls.

of funcnon of thymidine phosphorylase causes mirochond

neurogastrointestinal encephalomyopathy (MNGIE), an au

mal recessive disorder rvith mitochondrial DNA alterat

Geoeticsr It rs an aulosomal recessive disorder, and che

encoding thymidine phosphorylase has been identified as

MNGIE gene and mapped to chromosome 22q13,32-

Clinical manifestations of MNGIE rnclude prosis, progre

external ophthalmoparesis, gastrointestrnal dysmotility

malabsorption, cachexia, peripheral neuropathv, skeletal m

myoparhy, and leukoencephalopathy.Laboratory find

Muscle biopsies typically reveal mitochondrial abnormal

The diagnosis is made by assayof thvmidine phosphorylase a

ity in penpheral ler-lkocytes.ncreased hymidine may causem

chondrial nucleotide pool imbalance resulting in mitochon

DNA alterations through a mitochondria-specific rhym

salvage pathu'ay. Supportive treament is indicated.

THYMIDINE INASE (IK2)DEFICIENGYhymidrnekinase2 (

is a key enzyme rn micochondrial DNA (mtDNA) precursor

rhesis. TK deficienciescause tissue-specif icdepletion oi mcD



636 PARTX.Metaboliciseas6s

TK2 normally phosphorylates eoxlthymidine, deoxycytidine,and deoxyundine.Genetics: he gene s locatedon chromosome16q22- Clinically, in TK2 delicienry,affected ndividuals haveseveremyopathyand depletionof muscularmitochondrialDNAin infancy.No specific reatment s available,Supportive reat-ment is indicated.

Augoustid€s-SavvopoulouP, Papachrisrou 4 Farrbanks LD, er al: Parrial

hypoxanthineguanine phosphoribosyluansferase efciency as the unsus,peded causeof rena) disease pannrng hreegenerations:A cauhonary tale.

Pediafiics 2O02ilO9E17

Caneron J5, Moro R SimmondsHA: Gour, uric acid and purine metabolisrD

in paediarric nephrology,Pediatr Nepbrcl 1993;7 '105-118.

Cameron JS, Simmonds HA, Hereditary hyperuricemia and r€nal dis€ase.Setnin Nefihrol 200525:9-78.

Dabrowski E. SmathersSA. Ralstrom CS. et al: Botulinum toxin as a novel

rreatment for self-mutilation in Lesch-Nyman Syndrome.Det Med ChildN eutol 2005 47 636-639.

Jinnah HA, De Gregorio L, Harrrs JC, et al: The spectrumof inherited muta-

tions causing HPRT deficiency: 7i new casesand a review of 195 prevr

ously reported cases.Mutat Res 2000t463:309-326.

Loffler M, Fairbanks LD, Zameitat E, et al: Pyrimidine pathways in health

^nd diselse,Mol Med 2005t1,1,:430437.

Marinaki AM, EscuredoE, DuleyJA, ecaI Geneticbasrsof hemolytic anemia

cau*d by pyrimidine 5'nucleorjdasedefrciencr lood 2O01;97:3327-3332.

Nrshino I, SpinszzolaA, Hirano M: MNGIE: From nuclear DNA to mito-

chondrial DNA. Nearorfluscul Disotd 2001l'1117-10.

Nyhan Ii/L: Disorders of purin€ and pyrimidine metabolisn. Mol GenetMetab 2O05;86:2s-33.

Nyhan Vl, Vuong LU, Broock R: Prenataldiagnosisof Lesch'Nyhandisease.

P etrdtDiag" 2003,23 1807809.

RaceV, Marie S, Vincent MB et al: Clinical, biochemicaland moleculargeneric

correlations in adenylosuccinate lvase deficiency. Hum Mol Cenet

20O0;9:2159-2165.

SchredenDJ, Harris JC, Park K, er al: Neurocognitive furctioning in Lesch-

Nyhan disease nd partial hypoxanrhrne-guanine hosphoribosyltransferase

deiciency. I Int Neu/opsychol Soc 2001i7:8O5-812.

SchretlenDJ, Vard J, M€yer SN{, er al: Behavjoral aspectsof ksch-Nyhan

disease nd its varianrs. DeLj Med Child Newol 2O05t47:673-677.

Scriver CR, BeandetAL, Sly WS, et al ledsl The Metdholic ad Molecular

Bask of Inbe ted Diseasa Vol. 2, 8th ed. Nell York, Mccraw-Hill, 2001,

pp 2513J7O2.Sinmonds HA, Duley JA, Fairbanks LD, et al: When to inv€stigareor purine

and pyrimidine disorders: nrroduction and review of cLinicaland labora'

rcty ,ndlc tions. I lftherit Metab Dis 19972O:214-226.

van Gennip AH, van Kuilenburg AB: Defectsofpyrimidine degradarion,Clin-

ical, nolecular, and diagnostic aspeccs.Adz Ex.p Med Biol 2000t486:

233 241.

Wons DR Hafiis JC, Naidu S, et al: Dopamine transponers are markedly

reduced n l*sch-Nyhan diseasen vivo. Pror Natl Acad SciU S A 1996193:

5539-5543.

Progeria'smost striking eature esembles ccelerated ging,Thisrare syndrome,also referred o as the Hutchinson-Gilfordprog-eria syndrome (HGPS), has an incidence of -118,000,000.

Affected children do not become exuallymature or reDroduceasa result f \fvere aiJureo rhrive; arenr-ro-childransmissionhas not beenobserved. he clinical diagnosis f HGPS s basedon recognition f commonclinical eatures ndexclusion f other

syndromeshat haveoverlapping eatures.Mutations in IMNthe geneencoding amin A-/C,are the only mutationsknowbe associatedwith HGPS. Approximately 90% of individwith HGPS havehad an identifable MN/ mutation,

C NICAI MANIFESTATIONS.hildren with progeria usuappearnormal in early nfancy,but manifestarionsuch asmfacial cyanosis, sculptednose,"and "sclerodema"mav sugthe exist€nce f the syndromeat bi rth. Profound growrh {a

occurs n the 1styr of life. Thecharacterisricacies, lopeciaof subcutaneousat, abnormal posture, stiffnessof joints,bone andskin changes sually become pparenr n the 2nd ylife (Fig,90-1). Moror and mental developments normal.dominant clinrcal manifestations ncludeshort stature; wedistinctly ow for heighr;diminishedsubculaneousar; headproportionately arge for face; micrognathia; prominenr sveins;generalized lopecia;prominent eyes;delayedand abmal deDtition; pyriform thorax; short, dystrophic clavi"horse-riding"stance;wide-based hufflinggait;coxa valga,limbs,and prominent,stiff joints;and failure to complece ematuration.

Featuresrequentlypresenr reskin hat is thin, taut, dry,wkled, and brown-spotredn various areas;sclerodermatousover the lower abdomen,proximal thighs,and buttocks;pro

nerrtsuperficial eins; ossof eyebrows ndeyelashes;ersistpatent anterior fonranel; sculpted, beaked nasal tip; fnasolabialcyanosis; hin lips; protruding ears; absence flobules; hin, high-pirched oice;dystrophicnails; and progsive radiolucencyof the rerminalphalanges nd distal clav(acro-osteolysis).ifferentialdiagnosisncludesmandibularadysplasia,Cockayne syndromerHallermann-Streiffsyndroand neonatalprogeroidsyndrome \(riedemann-RautenstrWernersyndromes anotherdisease f premarureagingduedominantly o murations n the DNA helicase ene Table90

Figure 90-1. A 4.5yr old Bnl with height of 1.75yr and bone age of(From Wilkins L: Diaposrs and Treatmmt of Endocine Disordets in Chood and Adolescetce,3rd ed. Springfield, L, CharlesC Thomas, 1965



FIIIURE

Mll',|unberGuratraeftis)60netks0rset|lairg0yingiidtIl055

tlin hinniru

Sub(utaneou55tueos5SkiI iklfrcationAnkleheritioHA,:*eralostsOtaracls5honsraturc(0)GYalgd

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Chaplerl i ThePorphyrias

muscular dyscrophy1B, Charcot-Marie-Toothiseasemandibuloacraldysplasia,and atypical Werner svndromeTable90 1).

PR0GN0SIS.hildrenwith progeria suallv av ese"ere thsclerosis,nddeath ccurs sa result f complicationsf caror cerebrovascular isease, enerallybet*'eenage 5 and 20wirb a medranif e spanof =13yr Cataracls nd tumorshinfrequenclv been noted, but many changes associated

normal aging n adults, uchas presbycusis,resbyopia,senils, osteoarthricis, enilepersonalitychanges, r Alzhedisease,reno t found,

TREATMENI o specific reatment or thisconditronexists.This a progena foundarion (u.wrv.progeriaresearch.org),hmainrains ProgeriaRegisrry o help with diagnosis nd o dernoreclearlv he incidence nd molecularbasrs f chedisord

Bro$'n VT, Gordon LB, Collis l-S: Hutch,nson-G,lford progeriasyndron

a;cnc Rev,ewsat Ccnc Tesrs:N.ledlcalCenerics nformarion Rescurce

baseonlinel AvallabLe c hrrp://r'w$'senerestsors/(updaredAnsust 20

CapeUBC, Erdos VR, Madigan ll', er al: lnbrbinng farn€sylationof proprerents he characteristicnuclear blebbing of HLLrchinsonGilford pro

syndrone ProzNari Acad S./ U S A 200i ;102:12879 12884

Chen I, t-ee ., KudLow A, et al, lMr\H mutarions n atypical Werner\

drome. I-!,r.el 2003j-163r44(H45.

Eriksson.1v1, rol.n V! Cordon LB. ct al: Rccurrenr de novo point m

lions in lamin A cause Hurchnrson Cilford progeria syndrome. N

2001;423,293-298.

Hegele RA: DrawjnB rhe l ine rn progena svndromcs Larcer 2003

416417.

Porphyrias are metabolic diseases esufting from deficienciespecific enzymes of the heme biosynchetic pathu.a-r T

elzymes are most active n bone marrou'and [ver. !?hen tdiseasesare manifesr, accumularion of 1 or more intermedi

occurs nit ially in I ofthese t issues. r,vthropoietic orphyria

rvhich overproduction of heme path*ay intermediates occursmarily in bone marrorv erythroid cells, usually present at birt

in early childhood u.ith cutaneous photosensitiviry, or in the

of congeniraler\throporetic porphyria. even in utero a\ nu

mune h,vdrops..Nlost orphyrias are hepatic, with overpro

cion aod init ial accumulatiorr of porphyrin precursor

porphvrins occurring 1st n the liver.Regulacor,v echanism

heme biosvnthesis n liver are drstinct from those in che bmarrow and appear !o account lor activation of hepaticph,vriasduring aduLt li ie rather than childhood. Homozyforms of che hepatic porph,vrias may manifest clinically priopubertl and asymptomatic heteroz-vgouschildren rnay preu'ith nonspecilic and unrelated symptoms. Parents often reqadvice about Long-term rognosisand intormation abou! m

ll4andibularypoplasia - +

,{heDsderc5i5 + +

osteopeoia/o(mporcsis + +

L!rySedtopi'yiShwa) + +

Ilymi( rcphy + -

D lbrdbleItpogonadhm + +Grcersur(ep'btt) + -

MlM,MendelianderitancnMro+,pnltinj-,absnli,lodiftedtDir1egekA:'rwirqleinenpng€iiy oms on r 001J62r416*417

LAB0RAT0RY INDINGS.hriable degreesof insulin resistance

ioccasionallv,nsulin dependenr iabetesmellirus),abnormalines

ar e no demonstrable bnormaliries f chyroid,parathyroid,pitu-

itar-v, r adrcnal tunccron.

M0IECULABPAIH0GEi{ES|S. he nuclear lamrna, a procein-

containing layer arcached o the inner nuclear membtane, is com-

by alternative spl ing of rhe LMNA gene transcript. SeParale

genes ncode ami Bl and 82. Lamin A is normally svnthesized

as a precursormo cuJe prelaminA). Alternativesplicingwichrn

exon l0 givesrise to tu'o different mRNAs that code for prelamin

A and lamin C. PrelaminA, rvith 564 amino acids,ha s 98 uniqLre

carboxy-termrnal mino acids.Lamin C has six uniquecarboxv

termrnaLamino cids.Because relamin A containsa CAAX (cvs-

teine-alipharic lipharic-anv amino acid) box ar its carboxyl

terminus, r is modilied by farnesylation,whereas amin C is noc.

After farnesylation, cleavage of the last three amino acids, and

methvlahon of che C-terminus,an internal proteolytic cleavage

occurs, removing the last 15 coding amino acids, to Senerate

mature lamrn A with 646 amino acids. The most common HGPSmutation is a G608G (GGC > GGT) muration in exon 11. This

mutalion results n an activation of a crvptic splice site within

exon 11, result ing n production of a rranscript hat deletes50

amino acids near the C-terminus.The HGPS G508G mucation

and consequent abnormal splicing produces a prelamin A

that relains the C,{AX box but is missing he site for endopro-

teolytic cleavage.This HGPS mLrtation acts as a dominant nega-

tlve mutatron.A grorving li sc of other diseases s associated with differenr

mutations in IMNA, which have come !o be knoE n as

laminoparhies. These nclude Emery Dreifuss muscular d,vstrophy

tvpe 2, familial dilated cardiomyopatbyand conduction s,vstem

defects, Dunnigan t,vpe amilial partial lipodysrrophy; limb girdle



638 PABTX MetabolicDiseases

agementoi thesedisordersand drugs rhat can be taken safely o

lrcat other common conditions.

The D\A sequences nd chromosomal locatxrns arc escablished for the hrLman genesof rhe enzvmes n this pathwan and:nult iple diseasc clated mutations have been iound fol eachporph,vna.Al l bu t 3 oi the inheritedporphyrias displav autosonraL dominant jnheritance.Although iniriaL diagnosis of por-ph,rria by biochemicalmerhods emainsesscntial, r is especrallyirrportanr in chilclrcnco conlirm the dragnosis ,vdemonsrracing

a speciEcgene lnu tation(s).

THE EME IOSYNTHETICATHWAY

Heme is required for a variery of hemoprotcins such as hemo-globin, m,voglobin, respiraror,v c_vtochromes, and c,vrochrome

P450 enzyrnes (CiYPs). k rs believed rhat the ll enzyrnes in thepathway for heme bursynthesis re acrive n all r issues.Hemo-globin s,r'nrhesisn erythroid precursor cells accounts for =85-nzo

r f . l ; i l y hcm r un rhc . r ' r rhuman. .Hepa to . r t c .a . co r r r r o r rnu r t

of the resr.primarily ior s,vnrhesisf CYls, u.hich are especially

abrndant in the liver endoplasmic criculLLrnER), and turn overnrore rapidly than many other hemoproteins,such as the mito-

chondnal respiratory cltochromes. As shorl,l in Figure 9l l,

pnth\.ay inrcrmediates re the porphvrin precursors i-aminole-

vulinic acid (l\Lr\, alsoknorvn as l-aminoler.uLiniccid)an d po rphobilinogen (l' ]BG),and porphyrins (mostly in rheir reduced

forras, knou'Lr as porphvnnogens).Ar least in humans, these

intermediates o not accumulale n signif icanramounts under

normal condit ions or have rnportant physiologic r.rnccions.

A deficierrcy oi each enzyme in rhe pathrvay, *'irh rhe excep-

tion of che1st, s associated -itha differentporphvria lTable 91 -

1). The 1sr enzyme,AI-A synthase AIAS), occurs n 2 fonns.

Al erythroid specilic form, f ermed ALAS2, is deficienr in X

linked sideroblastic nemia,due fo mutationsof rhe AI-A52 gene

ol chromosorneXp1l.2. The ubiquitorLs brm of rhis enzyme,

rermedALASI, is found in all r issuesnclnding iver,and ils gene

is locatcd on chromosomc3p21.1. Discasc elatedmutations of

AI,AS L have rot been described.

Regulation of heme svnthesisdiffers rn the 2 m:rlor heme-

tbrming t issucs I-ivcr henc biosynthesiss primary conrrolledbyALASl . S,vnchcsisf ALASl in liver s reg acedby a "free" heme

pool {seeFig. 91-li, rvhich can be augmenrcdb, vner;r' ly vnsized heme or bv exis ring hcme released rom hernoproreins destrned or brcakdown to biliverdjn by heme oxygenase.

In the cryrhron, no\el regulatory nrechanisrns allorv fbrproduction of drc ver,v argeamountsof hemeneedeclor heglobin synrhesis. he response o stimuli for hemoglobinsynsi soccursdLrring el ldifferenriation, eading o an increasel number- Also, unlikc th e liver, heme has a shmulatory rolehemoglobin ormation, and the stimularion of hemc s,vntheerythroid cells s accompaniedby incrcases ot onl,v ll ALA

but also b,v sequenrial induction of other hcme biosynthenzymes. Separate ertthroid specilic and noner;-throid

"housekeeping" ran\cripts are known ior the 1sc4 enzvmethe pathu'ay, The separarc iorms of ALAS are encoded by ge

on differentchrooosomcs, bur for eachof the othcr 3, erythrald nooervthroid trdnscrpt s are rranscribedb, valtcrnativep

moters n the samegene.Heme also regulates he rate of its srhesis n erythroid cellsbv controll ing thc transporr of iron iretrculocyles.

Intermediares of the heme biostntheric pathway are efficienconverced o hene irnd, Lrormally,otly small amounrs of inrermediates are excreted. Some may undergo chemical modcations bcfore excretion.Whereas he porphyril precursors

and I 'BG are colorless, nonfluorescenr,and largeL-v rcreunchanged n urine, PB(i ma1'degrade o colored producrs s

as rhe L)rolv11ishigrnent calLedporphobilit or spontaneopolymerize o ur<>porpb,vrLls.orphvrins are red in color a

displavbright red f luorescence hen cxposed o long wavelen

ulrravioler ight. l 'orphlnnogens, rvhich arc colorlessand tr

fluorescent, are the reducecl orrr of porpbyrins, and lr'hen t

accumulatc,ar c readily aucoxidized o the correspondingp

phyrins outside the cell. OnLl' the c1'pe II isomers of uropphynnogenand coproporphvrinogenare cor'rvertedo herneF ig .91 1 ) .

ALA and IrB(] are excreted n urinc- Excrcrion of porphvr

an d porphvrinogens n urinc or bile s determinedby the num

of carboxll groups. those rvirh many carboxvl groups. such

uroporphvrin (ocrac;rrboxllporphyrin) and heptacarboxylp

phyrin), are rvater soLuhle nd readiJ,v xcrctcd n urinc. Thrvith ferver carl.oxll grorrps. such as protoporphvrin (dicarbo

porphvrio), are not warcr solr.rble nd are excreted n bile afeces. Coproporph,vrin (terracarboxyl porphyrin) is excre

0t5EA5rABSfiEVrAflo

ij Am olevuliniidderyiraraie

ro.ph/ ADPI

AtuL.ntermrtteftr0[lri (AlP]

lomozyqowAlP(onqenitari'lhropoielirorphyrai:EP) Utapophynaqenll ynth,ta

iURtr'Porpi l r i .utaneidd ara )rt i re

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Hpprtocrythropor:porpilr (lraF)

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aapnpatphwiaaet r)datc(lY))

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fiUIATloilSf IHls ZYmt PnEEilIATl0ll

Nomozygoue flosrlyostubary

fleteroryqour Po$pubertyllomo?ygous 0ildhood|]omo?yqoLrs lnuteroi nfan(y

None Adrllls

fleterozygoui AdiltsNooe Adrlr5flomoz|1tous [hildhoodfletemzygous PgtpubenyNcmo4llous (hiidhood

Hrleuyqoirs PoitpubeftyHomozygous th dhaodHopmlylousheteroalelkith th dhmd

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EITZYMIABBREVIATION)

dehjd tnte ALAD)

Pu hah ney n deo i nateP860

J(

XX

xx

I

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x

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X

.AtP&d r1tPircoftdend r lai lFoar. rlphynas,bltbtait al:Il(frFs i dilho.itezi( prolopoahr5u9Fn nnihopoklromFrmnttp| : i5dUet0nhb(0noihepi | tUf00AUls0m; |donmdlmha| i imeolapar Iade[ ( iency0lU800isaplEdl



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64ll PABTX ilerabolic iseases

partly in urine and pardy in bile. Because oproporphyrin ismore eadily€xcretedn bile than s coproporphyrrn II, impairedhepatobiliary unction may increaseotal coproporphyrinexcre-tion and the ratio of these somers.

CTASSIFICATION1'ID IAGNOSISFPOBPHYRIAS

Two classification chemes eflect either the underlyingpatho-physiologyor clinical eatures, nd both are useful or diagnosisand reatment see able91-1). n hepaticand erythropoietic or-phyrias, he sourceof excess roductionof porphyrin precursorsand porphynns s the iver and bonemarrow, respectively. cuteporphyriascauseneurologicsymptoms hat are associated ithincreasesf 1 or both of theporphyrin precursors LA and PBG.In the cutaneous orphyrias,photosensitivity esults rom trans-port of porphyrins n blood rorn he iver or bonemarrow to theskin. Dua[ porphyria refers o the very rare occurrence f defi-ciencies f 2 differenrhemepathway enzymes,

It is notable hat acute ntermittentporphyria (AIP),porphyriacutanea arda (PCT), and erythropoieticprotoporphyria (EPP),the 3 mostcommonporphyrias,are very different n clinicalpre-se[tation, precipitating actors,methodsof diagnosis, nd effec-tive therapy (Table91-2). EPP s probably rhe porphyria rhatmost commonlybecomesmanifesc eforepubercy. wo of the 4acuteporphyrias, hereditarycoproporphyria (HCP) and varie-gateporphyria(VP),can alsocauseesionsndistinguishableromPCT (see able91-1).Congenital rythropoietic orphyria (CEP)causesmore severe listering esions, ften with secondarynfec-tion andmutilation. EPP s distinct rom the other cutaneous or-

phvrias n causingnonblirrering hotosensiti\ 'rtyha t occursacutetyatter sunexposure.

FISSI-I-INEAB0BAT0SYDlAGilO$lC TESTING. few sensitiveand soecific irstline laboratorv esn should be reled on when-ever symptomsor signssuggest he diagnosis f porphyna. f afrrst-lineor screeningest is significantlyabnormal, more com-prehensive estingshould follovv to establish he type of porphyria, Overuseof laboratory tests for screening an lead tounnecessaryxpense nd evendelay n diagnosis.n patientswhopresentwith a past diagnosisof porphyria, laboratory reportsthat were the basis or the original diagnosismust be reviewed,and if thesewere nadequate,urther testingconsidered.

Acute porphyria should be suspectedn patientswith neuro-visceralsymptomssuch as abdominalpain after puberty,wheninitial clinical evalualiondoes not suggestanother cause,anduritaty porphytix ptec&rcors ALA and PBG.)should be mea-sured, Urinary PBG is virtually always rncreased uring acuteartacksof AIP, HCP, and VP, and is not substantially ncreasedin any other medicalconditions.Therefore, his measurementsboth sensrtive nd specilic.A method or rapid, in-housecestingfor urinary PBG,suchas he TracePBGkit (TraceAmerica/TraceDragnoscics,ouisville,CO), should be available n houseat allmalor medical facilities. Results rom spot (singlevoid) urinespecimensare highly informative because very substantialincreases re expected uring acuteattacksof porphvria.A 24 hrcolleccion an unnecessarilyelaydiagnosis, he samespot urinespecimen hould besaved or quantirative etermination f ALAand PBG, n order coconfirm hequalitativePBG esult,and also

detect patientswith ALA dehydratase orphyria. Urinary pophyrins may remain ncreasedonger han porphvrin preculsin HCP and VP. Therefore, t is useful o measureotal urinaporphyrins n thesame ample, eeping n mind rhat urinarypophyrin increases re often nonspecific,Measurement f urinaporphyrinsalone should be avoided or screening, ecauseheareoften ncreasedn many disorders ther han porphyrias, uaschronic iver disease, nd misdiagnosesf porphyriacan resfrom minimal increasesn urinaryporphyrins hat haveno dianostlcslgnlncance.

PBG is a colorlesspyrrole rhat forms a violet pigment wiEhrlich reagent (p-dimethylamrnobenzaldehyde).ther sustances, rincipally urobilinogen, also react with Ehrlich aldhyde, The Vacson Schwartzand Hoesch ests,which involvrnitial addition of Ehrlich reagent o urine, are considered bslere. A reliable quantitative method for both ALA and PBwhich uses mall amon and cationexchange olumns o separinterfering substances efore adding Ehrlich reagent,has beavailable or manyyears.ALA ls reacted o form ap1'rrole,whris thenalsomeasured sing Ehrlich reagent.The TracePBG kis based n this method.

Measurement of erythrocyte porphobilinogen deamina(PBGD) s not usefulasa firstline test n rhe acutesettingbecauir does not differentiate atent from acriveAIR Moreover, henzymeactivity is not decreasedn all AIP patientsand is nev

deficient n other acuteporphyrias.BlisteringCutsneous orphyrias, listeringskin lesionsdue

porphyna are virtually alwavsaccompanied y increasesn totplasmapotphyrins. A fluorometricmethod s preferred,becauthe porphyrins n plasma n VP are mostly covalendy inked plasma proreins and may be less readily derectedby higpressure iquid chromatography HPLC),The normal range oplasmaporphyrins s somewhat ncreasedn Fatientswith enstase enaldisease,

lionhlistering utaneousorphyria.hhough a total plasmapophyrin determinacion ill usuallydetectEPI an erythrocyte rtoporphyrin determination is more sensirive. ncreaseserythrocyte protoporphyrin occur in many other conditionTherefore, he diagnosis f EPPmust be conflrmedby showingpredominant ncrease n free protoporphyrin rarher than zin

protoporphyrin. nterpretationof laboratory repons can be d6cult, becausehe term "freeerlthrocyteprotoporphyrin" somtimes actually epresents inc protoporphyrin.

SEC0ND-I|I{E ESTlilG,More extensive esting is v .ell justifiwhen a firstline test rs positive.A substantial ncreasen PBmay be due to AIB HCP, or VP. Theseacuteporphyriascan bdistinguishedby measuring erythrocyte PBGD, urinary pophyrins using he same pot urine sample), ecalporphyrins,anplasmaporphyrins,The variousporphyrias hat causeblisteriskin lesionsare differentiated y measuring orphyrins n urinfeces,and plasma.Confirmationat the DNA level s importaonce he dragnosiss established y biochemical esring.Furthdetails are provided n the follou'ing sectionson each type porphyfia.

TESTINGOB UBCLlillGAt0flPHYBIA.t r sofien diffrcult o dianose or "rule out" porphyria in patients who had sugges



to euid rhe choiceof tests or rhe family members.The index

casi or nother arnilymemberwith conlirmedporphyriashould

be retestedf necessary.dentilicationof a disease-causinguta-

tion rn an index casegreatly facilitatesdetecrionof additional

Sene arrlers.

6-AMINOTEVUTINICCIDDEHYOBATASEPOBPHYRIAADPI

This s the most ecendydescribed umanporphyriaand s some-

times ermedDossporphylio aket th,envestigator ho described

the 1st 2 cases.fhe

tern pluttboporpDyriaemphasizeshe sim-

ilarity of this conditionto leadpoisoning,but rncorrectlymplies

that it is dr-reo lead exposure.

PATH0t0GY NDPATH0GENESIS.LAD catalyzeshe condensa-

tion of two molecules f ALA to form the pyrrole PBG(seeFig.

91-1).The enzymes subject o rnhibitionby a numberof exoge-

nous and endogenous hemicals.ALAD is rhe pnncipal lead-

binding protein m erl/throcytes, nd lead can displace he zinc

atomsof the enzyme.ErythrocyteALAD acrivity s alsoa sensi-

rive ndex of lead exposure,A1lADP casesnheriteda differentALAD mutatron rom each

parent.ElevenALAD mutations,mostl point mutations,hav€

beeo dentified,someexpressing arrial ctivirv,such hat heme

synthesiss partially preserved. he amount of residualenzyme

activity may predict the phenorypic severicyof this disease.Immunochemical tudies n 3 cases emonstracedonfunctional

enzymeprorein that cross reactedwith anti-ALAD antibodies.

Late-onset asesassociatedwith a myeloproliferativedrsolder

may be heterozygous r have a somaticmutatron, with expan

sion of an affected lone of erythroidcellsADP is often classified sa hepaticporphyria,although he sice

of overproductionof ALA is not established. patient with

severe, early-onset diseaseunderwent liver transplantation,

rvirhout significantclinical or biochemical mprovement,whrch

might suggesthat the excessnrermediates id not originate n

the liver Excess rinary coproporphyrin II in ADP might origi-

nate ro mmetabolismfALA to porphyrinr.:gensn a tissue ther

rhan the site of ALA overproduction Adminisrration of large

doses f ALA to normalsubjecrslso eadso substantialopro-

porphyrinuria.ncreasedryrhrocyteroloporphyrinma), as ni ll orherhomozygousorphyrias, eexplained y accumularion

of earlierpathway ntermediatesn bonemarrow erythroidcells

duringhemoglobin ynrhesis,ollowed by their transformation oprotoporphyrin after hemoglobinsynthests s complete.As in

other acuteporphyrias, hepathogenesisf the neurologicsymp-

toms s poorly understood see eccion n AIP).

CtlNlCAt MANIFESTATI0NS.n most cases, ymptoms esemble

otheracuteporphyrias, ncludingacuteartacks f abdominalpain

and neuropathy. Precipitating facrors, such as exposure to

harmful drugs,havenot beenevident n most cases. our of the

6 reportedcaseswere adolescentmales.A Swedish nfant had

more severe isease, rth neurologic mpairment and fai lure ro

Chtptergl ThaPo4lryrias 6

rhrive. A 63 yr old man in Belgiumdevelopedan acute motpolyneuropathy oncurrenrlywith a myeloproliferative rsord

tAB0BAT0RY INDINGS. rinary ALA, coproporphyrin lI, aer],throcyte zinc procoporphyrin are substantially increas

Urinary PBG s normal or slighrly rncreased. rythrocyteALAactivity is markedly reduced, and both parents should haapproximatelyhalf-normal activity of this enzymeand norm

urinary ALA.

DIAGN0SISNDDIFFEREI{TIAL|AGN0SlS.he 3 otheracute ophyrias are characterized y substantialncreasesn both ALand PBG. n contrast,ALA but Dot PBG s substanciallyncreain ADP A marked deficiencyof erythrocyteALAD and hanormal activity n the parents uppor! he diagnosis.Other cauof ALAD deficiencnsuch as ead poisoning,must be excludSuccinylacetoneccumulatesn hereditaryyrosinemia ype1 ais structurally similar to ALA, inhibits ALAD, and car cauincreased rinary excretionof ALA and clinical manifestatithat resemble cuteporphyria, Idiopathic acquiredALAD deciency has beenreported. Unlike lead poisoning, he deliciALAD activity is nor restored by the in vitro addition sulfhydryl eagents uchas dithiothreitol. Even f no other cauof ALAD deficiencys found, it is essential o confrm the dianosis

ofADP by molecularstudies.

TREATMENTreatment experiences Lnited but is similarother acuteporphyrias.Glucose eems ot veryeffeclivebut mbe ried for mild symptoms,Hemin therapywas apparentlyefftive for acuteattacks n adolescenrmale cases, nd weekly nsions orevenced ctacks n I of these cases.Hemin wa neffectiveeither biochemicallyor clinically in the Swedrsh hwith severe rsease,nd produceda biochemical esponse utclinical mprovement n the Belgianman wirh a late-onsetorwho had a peripheralneuropathybut no acuteacracks. emrnalsoeffective n treatingporphyrialrke symptoms ssociatedvhereditary yrosinemia, nd can significanrly educeurinary ALand coproporphyrin n leadpoisoning.Avoidanceof drugs hare harmful n otheracuce orphyriass advisable,jver ra

plantationwas not effectrven the child with severe isease.

PROGN0SIS.he outlook is generally good ir typical casalthough recurrentattacksmay occur The coutsewas unlavable n cheSwedish hild with more severe isease, nd rs unctain in adultswith late-onset isease ssociated ith myelopIiferative isorders.

PREVENTI0NN0 GENETIC0UNSEtING.eterozygousareshould be aware that subsequent hildren are at risk for tdisease, s n any autosomal ecessiveisorder.Diagnosisn uris possible, ut has not been eported,

ACUTENTERMITTENTORPHYRIAAIP}

This disorder has also been tennedpyrroloporphyria, Suteporphyia, and ifltefttlittent acute porphyria and is the mcommon ypeof acutc orphyria n mostcuuntrie..

ETl0t0GY- IP resuhs rom the deficientactrvrty of the houkeeping orm of PBG deaminasePBGD).This erzyme s aknown as hydroxymethylbilaneHMB) synthase;he prior teuroporphyrinogen synthase s obsolete.PBGD catalyzesdeaminationand head-to-tarl ondensation f 4 PBG molecto form the linear errapyrrole,HMB (alsoknown aspreuropphyrinogen;eeFig. 91 1). A uniquedipyrromethaneofabinds the pyrrole intermedrates r rhe catalytic sice r.rntpyrroles (including rhe dipyrrole cofactor) are assembledn



642 PARTX Mebbolic oiseases

Iinear fashron, after rvhich rhe tetrap,vrrole H\.{B is reLeascd. heepo deamjnase enerateshe dipyrrole cofactor o fornr fhe holodearninase. nd fhi s occurs more readrl,v rom HMB thar iroml'BG. lnclecd,high concentrarions f PB G mal inhibir formarionof rhe holodeamilase. The product HMB can c1'clizc onenzymalicall,v o form nonphysiologicaluroporphylinogen I, but rnth e plesence f the nexc enzyme n the pachrvav s more rapidlvclclized to iorm uroporphvrinogen ll .

Eryrhroid and housekeeping orms ol the enzvrne re cncodedby a singlc geneor hurnan clrromosome l I I1t124.1->qZ4.2),

r,r 'hich ontains 15 exors. fhe 2 isoenzlmesare both lnonomericproteins and diifer or-rly hghdv in molccurlrr weighr (=40 an d42 kd, respectrvelv), nd rcsult rorn alternative plicingof exons1 and 2. The crvthroid specif ic soenzyme, hcrcfore, s encodedb, vexons 2 through 15, and rhe eryfhrordpromoter. vhich un cti(xrs onlv in erychroid cells, is locarcd immediateLy pstreamlron exon 2. Thc housekeepingsoz_ynles cncodccl l exons 1ancl3 rhrough f-i, and rs promoter s nrnediateh upstream ionrexor I (l is lcring sequences ind thc erlrhroid specif icD\A-

bindrng factorsNF E1 and NI,-1,i2,eading ro c\pressi(D of rhe

cr,vthroidpromoter.The housekeepirgpronloter f l lncoons in al lcell types, rcl uding erylhroid cclls.

The pattern oi inhcritanceof AIP it autosornaLlominanr, vithr.ery are homozygous ases hat present r childhood. .{ore rhan200 l:BCD rnutati()ns, nclLrdingmissense, onscnse, nd splic

iog rnutations and insertionsan d dclctions have been rdenril iedin i\ lP, ald in manv populatron groups, lclucling l>lecks. \ ' lostmlrtarions are lound in only 1 or a fcu families. But due rofounder eifecrs,somc ar c rrore commoLr n cerrain geographic

nrcas such ns northern Su.eden V'19llX), Holland iR116\fl,Argentina ((il l6R), Nova Scotia (l(17iW), anrl Srviczeriald(If283X). De novo mutations may hc fbr.rnclu =37u of cases.

Ohester porphyna was initiallJ' describcd as a variant forrn of

acutc porphyria in a large Lnglish famill-, brrr \ras iound ft) be

ciuc ro a PBGD rnutation.' lhe naturc of rhc PBCD mutation

does not account ior the severity of che clinical presentation,

n'hich varics markedll r, ithin lamilies.

\. lost murations ead ro approximatelyhalf-norrnalactivity of

the housekeeping ard eryrhroid isozymes an d half norrnalamounls of rheir respectivc nzymeproteins D alL issues f het-

eroz,vgotes.n =5!16of unrelatedAI P parlents, hc housekeepingisoz,vmes deficicnt.but the erythroid specrfic sozymes norrnal.

\4utarions caLrsinghis variant are usuallv found rvjthin cxon 1

or irs -i ' splice clonor sire or iniriation of rranslation codon.Lnrnunochemical methods can distinguish mLrfations hat are

CRlN4-posirrve r.e., havJng cxcesscross reactive mnunoi()gic

material CRl,\.11elative t) he mutanI cnz! me activit,v)!whereas

CRI\{ negative mutafions either do rot synfhesizca mutanl

enzlme protein. or the proteiD s not staL)le Ll dn()t immunolog

icall,v detectable using ann-PBC;D intibodres. A chiid rl, ith

homoz-vgousAIP was founcl to have inheritcd a diftcrcnt CRIN'I

p()sitrve utarion from eachparent.

PATII0L0GY N0 PATH0GENESIS.nducrion of rhe rateJimiting

heparic nz,vneAl-AS1 s thought to underlieacureexacerbations

of rhrs and rhe other acure porph,vrias.AIP remarns arent (o ras)'mptomatic) n the great mxjority o{ rhosc rvho are heterozv

[jous carriersof PBGD mutatiots, and rhis s aimosf a]rlays the

casebeforepuberty. n rhose vith no hisrorv of acutesymproms,

porphvrin precursorexcrccion s usuall,v ormal, suggesling hat

half nornal hepatic PBCD acrivity is sui6cienc and hepatic

ALAS1 accivity s not rncreased.Many nongenetic acrors chat

lead to clinical expressiono[ AII ' , including cerrain drugs an d

steroidhormonesJ ave he capaclty o inducchepaticAI AS1 and

CYPs. tJnder condit ions n r.hich heme synchcsiss increasedn

the liver, hrif normal PBGD actrvity ma-v become limirrng and

ALA, PBG, and othe. heme parhway intennediates malv accu

muLate. n addit ion, heme synthesrs ecomesmpaired and heme

mediatcd rcprcssionoi hepatic Al,ASl is lesseffecrive.

Ir is not proven,horvc\jer-ha t hepaticPBGD renains conar =50-! ' .oi normal dcriviry during exacerbarions nd remof AIP, as in er_vthroc-vrcs.n earl,v cport suggested haenzvmcactivit l. s consrderaLrlyess han half-nornlal n rheduring an acuteatrack. lepatic PBGD activity night be rediurther once,{ll ' becorncsactivared f, as rccenrly suggexcess BC, nterfcres,vlthassembl,vf ch edipyrromerhanetor for dris cnzymc. t also seems ikely chatcurrentlv unkngeneti. f ircors play a contriburing role in, for examplc! pau.ho cortinue to hat,e artacks even rvhen l<rtou'n prccipitant

avoided,The fau thar,{lP is :rlmostalwa,vs atenr bcfore puberry

gesfs h:rt cndocrine actors,adult Icr,els f sreroidhormoneimporrant ior clinical exprcssion.Symptoms arc more comin u'omcn, which sr.rggesrsrole for fcr rale hormones.Prcstrual attacks are probrbll due to endogenousprogesteAcutc porphvrias ar e sometirncs exacerbared bv cxoge' te ro rJ . . r r r . r r . l r n l I ' r . co r r t rac ! , p l r rn rc ld i l i o ' r ( \ r 'D lJprogesfins.Surprlsingll-, regnancy s usuallyu'ell tolcratedgc:cing rLrat beueficial rnetabolic changesma,v arncliorat

cffuctsof high Jevels i progesterone.

l)rugs rhat are unsafc in acute porphvrias (Table 91 3) incthose har.ing rhe capacit,v o induce hepatic ALAS1. r.vhcloscl,v ssociated ,vith nducrion oi (lYPs. Griseofulvin exanple oi a .hcrnical thrt can iDcrease eme turnover by

m.rting the destruction of specihc (lYPs co form an inhibitoferrochelaraseFE(il{. th c linal enzvme n rhe pathwa,v), uN-rncthyl pror6p6rphyrrr. Sulfonarnideandbiotics are harLrutapparett l l not inducersoi hepaticheme svnthesis.Ethand orhcr alcoholserc inclLrcersf ALr\ synthasc nclsomeC

Nutrit ional factors,principalll-. educed ntake of caloric

carbohvclrates. s nlay occur $.ith il lncss or attempfs to

UI{5AfE

Bartituctes*tllfonamideaniol15'Mepr0bamaie*

,rh0mebutariate,*

butamate*)[arisoprcdo]"6lutethmLdr*Meihyprylontth(horvynoL'MepnenyloinPhenytlrin*5ucof rde![abimazepne*IonazepamPnnidone*Vaiprciccd'Pyftolone5min0pyrine,nllpyrine)6ri5eofLjn*

EqolsMetodopEmde*RibnFn*

PyGzhamide*Di(loftnac*PngeneonendynlhetpmEen5*Danazo'AkohlrlA[E h]bors6pecalynapril)Gkiurnh,rnnelblo(keIerpKialyedipineJKet0c0nazl)leRifumpn

SlFt

tarcctcrdl!P5

A5prfn

Arelirinophen

fnenct lzfe5Pel inalli dl1fi!at

nfepto:nyci; Ji:riar-io5

BDmCe!

n 5 u t 1

Aircp e(rmetdrne

llanitiirne

Aietin mhm(frira

Afctazclariie

A opurf !

lm or e

Bethdnidre

Bumetanide

ainei re

lcumirnr:luoxerre

iaD;pPftn

aent imnir(ra1.":hid?

CtuMlpr.iFLn..cl

5u( y honi

Tetirqliins

Ihr pifiil nnq cr not dudealauilibhfdnadonbodruqlelyr drulerphlrlallh€'ourc:hronlulteior ruq5otblEl] e{e

'PoqhIzirIned,r5i cirrEindicr0n.w?mqpit(d!t n,,r dvefi?llerln U.5 bel]nqo ttu edrugrrl|c,ko ted rhaflnfrlpo0hym,r h p&€nnrplraH! hirmful&uLe 0]r!fts iody $d ony rerfew henog€nrqterLrcmbndio$ h errrsFntn exrr€ftarel {rere5 c:e vidrnftrrEarc

'Po0hlm5 BEd apRrarimnU abtllnqu firdtuq ow$Elirisdilgra.!2rd€i5qley tlfi50!



\,r'eight, an increase orphyrin precursorexcretionand tnduce

anail. of porphlrra. ncreasedarbohvdfatentakemavamelio-

.n re" r t r . i r .

Recen tind ing ' nd icarehar hepat ic LASI is

regulatedby the peroxisomeProliferator-activatedeceptory

co"activatoru (PG'C-1cr),hichmay represencn mporrant ink

betweennurritional statusand acureporphyrias.

rologic manrfestations.

EP|DEM|0L0GYIP occursn all races nd rs he mosl common

controls,Populationscreening y erythrocyrePBGD activiryor

DNA analysis evealeda prevalence f =200 hecerozygoteser

100,000n FinLand,nd1 in abour ,675 60/100,000)in rance.

nosnc crlterla,

CLlNlCAt MANIFESTATIONS.eurovisceral manifestations of

acure porphvrias may appear any time after pubeny; but rarel,v

before. Verv .are casesof bomozygous AIP develop severeneu-

rologic manifestations early in chrldhood, and acu!e attacks do

not occur.

In affected heterozygotes, acute attacks are characterized by a

constellation of nonspecrfics,vmptoms,which may become severe

and life-threarening. Abdominal pain occurs in 85-957o of cases,

rs usually severe, steadn and poorly localzed, but somenmes

cramping, and accompanied by srgns of ileus, including abdom-

ChaFergl r ThePoiphyrias

inal distention and decreasedbowel sounds. Nausea, vomiti

carecholamines, Ocher common manifestations include me

\!mptomsi pain in the extremities.head, neck. or chesti mu

weakness: and sensorv loss. Becauseall these manifestations

neurologic rather than rnflammacory there is little or no abdinal tenderness, ever, or leukocytosis.

Porphyric neuropathy is primarily motor and appears to le

from axonal degeneration rather than demyelinization. Sen

involvement is indicated by parn in lhe extremities, which m

be descnbed as muscle or bone pain, and by numbness, pa

thesias, nd dysesthesias.aresisma y occur early in an att

bur is more often a late manifestation in an attack that is not

ognrzed and adequately treared, Rarely, sevete neuropalhy

velops when there is lrtrle or no abdominal pain. Motor weak

most commonly begins rn the proximal muscles of the up

exlremities and then progresses o the lower exrremities and

periphery. It is usually symmetric, but occasionally asvmmetri

focal. lnitrall,v, tefldon reflexes may be little affected or hype

tive and become decreasedor absent. Cranial nerves, most c

rnonly the 10th and 7th, may be affected, and blindness finvolvement of the optic nerves or occiprtal lobes has b

reporced. More common central nervous system manifestat

include seizr.rres, nxiecy, insomnia, depression, disorientat

hallucinations, and paranoia. Seizuresma1'result from hypo

tremia, porphyria itself, or an unrelated cause. Chronic dep

sion and other mental symptoms occur in some pacients,

attriburion to porphyria is often diffrcult.

Hyponatremia is common duflng acute attacks. Inappropr

antidiuretic hormone (ADH) secretion is ofren the mosc li

mechanism, but ir is diffrcuk to document and other mechan

musf be considered in rndrvidual cases.Salt depletion from ex

renal sodium loss, gastroinrestinal loss, and poor intake h

been suggested as causes of hypooatremia in AIP In s

pa[ients, unexplained reductions in total blood and red blood

volumes were found and increasedADH secretion might thean appropriate physiologic response- Other electrolyte ab

malities may include hypomagnesemraand hypercalcemia.

The atcack usually resolves qurte rapidly, unless trearme

delayed. Abdomrnal pain may resolve within a few hours

paresis wichin a few days, Even severe motor neuroparhy

rmprove over months or several years, buc may leave some

srdual weakness. Progressron of neuropathy to respiratory

bulbar paralysis and death is uncommon with approprjate t

menr and removal of harmful drugs. Sudden death may r

from cardiac arrhythmia.

tAB0RAT0BYFINDINGS. evels of ALA and PBG are substant

increased during acute aftacks and these may decrease afte

attack but usually remain increased unless the disease becoas,vmptomatic or a prolonged period. A populatton based s

in Sweden indicated that symptoms suggestiveof porphyria

occur in heterozygotes during childhood, in contrast to ad

even when urinary porphyria pt€cursors are nor elevated.

study lacked, however, a comparison with the frequency of

nonspecrfic symptoms in a control group of children.

Porphvrins are also markedly increased, whrch account

reddish r.rrine n AIP These are predominantly uroporph;r

which can form noneozymatically from PBG. But becaus

increased urinary porphyrins in AIP are predorninantlv rsome

rheir formation is likely to be largely enzymatic, whrch m

occur if excessALA produced in liver enters cells in other tls

and is tben converted to porphyrins via the heme biosynt



644 PABTX Motdbolic iseasos

pathway. Porphobilin, a degradation product of PBG, anddipyrrylmethenes ppear o account or brownishurinary discol-oration, Total fecal porphyrins and plasma porphyrins arenormal or slightly ncreasedn AIP Eryrhroclte protoporphyrinmay be somewhatncreasedn patientswith manrfestAIP

Erythroc;te PBGD activiry is approximarelyhalf-normal inmos! patients 7U8O%) with AIP, The norrnal range s wide,however,and overlapswith the range or AIP heterozygotes. snoted, somePBGDgenemutationscause he enzyme o be defi-cient only in nonerythroid issues.Also, PBGD s highly depen-

dent on e rychrocyte ge,and an ncreasen erythropoiesis r-reoconcurrent llness n an AIP patientmay raise heactivity nto theIrormal ange.

porphyrias see able91-2),MeasuringPBG n serum spreferredwhenthere s coexistent evere enaldisease, uc s lesssensitivewhen renal function is normal, Measuremenr f urinary ALA isless ensitivehan PBGand also essspecific, ut will detectADP,the ourth type of acuteporphyria.ErythrocyrePBGDactivity sdecreasedn most AIP patients,and helpsconfirm the diagnosisin a patrefltwith high PBG. A normal enzymeacdvity in ery-throcytesdoes not excludeAIP, however, or reasonsdiscussedearlier.MeasuringerythrocyrePBGD s quite useful or screeningfamily members f a patientwirh AIP known ro have ow enzymeactiviry n erythrocytes.However,5-1570 of indiv idualscan bemisclassified srng the eflzymatic assay.This is not useful ininfants <4 mo of age, when rhe enzymecan be physiologicallyincreased n erythrocyles.Erythrocyte PBGD activity may befalsely ow if processing, torage,or transport of the sample scompromised. Simultaneousmeasurementof multiple hemebiosyntheticpalhway enzymes, s offered by some commerciallaborarories,s less eliable han assayshat urilizespecilicsub-srrates. report of low activitres f both erythrocyreALAD andPBGD suggests n unreliable esult,

Knowledgeof the PBGD mutation n a family enables eliableidentificationof other gene arriers,PBGD deficiency anbe doc-umentedn a ferus y measuringheenzyme ctivity n amnioricfluid cells,or more reliably by frndinga PBGD mutadon n thes€cel ls.

C0MPtlCAT|0NS.IP and other acuteporphyriasare commonlyassociated ith mild abnormaliriesn liver function.The risk ofmore advancediver disease nd hepatocellular arcinoma s alsoincreased uring adult ife, perhaps 0- o 7O-fold, ven n asymp-tomatic ndividualswho have ncreased orphyrinsor porphyrinprecursors.Few patients who developed his neoplasm hadincreasesn serumo,-fetoprotein, herefore,cufrent recommen-dationsare hat patientswith acr-rceorphyrias,especially 50 yrold, be screened t leastyearly by ultrasoundor an alternativeimaging method.

The risk of chronic hypenensionand impairedrenal funcrionappears o be increased n AIP Hypertension or a possible

nephrotoxiceffectof ALA may explain mpaired enal funcrionin AIP, which may progress o severe enal failure and requirerenal ransplantation.

Increasedserum thyroxin levels due to increased hyroxin-binding globulin occur in some AIP parients. Hypercholes-terolemiaand elevatedow-density ipoproteincholesterol ppearco be esscommon n this disorder han previously hought.

TREATMET'lTHemin. ntravenoushemin, combined with symptomaticand

supportivemeasures,s the treatmentof choice or most acuteattacksof porphl,ria.There s a favorablebiochemical nd clin-ical response o early reatmentwith hemin, and less esponseftreatmeflt s delayed. t is no longer recommendedhat therapy

with hemin for a severe ttack be srartedonlv after an uncessfulrialof inrravenousiucoseor several ayr.MiJdatrawithout severemanifestations uchasparesis nd hyponatremay be treared nitially with intravenousglucose.After invenousadministration,hemin binds o hemopexinand albuin plasma nd s rakenup primarily n heparocyte..emin entersand augments he regulatoryheme pool in hepatocrepresses he synthesisof hepatic ALAS1, and dramaticreduces orphyrin precursoroverproduction.

Hemin+ is available for intravenousadminisrration n

United Stares sa lyophilizedhematinpreparation PanhernOvation). Degradationproducts begin o form as soon aslyophilizedproduct s reconsrituted ith srerilewater, and thare responsibleor phlebitisat che iteof infusronand a transancicoagulant ffect. Loss of venous accessdue to phleis common after repeated administrarion. StabrlizatroIyophilizedhematinby reconstiturionwith 307o human albucarrprevent hese dverse ffects, nd s recommended,specif a peripheralvein is used for the infusion. Uncommon seffectsof hemin include ever,aching,malaise,hemolysis,aphylaxis,and circulatorycollapse.Hemearginate,a more stahenin preparation, s available n Europeand SouthAfrica.

Hemin reatment should be nstitutedonlv aftera diagnosacute orphyrra as ee nnirially onErmed'bymarked"incin urinary PBG determinedmost rapidly r.rsiog kit, asdesct

earlier),When prior documentation f the diagnosiss availfor review, t is not essentialo confrrman increasen PBG wevery recurrent artack, if other causesof the symptomsexcludedlinically. he standardegimen f hemin oi rrearmof acuteporphyric attacks s 3-4 mg,4<gaily for 4 days. Lodoses ave esseffecron porphyrinprecursorexcretionaod prably less clinical benefit. An investigationalapproach iscombineheme herapy with an inhibitor of heme breakdosuchas in proroporphyrinor tin mesoporphyrin,o prolongefficacyof the administered eme.

Genetal nd SupportiveMeasures.Drugs that may exacerporphyrias (seeTable 9l-3) should be discontinuedwhenepossible,and other precipitaring actors dentified.Hospitaltion iswarranted,except or mild attacks, or treatmentof sepain, nausea,and vomiting; for administrationof hemin a

fluids; and for monitoring vitaLcapaciry, utritional status,nrologic unction,and electrolytes. ainusually equires narcanalgesic;here s low risk for addictionafter recovery romacuteattack. A phenothiazine uch as chlorpromazines neefor nausea, omiting, anxietn and restlessness.hloral hydror low dosesof short-acringbenzodiazepinesan be givenrestlessnessr nsomnia. p-Adrenergicblocking agentsmayusefulduring acu!eattacks o control tachycardra nd hypersion, but may be hazardous in patients with hypovoleand incipient cardiac failure. becausencreased atecholamsecrerio;may in this srtuation e an imporrant ompensmecnanlsm,

Carbohydrate-oading. he effectsof carbohydrares n repting hepaticALAS1 and reducingporphyrin precursorexcreare weak compared o those of hemin. Therefore,only m

attacks nild pain, no paresis r hyponatremia) re trearedwcarbohydrate oading.Glucosepolymersolucions y mouthsomerimes olerated. At least 300g of intravenous glucousually given as a 1Oo/" olution, has been recommendedadults hospitalizedwith attacksof porphyria. Amounts up500 g daily may bemore effective,but largevolumesmay fadevelopment f hyponatremia.

*Hemin is rhe gen€ncname for alt heme prepararionsused or inEa"en

administradon- Henin is also a chemical term thac refers to the oxidr(ferric) form of beme /iron proroporphrrin IX), and is usualty isolate

hernrnchloride. In alkalin€ solution, the €hloride s replac€dby $e hydro

ion, forming hydroxyhen].e, r bendtin.



before this can be.ecommended. Cimeridine' a well-known

Dro l t ransp lan ta t ion .'s Padentl often do well with avoidance

o[ drugs known or strongly suspected,o t the acute porphynas are listed in

Table 91-6. Updaredand more xtensive istingsare availableon

an i eractive website of th European Porphyria Initiative

probably be avoided rn patients with acute porphyria. Danazol

can be carried out safely inspecrallY iI barbiturates are

ommended as an inhalation

agenr and propofol and midazolam as intravenous induction

a contraindicaced dmg sometimes used to treat hyperemesis

gravldarum.

Diabetes mellirus and other endocrine condirions are not

known to precrpitace attacks of porphyria ln fact, the onset of

diabetes mellitus and resulting high circulating glucose evels may

decrease he frequency of attacks and lower porphyrin Precursorlevels in AIP

PBOGN0SIS.The outlook for patients with acute porphyrias has

improved markedly in the past several decades. n Finland, for

exanple,74lo of pacients with AIP or VP reported that they led

normal lives, and less han % had recurrent attacks during several

years of follow-up. In those presentrng with acute symptoms,

recurrent aftacks were mosr Lkely within the nexr 1-3 yr More-

over, only 57o of gene carriers who had never had atracks devel-

oped symptoms. The improved outlook may resuh from earlier

detectlon, belter treatment of acute attacks, and replacement of

harmful drugs such as barbiturates and sulfonamides with safer

drugs. A smaller number of patients, however, continue to har,e

Chaptelgl ThcPorPhYlias

recurrentatlacks,chronic parn, and orher symptomsevena

avoidrng nownexacerbatingactor:.

high n carbohydrace 60-7Oy'of total calories) nd sufficiemaintain weisht is recommended. here is little evidence

additional dietary carbohydrarehelps further in prevenattacks,and t may ead coweightgain.Patientswho wish to excesswerght should do so graduallyand rvhen cheyare ccally stable. ron del iciency, hich can bedetected y a ow seferritin, should be corrected.

GnRH analogs,which reversiblysuppress vulation, can

dramaticallyeffective or prevenlrng requentlv ecurring uphaseattacks,but baselineand continuinggynecologic vtron and bone densirymeasurements re lmportan!, and t dermal estrogenor a biphosphonatemav be added o pre

bone oss.Hemrn adrninisrerednceor cwiceweeklycan prefrequent,noncyclicattacksof porphyria n somepahents.

GEI{ETIC OUNSEL|i{G.hildren with a family history ofphyria are often seenby pediatncians or evaluacion nd co

seling, nforrnation and laborarory' results rom a relativewproven porphyriamust be reviewed n order to guide estinrhe child, which is di fferentdepending n the type of acutephvna. A muration denti lied n the index case an be sougthe child. If the child is found to have nherited he mutacounselingco avoid porentially harmful drugs is approprCounseling houldalsoemphasizehat thegreatmajority of thwho rnherit a PBGD mutationneverdevelopsymptoms, ndprognosrsof those who do is favorable. Therefore,a norhealrhy ife is expected,especiallywith avoidanceof hardrugsand other factorsand prompt recognition nd treatmesymploms should they occur Given the favorable outlookmosr mutation carriers,evenduring pregnancnhavrngchilis not precluded,and prenatal diagnosisof acuteporphyriless mportant han it i s for manyother rnherited iseases.n

rtanceof a PBGD muratronshould be resardedas confideinlormacion nd not inlerlerewirh emplovmenr r insueligibiliry.

CONGET{IIAIRYTHBOPOIET|COBPHYRIACEP}

Also termed Gtinther disease,his rare disease suallyprewith photosensirjviry hortly after birth, or io urero as nomunenyorops.

ETI0L0GY EP s an autosomal ecessive isease ue o a madeficiency of uroporphyrinogen II synthase(UROS). MUROSmutatrons avebeendentifiedamoneCEP amilies.L

onset iseasen adulrs s likely o be a'sociared irh myelliferativedisorders nd expansion f a cloneof erlthroblastscarry a UROS mutation.

PATH0t0cY NDPATH0cENESIS.ROS,which is markedlycrent n CEP,caralyzesnversionof pyrrole ring D of HMBpyrrole ring shownon the righr end of the molecule n Frgur1) and raprd cychzationof the linear tetrapyrrole o form porphyrinogenIL This enzymes also rermeduroporphyrincosynrhase. he humanenzyme s a monomei The gene oenzymes foundon chromosome0q25.3->q25.3,nd con10 exons.Eryrhroid and housekeepinganscripts aregenebv alternative romoters ut encode hesame nzvme. he hokeeping ransciiptcontains xon 1 (untranslated)pliced o e




28 through 10, while the erythroid rranscript contains exor 2A(untranslated) also spiiced to exons 28 through 10. The house-keeping promoter is upstream of exon 1, whereas the eryrhroid-specrficproximal promoter is upstream of exon 2A and containserychrord transcription factor binding sires ncluding GATA1 andNF-E2. Thus, there is erythroid-specifc regularion, but theenzyrne product is the same in all tissues.

In CEq large amounts of HMB accumulate in erythroid cellsduring hemoglobin synthesis and cychze nonenzymatically toform uroporphyrinogen I, which is auro-oxidized ro uropor-

phyrin L Some of rhe uropurphyrinogen I rhar accrmuLresis merabolized to coproporphvrinogen I, wbich accumularesbecause it is not a substrate for coproporphyrinogen oxidase.Thus, both uroporphyrin I and coproporph,vrin I accumulate intbe bone marrow and are then found in circulating erythrocytes,plasma,urine, aod feces.

A variery of UROS mutatrons have been rdenrified in CEP,including missenseand nonse[se mutations, large and small deletions and insertions, splicing defects, and nfionic branch poinrmutarions. At least 4 mutations have been identified in rheerythroid-specific promoter. Many pacienrs inherited a differentmutatron from each parent, and most mutations have beendetected in o y 1 or a few families. An exception is a commonmutation, C73R, whrch is at a mutatronal hotspor aod was foundin =3 3% of alleles.

Genotvpe phenotype correla ons have been based on rhe invitro expression of var ious CEP mutanons and the severity ofassociatedphenorypic mamfesrations. The C73R allele, which isassociated v'icha severephenotype in homozygotes or rn patientsheceroallelic for C73R and another mu[arion expressing littleresidual actrvitg resulted in < 17o of normal enzyme activity.Patients wirh the C73R al lele and heteroallelic for other muta-tions expressing more residual activrty have mrlder drsease.

Hemolysis is a common feature of CEP Excessporphyrins incirculating erythrocytes cause cell damage, perhaps bv a photo-toxic mechanism, leading to both intravascular hemolysis andincreased splenic clearance of ert/lhrocvtes. Also important isineffective erythropoiesis, wich intramedullarydesrruction of por-phyrinJaden erythroid cells and breakdou,'n of heme. Expansionof the bone marrow due to ervthroid hyperplasia mav contribute

to bone loss. Nutrrent de6ciencies sometimes cause ervthroidhypoplasia. Despite the marked deficiency of UROS, heme pro

dr-rction n the bone marrow is increased,due to hemolysis and acompensatory increase in hemoglobin production. This occurs,however, at the expense of marked accumulation of HMB, whichis converted to porphyrinogens and porphyrins.

CtlNlCAt MANIFES l0NS. In severe cases,CEP can cause fetalloss, or be recognized in utero as intrauterine hemolytic anemiaand nonimmune hydrops fetalis. CEP may be associated withneonacal hyperbilirubinemia, and phototherapy may uninten-tionally induce severephorosensitivity.

The most characteristic presentation is reddish urrne or pinkstainrng of diapers by urine or meconium shordy aFter birth (Fig.

91 2). Wifi sun exposure, severe blistering les ions appear on

exposed areas of skin on the face and hands, and have beentermed ltydroa aestiualebecause hey are more severewrth greater

sunlighr exposure during summer (Fig. 91 3). Vesiclesand bullae,as well as flabrlry, hypertrichosis, scarring, thickenirg, and areasof hvpo- and hvperpigmentation are very similar to those seen nPCT, but usually much more severe. nfeclion aod scar.ing som€-rimes cause loss of facial feacuresand fingers and damage ro thecornea, ears, and narls. Porphylns are deposrted in dentine andbone in utero- Reddish-brown teeth in normal light, an ap-pearance termed erythrodontia, displa;,'' reddish fluorescenceunder long wave ultraviolet liglt {Fig, 91 4), Hemolysis andsplenomegalv are features of many cases.Bone marrow compen-sation may be adequate, especially in milder cases.Pacientswithsevere phenotypes, however, are often transfusion-dependent.

ligure 91-2. Congenital r_]'thropoieticorphyria. he diaperoI an affba 1. emonstrareshe edco1o. { urine.}'ron PaUef S,MaciniAJ:H,]rClinicalPedidttic etnarologl .lrd ed.Philadelphia,lsevier aunderc,

Splenomegaly may contribure ro the anemia and cause eukonia and thrombocytopenia, which may be complicated by sigicant bleeding. Neuropathic sl.mproms are absenc, and therno sensitivi ry to drr :gs, hormones, and carbohydrate restrictiThe liver may be damaged by iron overload or hepatitis acquifrom blood lransfusions.

Milder casesof CEP with onset of svmocoms in adult life awirhour eryrhrodontiama v more rlosell mimic PCT. These aonser casesare likely to be associatedwith m-veloproliferativeo rde r . .andexpans ion fa c lone rce l l s a r r y ing UROSsommutation.

tAB0BAT0RY FINDINGS,Urinary porphyrin excrelion and cirlating porphyrin levels n CEP are much higher than in almost

other porphyrias. Urinary porphyrin excretion can be as high50-100 mg dail-v, and consisrs mosdy of uroporphyrin I coproporphyrin I. ALA and PBG are normal. Fecal porphyn

are ma_rkedly increased, with a predominance of coprop

Pnyrln r.

Marked rncreases n eryrhrocyte porphvrins rn CEP conmostly of uroporphyrin I and coproporphyrin L These pphyrins are also increased n bone marrow, spleen, plasma, ato a lesser excent) iver . The porph;rrin partern in erythrocytesinfluenced by racesof erythropoiesis and erythroid maturation.pledominance of procoporphyrin has been noted rn some C

Figurc 9l l. Congenitaleryrhropoieticporphyria. Vesicles, ullae, and cr

on sun exposedareas (From PaLlerAS, Macni Al: Hureitz Clinical Pedia

Dermatologl,3rd ed. PhiJadelphia,lsevier Saunders, 006, p 517,)



Figurc 91-4. Congeniralerlthropoieric porphyria. Brownish teeth that fluo-

p s17. )

patients, nd n 1 suchpatient!uroporphyrinandcoproporphyrin

increased hen erythropoiesis as srimulated y blood removal

DIAGN0SISNDDlfFEltl{Tl,AtDIAGI{OSIS.he diagnosrs f CEP

shouldbe documented y full characterization f porphyrinpar-

ternsand denrification f the underlyingmutations ln later onset

cases,an underlying myeloprohferative isorder and a UROS

somaticmutation shouldbe suspected nd studied n detail'

red-brown discolorationand increased orPhyrins n amnioric

Iluid, measuring orphyrins n fetal erythrocytes nd plasmaand

UROS acuvitv in culrured amnioric fluid cells, or identiffing

UROSgenemutations n chorionicvtlli or culturedamnioriccells

sunlightexposure,minimizing skinn! of anY cutaneousnfectionsareg CE P(see able91-4) Sunscreensometimes eneficial. ransfusions

to achievea level of hemoglobrn ufficienc o suppless lythro-

poiesis ignrficantly an bequrte effective n reducingporphyrinievelsand photosensitiviryConcurtenrdefetoxamrne o reduce

iron overload, and hydroxyurea to suppresservthropoiesis

further may provide addidonal benefit. Splenectomyeduces

hemolysisand transfusion equirementsn somepatients.Oral

charcoalmay increase ecal loss of porphyrins, bur may con

cribute ittle irr more severe ases. nrravenoushemin may be

somewhateffeccive, ut has not been exlensivelystudied and

seems nlikely to provide ong-termbenefit.Chloroquinehasnot

beenbeneficial.Bonemarrow or stemcell ransplantation, hrchhasmarkedly

reduced orphyrin evelsandphotosensltiviry nd ncreasedong-

rermsurvival,shouldbe consrdered,speciallyor severe rsease

Gene herapymay be accomplishedn the future.To date,human

Ghaptei r ThePorpftYria

UROS cDNA has been subcloned into retrovital vectors, w

hare been used o lransduceFbroblast*an d lrmphobla'rs

padents u'ith CEI resulrrng n significant levels of enzvme ex

iion. Transducuon of hematopoietic progenitor cells arrd

erythroid cells was also achieved.

PB0G 0SlS. The outlook is favorable in milder cases an

patienm wlth more severe disease reated by transfusions

ii"nt to .upp.... erlthropoiesis and bone rnarrow porph

production at least partiallv. Successfulbone marrow or stem

transplantation has proven effective.

PBEVtilTlo$ tlDGENETICoUltlSEtlNG.enetic ounseimoorcant or affected amilies,becauseCEP can be recog

before birch and a severephenotype can often be predicte

idenrifying he nature of the UROS mutation\.

PORPHYRIAUTAIIIEAABDAPCTI

Thrs s rhe mosrcommonan d readily reated umanporp(see able 91-2). t occurs n mid or late adult ife, and s ra

children, Prevrous erms include symptorfiaticporphlri',

symptomatica, nd diosyncrrlti.porpDyrr,r. he underlyingis a iiver-specific,cquireddeficiencv f uroporphyrinogen

boxylase UROD) with contributionsby severalypes of gfactors, UROD mutations are found in famihal PCT

homozygous orm of familial PCT is HEB which has a

severe resentation, sually n childhooO.

ET|OI0GY. CT is due to a marked deficiency f hepaticURThis enzyme efrciency us t be substantial'20'lo of n

activity or less) or PCT to becomemanifest,and ts develois atribured to generation f a UROD inhibrtor specilicallyliver This inhrbiror,which has noc beencharacterized,s defrom a hemepathway intermediatesuchas uroporphyrinand CYPs suchas CYP1A2, as well as iron, are involvedformation (Fig.91-5J.Evenwith substantialnhrbition of hUROD activity, the amoun! of enzvme protein meaimmunochemicallyemainsat its genetically etermined e

UROD catalyzes he decarboxylation f the 4 acetrcacichainsof uroporphyrinogen anoctacarboxylporphyrinogform coproporphyrtnogena tefi acarboxylporphyrinoge

Glycine+ SuccinylCoAI

ALASII

6-Aminolevulinicci d

II

I CYPIA2

CoproporPhyrinogen

IIl- E^2+I -

Heme

t'igurc 91-5. Formation of a specinc nhibrror of uroporphvrinogen

boxylase n rhe iver in porphtria cutanea arda. AL.\S, &aminolevuti

synthase; CYPlA2, c-vtochrome P450 1A2r UROD, uroporphy



648 I PARTX MetabolicDiseas€s

Fig. 91 1). The enzyme reaction occurs rn a sequertjal, clockwisel:ashion,wirh lhe i nrermediare ormarion oi hepra-. hexa-. an d

strate. Human UROD is a dimer with rhe 2 acrive sire cleftsjuxtaposed. The UROD gene is on chromosome 1p-j4 and con-ta ins 0exons . ' " r ' i r hon lvp rum o le r . l he re fo re . h i gene s r ranscribed as a sinele mRNA in all trssucs.

Th e majoritv of PCT parrenrs =80%) have no UROD mura-rions and are said to have sporadrc (rype 1) disease.Some are het-

erozygous for UROD mutarrols and are said to have farnilial

cause PCT unless a UROD inhibitor is also generated. Becausepenetrance of the genetic ait rs loq many parienrs with familial PCT have no famrlv hi orv of the disease.

lnduction of hepaticALAS1 rs nor a promin t feature nPCT,although alcohol may increase this enzyme ightLy.. ron andestrogens are also not potent inducers of ALAS1 and drugs thatar epotelt inducers f ALASl and CYPs ar e much less ommonlyrmplicated n PCT rhan in acurepurphyrias.

Blistering skin lesions resulc from porphyrins tlar are releasedfrom the liver Sunlight exposure leads to generation of reactiveoxy_genspecies n the skin, complement activation, and lysoso-mar oamage.

E es probably relate to geo-g ctors suchas hepatit jsC ande he United K insdom was esti-mared r 2 -51 1 ,000.000. nd hep fe ra lencen cheUn i red ra lesand Czechoslovakia .i 'asestimaled ac =1/25,000 and 1/5.000.respectivel). The disease *.as reported to be prevalent in theBanrusof South Africa in associationwirh iron overload.PCT ismore common in males, possible due to greater alcohol intake,and m wornen it is commonly associated with estrogen use.

A massive outbreak of PCT occurred in easrernTurkev in thelq50 \ . !Vhea r nrended or p lan r ing and r re . r redw i th hexa-

chlorohenzene as a fungicide was consumed bv man,v at a timeof {ood shortage. Cases and small outbreaks of PCT after expo,sure to other chemicals including dr- and rrichlorophenols and2,3,7,8-cetrachlorodibenzo-p-dioxin (TCDD, dioxin) have beenreported. The manlfestatlons rmproved in most cases when lheexposure rvas stopped. There are, however, reported cases ofdelayedonsecmany yearsafter chemicalexposure.

PATH0[0GY ND PATH0GENESIS.CT is currentlv classif ied ntot c l i n i ca l l y im r la r 1pe r ,Gene ra t ion f a UROD inh rb i ro r n rheliver plays an important role rn all 3 qvpes.The -80% of parientsrvrth type I (sporadic) PCT have no UROD mutationsr andUROD activity is normal in nonhepatic issues.n familial (type

2) PCT, a UROD mutation is associated wirh a partial (=50%)deficrency i UROD in nonhepatic i* 'ue.. fh e genericalllderer.mined level of rhe enzl.me is also 50% in rhe lir.er, bur rs muchlower when a UROD inhrbiror is generated and the diseasebecumes linrcallr acrive.Type t is rare. and deocrrbe, C f rvrrhnormal erytbrocyte UROD activity occurring in more than 1family member UROD muradons or another seneric basis haveno r been denril ied n rype 1. an d tamilial occurrence 5 the ont]feature that distinguishes it from tvpe 1.

CYPs, especially CYPY1A2, can catalyze the oxidation of uro-porphyrinogen to uroporphyrin. This uroporphyrinogen oxidase(URO-OX) activit]' is enhanced by iron, and leads ro formahonof a UROD inhibitor (seeFig. 91-5). CYP1A2 seems ssentralordevelopmenr of uroporphyria in rodents, because experimental

n ropo rphy r rad , ' cs no ' 6 .u " ,op in CYPIA2 knoek lu r m iS tud iesw i rh CYP2El Inockuurr rugge ' r ha t h i \ enTvmemalso contriblrte. Mrce wrth disruption of one UROD allele aeither 1 or 2 disrupred HFE alleles provide an important modfor PCT wichouc adminrsrration of halogenated cliemicals.

patlelrt.

lron. A normal or increasedamounr of iron in the liver is ess

major cause of hemochromatosis i *.hire people, is increasedboth tvpe 1 and cype2 PCI and 10% of pacienrs re C282homozygotes. In sourhern Europe, where rhe C282Y is lessprevlent, rhe H63D mutatjoo is mote commonly associated.PCT moccur with secondary iron overload.

Hepatitis C. This viral infecdon is highly prevalent in PCTmost geographic locations; in the United States, for example,rs present in 56-747o of cases,which is simrlar to tbe (ate cir

oxjd ve stress Jn hepaticis C may favor rron mediated genetion reactive oxygen speciesand a UROD inhibitor

HIV Many reporcs suggest HIV rnfection can contribute to thdevelopmenc of PC! hoLrgh ess commonl,v than does hepatis C. The mechanism no t known.

Ethanol.The long-recognized assocjation between alcohol anPCT may be expJained y chegeneracion f acriveoxygenspec

increased production of endotoxm, and activation of Kupflecells.

Smoking and CytochromeP450Enzymes.Smoking has not be

CYPs and oxidative srress, Hepatic CYPs are thought to

CYP1A2 and 1A1 have been imphcated rn human PCT. The frquency of an inducible genotype was more common rn PCpalenls rhan in controls rn 2 studies

Antioxidant Status.Ascorbic acid de6cienc,vhas been rmphcarein conrriburing to uroporphyla rn laborarorv models and humaPCT. In 1 series, plasma ascorbate levels were substanciareduced in 847" of patients \\,rth PCT. Lorl'' levels of serucarotenoids were also described, furcher suggesting hac oxidaostress rl heparocytes s importanr in PCT.

Esttogens.Use of escrogencontaining oral contraceptives opostmenopausal strogen eplacemen!s very commonlv assoated wich PCT (type 1 or 2) in women. PCT sometimes occuduring pregnancy, afthough it is noc clear whether the nsk

lncreased.

CU'CAI. MAI{IFESTATIONSCutafleousManitestations. PCT is read ,v recognized by blisre

ing and crusted skin lesions on rhe backs oI rhe hands, rvhich arhe most sun-exposedareas of the body',and somewhat less commonly on rhe forearms, face, ears, neck, legs, and feet. The fluidfilled vesiclescommonlv rupture and become crusced or denudeareas, heal slowln and are subject to infecion. The skin on rhbacks of the hands is characteristically friable, and minor traummay cause blisters or denudation of skin. Small white plaque

tetmed tui\fu, ma1' precede or follow vesicle formation. Facihypertnchosis and hyperpigmentation are also common. Seve

scarring and rhickeningof sun-exposed kjn mav resemble cl



chanses reno l soecilicor PCT.Th esame indings ccur n VP

an d FCP,an d reiemblehose f ( tl and HE P bu t are usually

lessserrere, nsetof the drseasen childhood s rare' and is more

tAB0RAT0RYlN0lNGS. orphyrinaccumulatesn the ivermostly

and II.

Chaptelgl r ThePorDhyrias 6

DIAGN0SIS NDDIFFERENTIAIlAGN0SlSPLasma orph,vrins

aLways ncreased in clinically manifest PCI and a total plasm

porplvrin determination rs most useful for screening. A norm

value rules out PCT and other porphvrias rhat produce bltste

ing skin lesions. If increased, t is useful to determine the plasm

fluorescen.. emission maxrmum at neutral pH, because

maximum near 519 nm is characteristic of PCT (as well as CE

and HCP) and, most important, excludes VP, which has

distinctlv different fluorescence maximum lncreased urina

normal,

PC! but with an additional marked tncrease n erythrocyte z

stage renal disease.

C0MPLICATI0NS, utaneous blisters may ruptute and beco

infecred, sometimes eading to cellulitis. In more severedrseas

patients with end-scage enal disease, epeated infections can

mutilating, as in CEP, Pseudoscleroderma, with scarring, co

tracrion, and calcification of skin and subcutaneous trssue, i

rare complication. Other complications, such as advanced liv

diseaseand hepatocellular carcinoma, were alreadv discussed

TFEATMENI Management of PCT includes choice of 2 spec

aod effective forms of treatment, phlebotomv or low-do

hydroxvchloroquine, and removal of susceptibility factors wh

possible. The diagnosis of PCT mLrst be 6rmly established, aiondirions thar produce identical cutaneous esions exclud

because hese do not respond to treatments used in PCT. Tre

and tested for hepatitrs C, HIV, and HFE mutations. Some s

ceprrbility factors influence the choice of treatment.

Phlebotomy is considered standard therapn and is effec

both in children and adults with PCT because t reduceshepa

rron contenr. Treatment is guided bv plasma (or serum) ferri

and porphyrin levels,Hemoglobin or hematocrit levels shoul

follou.ed to prevent symptomattc anemia. For adults, a un

blood 1=456-1; is temoved at =2 wk intervals urtil a larserum ferritin near the lower lmit of normal (=15 ndml-)

achieved. A rotal of 6 to 8 phlebotomies is often sufficienr. Af

this, plasma porphynn concentrations continue to fall from p

treatment levels (g€nerally 10-25 pgldl-) to below the upper li

of normal \=1pg/dL), usually after severalmore weeks.Thi

followed by gradual clearing of skin lesions, sometimes nclud

pseudoscleroderrna. Lrver function abnormalities may impro

and hepanc siderosrs,needleJike inclusions, and red fluoresce

of liver tissue will drsappear Although remission usually pels

even rf ferritin levels later return to normal, it is advlsable

follow porphyrin levels and reinstitute phleboromies if th

begin to rise. lnfusions of deferoxamine, an tron chelator, may

used when phlebotomy is contraindicated.



650 PABTX MetabolicDiseases

An alternarive *'hen phlebotomy is concraindicared or poorlytolerared is a low-dose regimen of chloroquine or hvdroxy-chloroquine. Normal doses of these 4-aminoquinoline anti-malarials increase plasma and urinarv porphvrin levels andincrease photosensitivicf in PCI reflecring an outpouring of por-phvrrns from the liver This is accompanied by acure hepatocel-lular damage, with fever. malaise, nausea, and increased serumtraflsaminases, but is followed by complete remission of the por-phyria. These adverse consequencesof normal doses are largelyavoided by a low-dose regimen (chloroquine 125 mg or hvdroxy-

chloroquine 100 mg, Y. of a normal tablet, twice weekly), whichcan be continued undl plasma or urine porpbyrins are normalized. There is ar least some risk of rerrnopathy, which may belower with hydroxychloroquine. Prospective treatment trialscomparing chis reacmentwith phlebotomy are lacking. Low-dosechloroqurne ma)' not be effective in patrents homozygous for theC282Y mutation in the HFE gene,Therefore, the degreeof excessheparic iron may influence response o chis creatment. The mech-anism of action of 4-aminoquinolines in PCT is not known, butis quice specific, since these drugs are not useful in otherporphyrias.

In patients with PCT afld hepatitis C, PCT should be treared1st because this condition rs more svmgtomatic and can berreatedmore quicLly an d eflectrvell. reatmenc of PCT hr phle-

botorny may not be possible once rnterferon-ribavirin treatment

is complicared by anemia. Moreover, treatment of hepatiris Cmay be more effecrive after iron reduction. Resrstanceof hepati-tis C to treatment with rnterferon-d or pegylated interferon andribavirin has been eporred in patiencspreviousl,v reated for PC!

but prospective studies are lacking (seeChapter 355).PCT rn patients with end-stage renal disease is often more

sel'ere and difficult to rreaf. Although phlebotom,v is ofren con-

traindicated initiall,v, er1'thropoietrn admrnistratron can correct

anemia, mobilize iron, and support phlebotomy in manv cases.

Response may also occur after renal transplantacion, due in part

ro resumption of endogenous erythropoieric production.

Liver imaging and a serum o-fetoprorein determination may be

advisable in all PCT patients, perhaps at 6-12 mo intervals for

early detection of hepatocellular carcinoma. Finding low er,v-throcyte UROD activity or a UROD mutation identi fies those

with an underll,ing genetic predrsposition, whrch does not altertreatment but is useful for genetic counseling (see ater).

PR0GN0SIS.PCT is the most readily treated form of porphyria,

and complete renissron rsexpectedwlth treacment either by phle-

bocomy or low dose hydroxychloroquine. There is iittle infor

mation on rates of recur rence and long-term ourlook. Risk for

hepatocellular carcinoma is increased, and some suscepribilitv

factors such as hepatitis C can lead to complications even afcer

PCT rs n remission,

PREVEI'|T|0NllDGENETIC0UNSEtlNG.atients ith PCTmayhave concerns about risk ro other family members, A hericable

L,'ROD nutauon can usually be detected or excluded by mea-

suring erythrocvte IIROD acrivity, although DNA studies aremore sensitive. Relarives of Datientswith UROD mucations have

an rncreased isk for developingPC! and may'have increased

motivation ro avoid adverse behaviors such as ethanol and

tobacco use and exposures to hepatitis C and HI\'. Such coun-

seling would be given to an,vone,however. The linding of HFE

muratrons, and especially C282Y, should prompt screening of rel

ativesr some of r.r.hommay be C282Y homozygotes and &'arrant

I i i e longm un i ro r rng f re rum e r r t t t n .

HEPATOERYTHROPOIETICORPHYRIA

Hepatoervthropoietic orph,vriaHEP), vhich s the homoz),gousform of famrlial (type 2) PCT, resembles EP clinically.Excess

porphyrins originate mostl ,v from liver, wlth a paltern cons!.i'ith severeUROD deficiency. This rare disorder has no palar racial predominance.

ETl0L0GY HEP is an aucosomal recessivedisorder, altbough patients have inherited a diflerent mutacion liom unreparenrs. n contrast !o most mutalions in familial (tvpe 2) most causing HEP are associated with expressiot of some rual enzyme activiry. At least 1 genotype is associated withpredominanr excretion of pentacarboxyl porphyrin.

PATH0L0GY ND PATH0GENESIS.xcessporphyrins originatemarily from the liver io HEP, although che substanrial increaeryrhrocyte zinc procoporphyrin indicares rhat the heme biotheuc pathway is also impaired rn bone marrorv erythroid Apparently, porph,vrinogens accumulate in the marrow whemoglobin svnthesis s mosc active, and are merabolized roroporphvrin alter hemoglobin synthesis rs complece. The neous lesions are due to photoacti vation of porphy rins in as n other cutaneousporphyrias.

CUNICALMANIFESTATI0NS. ike CEP. rhis disease usuallvsenrswirh blisrering ,kin esions. l perrrichosis.carrrng.anurine in infancy or childhood. Sclerodermoid skin change

sometimes orominent. Unusuallv mild caseshave been descrConcurreni condrtions rhat affect liver funcrion can alter diseverity. For example, hepatirs A caused the disease ro becmanifest in a 2 year old child, and then improved with recoof liver function.

LASORATORYlt{DlNGS. Brochemical frndings resemble thoPCT with accumularion and excretjon of uroporphyln,

tacarboxyl porphyrin and isocoproporphvrin. But in addi

erythroclte zinc procoporphyrin rs substantially increased.

DIAGN0SISAND DIFFERENTIALIACN0S|S. HEP is drstineui

lrom CE P hv Incr ea5.s n borh uroporphyrin and hepra.irhporphyln, and rsocoproporphyrins. In CEP the exc€ss erytcyce porphyrins are predormnantly uroporphyrin and copro

phyrin racher than proroporphl'rin, Blistering skin lesionsunusual in EPI the excess erlthroc,vte protoporphyrin indisease s free and_noc complexed with zinc, and urinarypnylrns are normal.

IREATMEI'IT ND PR0GN0SIS.Avording sunJight exposure is m

important in managing chis disease,as rn CEP.Oral charcoalhelpful in a severecase associacedwith dyserythropoiesis. P

botomy has sholr'n litcle or no beneft. The outlook depend

the severity of the enzvme deliciency and may be favorable rf

light can be avoided, Retrovirus-mediaced gene transfer correporphyria in transduced lvmphoblastoid cells from HEP patie

suggescing hat gene therapv may eventually be developed.

PnEVENTI0NND GENETIC 0UNSEUNG, s part of geneticcseling in affecred families, it is feasible to diagnose HEP in u

either by analys is of porphyrins in amntottc fluid or DNA stu

HEREDITARYOPROPORPHYRIAHCP}

This autosomal omrnanthepaticporphvria s due o a deficof coproporph,vrinogenxidaseCPO). hediseaseresenracuteatlacks, as in AIP Cutaneous hotosensitivitymay obut much less commonly than in VP Rare homozvgouspresentn childhood.

ETI0LOGY partial (=50%) defrciencyn CPO activitv hasfound rn all cellssrudied rom patients {'ith HCP A much m



ture release f harderoporphyrinogen.

EPIDEMI0LOGYCP is lesscommon than AIP and VP, but its

PATHOTOGYNDPATH0GENESIS.ncreased LA and PBGdunng

rn HCP

GtlNtCAtMAI{|FESTATI0NSymptomsare identical o those of

AIP except that attacks are generally milder, and c.utaneous

lesions hit resemble hose n PCT developoccasionallySevere

acute orphyrias.Th cLnical featuresof homozygousHCP, whrch begin in

early childhood, may include ,aundice, hemolytic anemia,

hepatosplenomegalv,nd skin photosensitivity. hesesymptoms

ari getre.ally r-:ite istrnct rom thoseseen n heterozygotes

S Theporphyrin recursor\ LA and PBGculeattacks, ul ma ydecreaseore apidltncreasesn coproporphyrin II in urine and

Chaptelg'l ThrPorphYrias

coproporphyrrn.Plasmaporphyrins are usuallynormal or o

slightly ncreased.

DIAGNOSISNDDlttERCNT|ALIAG[{0SlS.he diagnosrsf H

mostlycoproporphyrin isomer II) in HCP,whereasn VP,co

porphyrin lll and protoporphytin are often rncleased PP

marely equally.Plasmaporphyrins are usuallynormal in H

and increasedn \?.

family members.

TREATMENTt{D PR0GNOSIS.cute attacksof HCP are tre

erally berter han in AIP

PREVENTI0NNDGENETIC0UNSEI-lNG.heseare he same

other acuteporPhYrias.

VARIEGATEORPHYRIAVP}

This hepatic porphyria is due ro a deficiencyof proto

phyrinogenoxidase PPO),which is inherited as an autos

dominant trait. The disorder s terrneduariegate ecauset

presentwirh neurologicor cutaneousmamfestions.Other tehave iocluded porPhyria eariegata,proto.opropotphJtw,South Aftican geneticporphyria. Rare cases f homozygouare symptomatrcn childhood.

EflOIOGYPPO s approximacely alf normal in all cellsstu

in patientswith VP The enzyme s more markedly deficie

rare cases f homozygousVP, with approxrmately alf-no

enzymeactivity in arents.Human PPO s homodimer hat containsFAD and is l

ized to the cytosohcside of the inner mitochondrialmemb

Membrane-brnding omainsmay be dockedonto hurnanFEthe next enzymen the pathway,whrch s embeddedn the o

srte side oI the memb.ane.PPO catalyzeshe oxidation ot

and by certainherbicideshat causeprocoporphyrin o acclate and inducephototoxicity in plants. nhibrtion bv bihmay account or decreased POactivity rn Gilbert disease

The hr-rman POgeneon chromosome q22-q23 consistnoncodingand 12 coding exons,A singlePPO ranscript s

duced n a varieryof tissues, ut putative tansclrptionalele

binding sequences a allow for erythroid specificexPreMany PPO mutadons ave been eported n VP farnilies A

sensemulation, R59W, is prevalent n South Africa. No



652 PABTX Metabolic iseoses

vincing genotype-phenotypeorrelationshave been rdentified.Mutations in homozygous ases f VP are more ikely to encodeenzymeproteinswith residualactivity.

EP|DEM|0L0GY.P is lesscommon than AIP in most countries.The R59\V mutation s highly prevalent n SouthAfrican whites(=3/1,000).This exampleof geneticdrift or "founder effect" hasbeen raced o a mafl or his wife who emierared rom Hollandro Sourh Airica in 1o88. In linland. rhe orevalences' L /100 ,000 nd sabour scommon sAIP

PATH0LOGYNO PATHOGENESIS.cute attacks develop in aminority (=25%) of hererozygotesor PPO deficiencnand areoften aftributable o drugs,steroids, nd nutritional factors harplay a role in other acute porphyrias.Protoporphylnogen IXaccumulates nd undergoesauto-oxidation to protoporphyrinIX. CoproporphyrinogenII may accumulate ue o a close unc-tronal association etweenPPO n the nner mitochondrialmem-brane and CPO in the intermembrane pace.Liver porphyrincontenr is nor ilcreased. The increasedporphyrin contenr inplasmaconsrsts f porphyrin-peptide onjugates,which may beformed from protoporphyrinogen. ncreasedALA and PBGduring acuteattacksmay be explained,as n HCP, by inductionof ALASl by exacerbatingactors,and by the normallyrelativelylorv activityof PBGD n liver Furthermore,PBGD s nhibitedbyproroporphyrinogen,he substrate or PPO.

CUNICALMANIFESTATI0NS.ymptoms develop in some het,erozygotes ter puberty.Neurovisceral ymptomsoccurringasacuteatracksare idenrical o AII but are generallymilder andlessoften fatal. Drugs,steroids,and nutritional alterations uchas fasting,which are harmful in AII can also nduceattacksofVP.Attacksoccur equally n malesand females, t least n SouthAJrica.Cutaneous ragility, vesicles, ullae, hyperpigmentation,and hypertrichosis f sun-exposedreas remuchmore commonthan in HCP They are likely to occur aparr from and be moreIong lasting than rhe neurovisceral ymptoms.Oral contracep-tivescanDreciDitateutaneousmanrfestatiols. cuteaftackshavebecome ess ommon, and skin manifestationsare more fre-quently rhe nihal presentation; his may be due co earlier

diag-nosis and counsel ing.The risk of hepatocellularcarcinoma sincreasedn Vl as n other acuteporphyrias.

Symptoms f homozygousVP begin n infancy or childhood.Thesechildrengenerally avesevere hotosensitivitS eurologicsymptoms, onvulsions, evelopmental isturbances, nd some-timesgrowth rerardation,but do not haveacuteattacks.

IAB0RATOSY|N0|NGS. rinary ALA, PBG, and uroporphyrinare ncreased urilg acuteartacksbut often lessso than irl AIP,and thesemay benormal or only slightly ncreased ttlng rernis-sion, Plasmaporphyrins, urinary and fecal coproporphyrin II,and fecalcoproporphyrin II and protoporphyrin are more per-sistently ncreased etweenattacks.Erythrocytezinc protopor-phvrin evelsare markedly ncreasedn homozygous l and may

be modestly ncreasedn heterozygousases.

DIAGN0SISNDDIFFERENTIALIAGN0SIS.P is readilydistin-guished rom AIP and HCI which alsopresentwith acuteactacksand increasesn PBG. Plasmaporphyrin analysis s especiallyuseful, becausehe plasmaporphyrins n VP are tightly proternbound, resulting n a characteris tic luorescence missionspec-ffum at neutral pH. Fecalporphyrins are increased,wirh ap-proximately equal amounts of coproporpbyrin III andprotoporphyrin.Fluorometricdetectionof plasmaporphyrins smore sensitivehan stoolporphyrin analysisn asymptomatic PPPO assays sing cells that contain mitochondria,such as lym-phocytes,are sensitiveor identifying asymptomatic arriersbutar enot widelyavailable.

TREATMENI cuteatracksare treatedas n AIP.Hemin is beficial for acuteattacks but not for cutaneous ymptoms,Liprotection s mportant n padentswith in manifestations,slong-sleevedlothing,gloves,a broad- mrred hat, and opasunscreen reparations.Exposure o shorr-wavelengrh ltralet light,whrch doesnot exci!eporphyrins,may ncrease kin pmentation and provide some protection. Phlebotomychloroquineare not effective.Surprisingll., ral activatedchcoal.was eported o increase orphyrin levelsand worsen smanrlestallons.

PROGN0SISND PREVENTION.he outlook of padenrswith has mproved,which may be attributed o improved teatmearlier diagnosis,and detection of lat€nt cases.Cyclic acattacks n womencan be preventedwith a GnRH analog,aAIP. A diagnosis f VP or any other acuteporphyria shouldlead to difficulry obtaining insurance, ecausehe prognosusr.rally ood once he diagnosiss established.

GENETICOUNSEIING.heseare the sameas n other acuteophyrias.

EBYTHROPOIETICBOTOPORPHYRIAEPP}

In this autosomal dominanr disorder, protoporphyrin accumlates due co a partial deficiency of FECH, the last enzyme in heme biosynthetic patbway. EPP is sometimes @tmed protopphyria ot etythrohepdtic protoporphyria, although the liver dnot concribute sr.rbstantially o production of excess protopphyrin in uncomplicated cases.

ETl0t0GY. FECH, the enzyme that is defcienr rn EPP, catalythe final step in heme synthesis, which is lnsertion of ferrous ir(Fe'?*)nt o protoporphyrin IX (seeFig.91-1), Th e enzyme s atermed heme sykthetase or protohetue fettolyase. The humenzyme is a dimer, and each homodimer contains a [2Fe-cluster, whrch nay have a role in bridging homodimers. FECHfound in the mitochondrial inner membrane where its active faces the mirochondrial matrix. It mav be associated w

complex I of the mitochondrial electron transporr chain, andferrous iron substrate may be produced upon nicotinamidadenine dinucleotide (NADH) oxidarion. FECH is specilic for reduced form of iron, but can utilize other metals such as Zand Co'* and other dicarboxyl porphyrins. Accumulation of fprotoporphyrin rather than zinc protoporphyrin in EPP ndica

that formation of the latter is dependent on FECH activrty

Th e human FECH gene s locaredon chromosome 18q21has a single promoter sequence, and contains 11 exons. TmRNAs of =1.5 an d =2.5kb were described,which mayexplained by the use of 2 alternarive polyadenylation signals. Tlarger cranscripc s more abundant in murine er;.throid cells, sgesringerythroid-specilic regulation of FECH. A vanety of FECmutarions have been reported in EPP, ncluding missense, no

sense,and splicing murations, small and large deletions, and rnsertio[.

The inheritance of 2 alleles associated with reduced FEC

activity is required for diseaseexpression. This is consistent w

FECH activities as low as 15-25% of normal in EPP patrents

most patients, a disabling mutation on one FECH allele is cobined with a common polymorphism affecting the other alle

whrch produces less than normal amounts of enzyme. T

intronic single nucleotide polymorphism, [VS3-4ST/C, results

the expression of an aberrantly spliced mRNA that is degrad

by a nonsense-mediatedRNA decay rnechanism, which decreathe steady-srate evel of FECH mRNA. Inheritance of EPP n m

affecred families i s correctly rermed autosomal dominant beca

the IVS3-48Ti C polymorphism by irself does not cause disea



with normal subunits would have enzyme activlty'

ln rianc casesof EPP,FECH activrty is normal, and both free

EPIDEMI0[0GY.EPP rs the 3rd most comrnon porphyria' although

irs orevalence s no r precisel' known (seeTable 9l-2l lt is

describedmostly in whrte people. hut occurs in other race' a'

well, including blacks. ihe IVS3'48T/C polv-morphism is

common in rvhlicesand East Asians buc rare in Africans, thtch

would be predictive of a lower diseaseprevalence n populations

of African origin.

FECH is deficient in these cissues

blasts has been noted in the bone malrow of some patients'

however, suggesring har FECH deficiency sometimes mPairs ery-

rhroid heme synthesrs.Liver damage that develops in a small proportion of EPP

D.rt ienrss atrriburedro excess rotoporphvrtn. which rs insolu-

61 . ,n *ut.. and is excreredonly by hepari( uptake an d biliary

excretion, Some mav be reabsorbed by the intestine and undergo

enteroheDatic circulation. Excess protoporphyrin can decrease

hepadc 6ile formation and flow, form crystalline structures in

hepatocvtes, and impair mitochondrial function.

CtlNlCAt MAiIIFESTATIONS- ymptoms of cutaneous photosensi-

tivitv beein in childhood, and consist of Pain, redness,and itching

occurrin-g within minutes of sr-:nlight exposure. Swelhng may

resemblJ angioneurottc edema, These are referred to as solar

urticaria and are usually worse in the spring and summer

Chaptcr l . ThePorphyrias

triglyceridemra nd somewhat ower levelsol erlthrucYte pfo

poiphyrin an d increasedsunhght rolerancedr-rringpreBna

have beendescribed.

porphyrins and porphyrin precursols are normal in uncom

cated EP P

DIAGNOSISND DIFFERENTIALIAGNOSIS. diagnosisof EP

conlirmed primarilv by 6nding a substantially elevated conc

tralron of eryth.ocyre protoporphyrin, which is predominan

must be interpreted with care

The increase n plasma total porphyrin concenrratjon ln EP

often less than in ocher cutaneous porphvrias. Great care mbe taken to avoid light exposure during sample process

becauseplasma porphyrins in EPP are partrcularly subiect ro Prodegradation. Other findings rnclude normal levels of urin

porphyrrn precursors and porphyrrns.

Measurement of FECH activity requires cells containing m

chondria and is not widely available. Demonstration of nol

FECH activity and a greater than expected proportjon of

protopoporphyrin in erythrocytes is importalt in idenrify

variant EPP Dr..r..A tudies are increasingly important {or c

firming the mode of inheritance and for genetic counseling.

The development of life-thr€atening hepatic complications

EPP is accompanied by abnormal liver function tests, ncrea

erythrocyte and plasma protoporphyrrn levels, and incre

photosensicivity, Increases in urinary porphyrins, espec

coproporphyrin, are attributable to hver dysfunction.

COMPtlGATl0NS. Biliary stones conraining protoporphyrin

sometimes symptomatic and require cholecysrectomy. L

diseaseoccurs i; 1-2% of EPP patienrs, including children,

viral hepaticis, alcohol rntake, iron deficrency' asting, or oral

traceptive steroids, may contribute. Liver histology sh

markid deposirion of protoporphyrio in liver cells and

canaliculi. Pattents with procoporphyric liver failure, which



654 r PART . MetEbolicDiseases

resentsa severephenotype, most often have "null mutations" andthe IVS3-48T/C polymorphism in the nonmutant allele, bur somenay have 2 mutant alleles and autosomal recessive nheritance.The bone marror;r. is probably the major source of protopor-phyrin, even in EPP patients wrrh heparrc failure.

TBEATMENT. xposure ro sunlight should be avoided wheneverpossibLe,which is aided by wearing closely woven cloching, Oralbeta-carotene eads !o clinical improvement and greater toleranceto light in some patients, usually 1 to 3 mo after srarling treat-ment. In mosr adulrs,dosesof 120-180 mg daily will maintainserum carotene levels in the recommended ranee of 600-800 mg/dl . bur do.e, up ro J00 mg daily mav he nieded. Mildskin discoloracion due to carorenemia is expeced. The recom-mended producc is Solatene (Tishcon), lvhich u,.asdeveloped as adrug specrficallvor treating rhis direase, arher rhan nuirit ionalproducts that are less standardized. Beta-carotene may quenchsinglet oxvgen or {ree radicals, but does not substantially alcercirculating porphyrin levels. Be er rolerance of sunlight nayresult in tanning, which provides ddirional protection. Oral cys-teine may also quench excited oxygen species and was foundmole recently to increase rolerance to sunlight in EPP

Other measuresro darken lhe skrn may also be helpful. Thisma 1 be accomplishedby n.rrrow band UV-B photorherapr orwrth topical products such as dihydroxyacetone and lawsone{ndph thoqu inone ) . a lo r i c res r r i c r ion nd d rugs or hormonepreparadons that imparr hepatic excretory fr-rncdon shor.rld beavoided, and iron deficrencv should be corrected rf present.

Treatment of protoporphlric lir.er disease must be individual

coal may rnterrupt the enterohepatic circulation of protopor-phyrin, promote its fecal excretion, and reduce liverprotoporph;'rin conlent. Spleflectomy may be benelicial whenEPP s complicated by hemolysis and splenomegaly.Spontaneousresolution may occur, especially f another reversiblecause of liverdysfunction, such as viral hepatitis or alcohol abuse, is contributing. Otheru,ise! exchange transfusioo, plasma exchange,and intravenous hemin to suppresserythroid and hepatic proto-porphyrin production may be beneficral.

Motor neuropathy resembling rhat seen in acute porphyrias

sometimes develops n EPP patients with livet diseaseafter trans-fusion or liver transplantation and is sometrmes reversible. A rti-ficial lighcs, such as operating room lights during livertransplantation or other surgery, may cause severe photosensi-tivily, w.irh extensive burns of the skin and petironeum andphotodamage of circulating erlthrocytes in parients withprotoporphvric liver drsease.

NVirhcontinued progression of liver disease, iver ransplantation ma) be considered. But because ivel dlssar. may recur inthe transplanted liyer due to continued bone marrow produccion

of excessprotoporphyrin, bone marrow transplantation (BMT)

should also be considered f a suitabledonor is available.BMTdid ameliorate hver disease n a murine model of protoporphyria,

and led to remissionof protoporphyria in a patient who under-

wenr BMT for acute myelogenous leukemia. Gene therapy srrate-gies are und€r study in murne models. For example, a dual genetherapy approach allowed selection of hemaropoietic srem cellswith erythroid-speci6c expression of the cherapeutic FECH gene,leading to a progressive ncrease of normal erythrocyres and cor-rection of photosensirivity,

PR0GN0SIS-Typlcal EPP patients have lifelong photosensitivity,b can othenvise expect rormal longeviry Protoporphyric liverd ase is often life-threatenrng; however, the incidence is low.

PBEVENTI0I{.Symptoms can be prevented by avording sunlight.Avoiding agents that may cause liver damage may help preventliver complicahons.

GENETIC 0UNSEIING. NA studies are i reasingly mpofor genetic counseling, especialll'rn famili in which a chiadult has developed protoporphyric hepatopachy. Thisusually identify a disabling FECH mrrtarion and the IVS3-48polymorphism. In some EPP families, however, 2 disassociated mulations are foLrnd, with a pattern of aucosrecessrve nhericance. EPP may in-rproveduring pregnancy.

DUAtPORPHYRIA

Dual pctrpbyria relers ro patients \.ith porphyria who havecrenciesof more than 1 enzymeof the heme biosynthetic pathMolecular documentation is Lmportant in such cases

UROD mutarrons. An infant with severepotphyria was fobased on enzyme measurements, o have rnherited CPO deficfrom 1 parent and UROS deficiency from borh parencs.Cotence of UROS and UROD deficiencies *'ere described

pa ent wilh an erythropoietic porphyla. A iamily u.ith delicies of both PBGD and CPO has also been descnbed.

PORPHYRIAUE OTUMORS

carefully. Hepatocellular carcinomas complicaring PCT and ahepatrc porphyrias usuallv are nor described as containingamounts of porphyrins. Eryrhropoietic porphyrias can devlace n life due ro clonal expansion of erythroid cells contaia specrfic enzyme deliciency in parients who have develmyelodysplastic or myeloproliferative syndromes.

General

AndersonKE, SassaS, Bishop DF, Desnick RI: Discrders of heme biosysis: X linked sideroblastic anerniasand the porphyrias. In ScriveBeaudetAL, Sly \i/S, et at leds): The Metabah. and Molealat BaInherited Disease,vol II, 8rh ed. \es York, Mc(]ra\'! Hill, 20{l2991-3062.

Hjft RJ, MejssnerPN, An analvsis of 112 acure porphyric arracks DTown, Sourh Africa. rvednne 2005;8+48-60.

Kauppinen Rl Potphyllas. La ..et 2005;365:241-252.

Congenital Erythropoietic Porphyria

l)upuis-cirod S, Akkan V, Ged C, et al: Successfulmatch-unrelareddbone maro.* transplantation for congenital ervthropoicric porp

(Gunth€r diseasel.E,rr / Pedidtr 2005;164:101-107.Pjomelli S, Poh-FLapatlick N{B, SeamanC, er al: Complete suppression

symptoms of congenrtal erychropoietic porphyria by long term trea

with highlcvel ranstusion s. Erg 1. l M? d 1985;314:1029-r031.

Soljs C, Aizencans CI,.{strin KH, et al: Uroporphyrinogen III synrhasthroid promoter mutarioRs n adjacenrGAIA1 and CP2elements ausgeniral eryrhropoieticpo.phyti^. J Clin Inuest 2001;107:753-762.

VerstraetenL, Van R€gemorterN, Pardou A, et at: BiochenicaLdiagnoa faral case of Gunrher's disease n a newborn with hydropsJeralis Cl in ChemClin Biochem1993;31:121-128.

Acutc lnrermittent Porphyria

Andant C, Puy H, Bogard C, et al: Hepatoceltularcarcinoma n parients

acure hepacic porphyria: Frequencyof occurrence and related facto

H etatol 2000;32.9 3 3 9 39.



t

2005;142:439-450

Ve1.erUA, Schuur-"ns MNl, Lindbers RLI': Acute porPhvrias: Patho8enesis

oi newological rianlfest..dons semin Liuet Dis 1998;18:43 52

SolisC, N{ariinez-Bermejo \, Naidich TB cr aL:Acute ntermirrent porPhvria:

Srudies fthe severe omozygousdomtnant diseasc rovide nsigh$ inro rhe

izat ionof a myth l 'enpe.t B/olMe d 1990i13:598-611'

Hereditary Coproporphyria and Variegare Porphyria

Hifr RJ, Meissne. PN, An analysx of 112 ac e po'ph,vric attacks iD Cape

Tor,n, South AfDca: Evtdence hat acute rnr mittcnt porphvia and varre

gare iorphv.ia djfie. in suscepribilir) and rerio Medi'ine (Babimofe)

Porphyria Cumnea Tarda

EggerNG, Coeger DE, PayneDA, et aL:Porphvria cutanea arda: N{ulriplic-

ity ofrisk facion lncluding HFE mutations, heparitisC. and inherked uro-

oorohvr inosen r.arborrla'e def i rrenevDrs DA 5,r 2002'4-:4le4Z6'

l l t ter ' r, i l , Porphrr i : cutrne.r arJa :n d re lareddr'orden ln Krdr'h K\ l

Snirh K, Guilard R (eds):Porphyrin Hanclbook, pa't II! vol l4 San Drego,

AcademicP.css,2003, PP 67-92

Erythropoietic ProtoPorphyria

Cox TNL Protoporphyria ln KadishKV, SmithK' Guilard R (eds)'Porpbviz

Halldbook, pa-tll, vol14. SanDicgo, AcademicPress'2003, pp 121 149

Goodivin RG, Kell V{, Laidler B et al, Photosensirivitv nd acute iver iniDrv

in myeloproliferative disorder secondarv to late onset Protoporphjrra

ca"r.i trv d.t.tion o{ a ferrrxhelatascgene rn hematopoietic cells Blood

11:1i90-1596.

ChaPtelg2 HyPoglycemia

cipitously o levels bar impair brain funccion,an elaborate

ulatory systemhas evolved.

The defense against hypoglycemia is integrared by the au

DEFIt{lTl0trl

There is evrdence rhat hypoxemra and ischemia may Poten

concentralion of <50 mg/dl (10-15% higher fot serum

plasma) represents ,vpogll 'cemia.

SIGI{IFICAI{CE1{O EOUELAE

Merabolism bv the adult brain accounts or chemajortry of

and chrldren can retard brain development and function. T

sient solatedhypoglycemiaof short duration doesnot appe

be associatedwrth rhese severesequelae. n the rapidly gror

brain, glucose may also be a source of membrane liprdstogether \^'ith protein synrhesis, t can provide structural plo

an d myelinatronchatar e mportant for normal brain matura

Under conditions of severe and sustained hypoglvcemra,

cerebral strucrural subslrates ma,v become degraded to en

usable ntermediates uch as acta!e,pytuvale, amino acids

ketoacids,which can support brain metabolismat the expen

brarn growch. The capaci!)' of rhe newborn brain to take uP

oxidizl ketone bodies is abour livefold greater than thar o

Glucoseha s a central role in fuel economy an d rs a source of



656. PART r MetabolicDiseasos

m€tabolize ketones, rhese alternate fuels cannor completelyreplace glucose as an essentialcentral nervous syscem CNS) fuel.The deprrvation of the brain's major energy source during hypo-glycemia and the limiced availability of alternare fuel sourcesdr-rring hyperinsulinemia have predicrable advetse corseqLrenceson brain metabolism and growth: decreased brain oxygeri con-sumption and increased breakdown of endogenous strucru.alcomponenrs with destruction of functional membrane integrit,v.Hypoglycemia may thus lead ro permanenr impairment of braingrowch and funcrion. The potenriating effects of hypoxia may

exacerbare brain darnage or indeed be responsible for rr whenblood glucose values are not in the classic hypoglycemic range,

The major long-term sequelae of severe, prolonged hypo-glvcemia are mental rerardation, recurrent seizure activlty, orboth. Subtle effects on personalrty are also possible but have notbeen clearll' defined. Permanent neurologic sequelaeare presentin 25-50% of patients with severe recurrent sympromatic hypo-gl1'cemiawho are younger than 6 mo of age. These sequelaemaybe reflecred n pathologic changescharacterized by atrophic gyri,reduced myelination in cerebral whrte matter, and atrophy in thecerebral cortex. Infarcrs are absent if hvooxia-ischemia drd notconrrrbure o cerehralmanifeslarions; he-cerebellums spared fhypoglvcemra s rhe sole insulr. These srquelaeJre more I ikelywhen alternative fuel sources are limited. as occurs with hvoer-insulinemia.when Lh eepisodes f hypoglycemiaare reperirive r

prolonged, or when rhey are compounded b1' hypoxia, There isno precise knowledge relaring the duration or severrry of hypo-glycemra to subsequent neurologic development of children in apredictable manner Although less common, hypoglycemia inolder chrldren may also produce long-term ner-rrologic defecrsthrough neuronal death medrated, in part, by cerebral excitotox-ins releasedduring hypoglycemia.

SUBSTRATE,]'IZYME,NDHORMONATI'{TEGRATIONFGTUCOSEOMEOSTASIS

lN THE NEWB0BN ISEECHAPIER107). Uoder nonstressed condi-tions, fetal glucose is derived enrirely from che mother t hroughplacental transfer. Therefore, fetal glucose concentration usually

reflects but i s slJghtly lower than marernal glucose levels. Cate-cholamine release,which occurs wirh fetal stresssuch as hypoxia,mobilizes fetal glucose and free fatty acids (FFAs) through p-

adrenergic mechanisms, reflecting p-adrenergic activity in {etalliver and adipose tissue. Catecholamines mal also inhibit fetalinsulin and srimulate glucagon release.

The acute incerruption of macernal glucose transfer ro lhe fetusat delivery imposes an immediare need to mobilize endogenousglucose. Three related events facilitate this transition: changes nhormones, changes n their receptors, and changes n key' enzyme

activitl'. There is a three- to fivefold abrupt increase n glucagon

concenuation within minutes to hours of binh. The level ofrnsulin usuallv falls initially and remains in the basal range forseveral days without demonstrating rhe usual bri sk response tophysiologic stimuli such as glucose, A dramatic surge in sponta-

neous catecholamrne secretion rs also characteristic. Eoineohrinecan also rugment growth hormone secrerion bv o-idrenergicmechanisms; grouth hormone levelsare elevated at brrth. Acting

in unison, these hormonal changes at birth mobrlze glucose viaglycogenolysis and gluconeogenesrs, activate Lpolysis, andpromote kerogenesis, As a result of these processes, plasmaglucose concentradon stabilizes after a transient decrease mme-diatel;' after birth, liver glycogen stores become rapidly deptetedwirhin hours of binh, and gluconeogenesrs rom alanine, a majorgluconeogenic amino acid, can account lot =10ok of glucose

tumover ln the human newborn infant by several hours of age.FFA concentrations also increase sharply in concert with thesurges n glucagon and epinephrine and are followed by rises inketone bodies. Glucose is thus partially spared for brarn utiliza-

non while FFAs and ketones provide alternative fuel sourcemuscle as well as essential gluconeogenic factors such as acoenzyme A (CoA) and the reduced forn of nicotinamide-adedinucleocide (NADH) from hepatic fattv acrd oxidation, whicrequired to drive gluconeogenesis.

In the early postnatal period, responsesof the endocrinecreas avor glucagonsecrerion o thar blood glucoseconcetion can be maincained. These adaptrve changes in hormsecretion are paralleled b1' similarly striking adaptive changhormone receptors. Key enzl'mes nvolved in glucose produc

also change dramatically in the perinatal period. Thus, thererapid fall in glycogeo synthase actrvitv and a sharp rise in pphorylase after delivery. Similarly, the amounr of rate limienzyme for gluconeogenesis, phosphoenolpyruvate carboxnase, rrses dramatically after birth, activaced n part by the sin glucagon and the fall in insulin. This framework can expseveral auses l neonaralhypoglvcemiaba'ed on inappropchanges In hormone secrerion and unavailability of adeqreservesof subs[rates in the form of hepatic glycogen, musca source of amino acids for gluconeogenesis,and lipid storethe releaseof fatty acids. n addition, appropriate activities ofenzymes governirrg glucose homeostasis are required (see

87-1) .

Ittl 0IDEB INFANTSAND CHlLDfiEN.Hypoglycemia in older inf

and children is analogous to that of adults, in whom gluhomeostasis is maintarned by glycogenolysis n the jmmed

postfeedin8 penod and by gluconeogenesrsser.eral hours ameals. The Lver of a 10 kg child contarns =20-25 g o{ gllrcowhich is suffcient to meet normal glucose requirements o6 mg&g/min for only 6-12 hr. Beyond this period, heparic coneogenesismust be activated. Both glycogenolysis and gluneogenesis depend on rhe metabolic pachway' summanzedFigure 87-1. Delects in glycogenolysis or gluconeogenesisnot be manifested in infanrs until the frequent feeding ac 3-4intervals ceasesand infants sleep through the night, a situausually present by 3-6 mo of age. The source of gluconeogprecursors is derived primarilv from muscle protein, The mubulk of infants and small children is substantially smaller relato body mass chan thac of adults, whereas glucose reqr

menrs/unit of body mass are greater in chrldren, so the abilitycompeflsate for glucose deprir.ation by gluconeogenesis s mlimited in infants and young chiLdren, as is the abiliry ro wstand fasting for prolonged periods. The ability of muscle ro gerate alanrne, the principal gluconeogenic amino acrd, maybe kmited, Thr-rs, n normal yotrng children, the blood gluclevel falls afrer 24 hr of fasrrng, nsulin concentrations fall apppriately to levels of <5-10 pU/mL, Iipolysis and kecogenesiactivated, and ketones may appear in the urine,

The switch from glycogen synthesis dunng and immedia

after meals to glycogen breakdown and later gluconeogenesgoverned by hormones, of which insulin is of central rmportanPlasma insulin concenlrations increase to peak levels of100 pU/mL after meals, which serve to lower rhe blood gluc

concentration through the activation of glycogen synthe

enhancement of peripheral glucose uptake, and inhibition glucose production. In addition, lipogenesis is stimulawhereas lipolysis and ketogenesrs are curtailed. During fastplasma insulin concentratlons fall to <5-10 pU/mL, and togewirh other hormonal changes, his fall results in acrivation ofconeogenic paihways (seeFrg, 87-1). Fas ting glucose concertions are mainrained through the activation of glycogenolysisgluconeogenesis, nhrbitioo of glycogen synthesrs,and activad

of Lpolysis and ketogenesis. It should be emphasrzed thaplasma insulin concentration of >5 pU/mL, in association wir

blood glucose concentratron of <40 mg/dl (2.2 mM), is abnmal, indicating a hyperinsulinemic state and failure of the neanisms that normally result il suppressioo of insulin secreduring fasting or hypogl;rcemia.



Chaptergz Hypoglycemia

in infancv an d childhood rtilect rnapproPnatc a(lapt' f()n to

iastlng.

CtINICAtMANIFESTATIONSSEE HAPIER07)

RITEASE*

PeApiralion'PaipLtaln ra(hy.ard)h o rTremuusmss

luryerNauSeaEm6Anqi(withormdloronaryneri6)

FTATURTSSSO(ITTDITHEREBMT1U(OP[IIIAHeadarhe'Mentalonfuscn'Vi5ualdurbancesJ aruy,diplop)

0rqani(eBonallyahange5lnJbit[10 onrentrateU)5art|lru5hringPale51he5,r5Dizine5i

Ahxia,in(oordinauonsomnolence,lelhaqySeizues[omaStrcke,emidq, phasDecerubmte]r ecortateo5ture

5ome0f tele e,nu|6 i I beatsMFd 'f epat$i I tie Yn9EadRmBi.b o3:ngaqenl5

G1\,1S4500

10%(12t126)

5%

\2/40)

10%

,;e' ,iii;^,

67./.10/1

I t r r l26 30 34 38 42 46

Gestationwk )

i1,/rnlft-.1971i47:8I1-88 l

.rremissed.Occasrolallv.hvpogl,vceniamaY be asymptomat

the mmedlacc ewborn period.Nervbornswirh h,vperinsulir

LncLuclcitterinessor tremors, apachl, episodes f c,van()sis

rulsions. intermirrentapnercspelJs r tachypnca, ,r ' 'eakr h

sugar o rormal Jcvcls; f rhe,"do not. orher dtagnoscs nu

considered.

3500

2504

50 0

ttaTuRtgSSoqATEDnHfTlvAllollFAuloiloMl(tRlro,sYSTEMt{oPltltPHnlNt



658 PARTX Metabolic iseases

CTASSIFICATIONFHYPOGTYCEMIAN INTANTSANDCHITDREN

NEONAIAT, RANSIENISMATLFORGESTATIONAI-GE,AND PRE.MATUBTNFANTSSE E HAPTEB07). hc csrirlatednciclencefsymptornaricypoglycernian neu,bornss I j/1.(l0tlhv ebirths.'lhis

incidences ncreasedevcralfbldn certain igh-risk eona-t.LL roufs (see ablc 92 2 and Fig. 91.1j. Thc prenarurcan dsrnrll for gcsrlrionalag c (SGA) nfantsar e vulneraLrlet> rhedevcloprrenr f h,vpogl,vcernia.he factors csponsiblcor rhehigh rcqoenc,vf hvpogllcerrian thisgroll. l, s well as n othergroLrpslrt| led lrrTablc 2 1, are claretl ) he nddequatel(]fesof livergl!cogen,musclc rotein,nd bod,vat rceded o susfil inthe subsrrirresequircd o rreetcnerg)DeeLls.hesenfaursar e

snrallbr ' r ' rrtueof prernaturirl or rrrrpairecl lacental rans

In confritst ro dcficiencvoa substratcsor etrzvntes! hc

signif icantns e in glucose.During rhe nirial 24 hr of lrf i: , plcoLrcenrratronsf acetorcefate nd Jl hVdroxybutyrate rrc li rr SGA niarrcs han n frdl temr rhncs, implving dinLnishcdscores, Lminishedat.v acid mobilization, mpaired ketogeor a combination of drese ondiri< >ns.imilishcd lipiclstorcmosr ikely bccause at itr ighceride) tcccling<>f ovbons rc

Asrociaredith nadequateubstnleafifiature ntymeln(lionnotherwiseonralneonatet

+enrturitl5rr llfore5tdt]nalaE,

Tranrienteonatalype rulinhmho rcsentn:lnkntofdabetirotfersna orqenathnaq€ll crdantwnB halchyxifdf ]f oxem:motlr,or

i]EONATAt,NIANTILE,R II.DI{OO|)TRSISTENTYPOGTYGMIAS

HornonaldirodeBH,rperr,n5m

llereiseK{rrh?'rneltaailGrhanneDaflinantKrpcnannelNDanrnanrqu(okne5el

|minarl htafiialethydroger5r liD,pelin5ulism/hyperamnnem5I1dftrme)A(qJredetadelornaBe|k$rti,(eceranrtndrome

n5.tlndlr iiratrl]n[lunl:']aLrfnyndror,rey nrry)oral ulton/rriatuqt{ongeIit,]lol15ofqlycojybrn

(ounterrcgulatoryormoneef lnryPrnftpcpltJ:fis,nhc redironhmrnoneei(i?niyAd€nocoftrdrcFtomcree hxr!Lld cf d 5ea5e

Ep ephr.neeni:enq

Glycogenolysi!nd9lu(oneogenelirisorde6

!aucc5ephoiphataieefuienryGSDal(iLrco5e'5-phospfrte ar'oca5el]fri,.n(rG5Db)

Arnyl0,5 lur05ida5edebranrflnqnzyme)eli(ierryGSD)

Lir'efh0rph0lla!eehden(yCSD6)Pfo5phory5e rase eii encyGii 9l

Gy.oqentnihetai?ef(enq G5D])

Fru.to5€,6 ihospiat;ieefide1(y

Ffuvatilarboxyie efrenq

6alattose

flaeditrryrurnle toehne

Lipolysisiioderu

FattyaddxidaondirnrdeB

Gl| t ne'ransporGrencqq !inrarycirnitinee6arrc,

[an t]nealm o!tranlleD!eCefriienij/[amitrr:eeri cie denflenr/

[a.nitce a rtcyrrandeTdseden(e].cy

ClD,qroqcirifate ealer|],yFinrrlnrni,r,la,e9(rccGJ5mhdre

lerondaryrnitne efraieni5very nq04 .nreiiumrhofl hain.y cAdehydrc_oene

oTHIR TtotoclEsSubrtrate-limihd(€totrhypo!ty(ginii

Poisoninl rlgj5arqare5

Ord ypocy(em(aqe n6

tn5ut1

Prlrprunolol

P r a n d n e

lisopfamiCe

A.keetri nrpe)-hypcg){ n/aor ratepolslrn)Trmeih0prmulhmetl.omzoh!r /h cnal;iluE)

Liv€rditaase

leve yrdomeflepitr

I rhos5

fleFtonr

Amino ddandorga0i(addisorderslVapsyrLrprn.. 5ta5ePnpon(acdFmid

[lathyharffaridemia

1'rosinc55Glutirr(ddurnI'ilydrcry melh/lohrl,: cidLrrid

lyttemic isodeE5P!5s(a( nnmaAarcfi'asecieiing-'-rniulniieErofltnrior

)Hearl fai lue

MalnLrlon

lVabiorptonAni nsu etepton[bodiesirr in5LrJnl $dies

Neondayperuisoiily

Rerrala ,'re

DErrhea

Burn5

Shork

Fcneur!cal

F5e,Jdahipo!em hrrcrytoli5,otqthenraiL(e55r€n5uinhezpyf n!u ncependentdbeiesne t,.

taitt:oLifl55enundo0{at,oFdL ping lrCome)fu parum dl,.ia



should be treatedwith diazoxide.

l]{fAl{TSEOBI{T0 DIABEfIC oTHERSSEf CHAFIEI1o}. of the

transient hyperinsulinemic states, infants born to diabetic

mothersare tfuemostcommon.Gestadonal iabetes ffects ome

ins themto hvposlvcemia."trloth..r

t"hosJiiabeteshas beenwell controlledduring preg-

listed n Table 92-2.Infants born with crytbroblastosisfetalis may also have hyper-

insulinemiaand sharemanyphysical eatures, uchas argebody

size, with infants born to diabetic mothers.The causeof the

hypirinsulinemia n in{antswith erythroblastosiss not clear'

PERSISTEilTRRECURRET{TYPOGTYCEMIAilll{fANTS ttlDCHItDREt{

HYPERISUUiIISI|, Most children with hyperinsulinism hat

causes ypoglycemiapres€nt rl the neonatalperiod or later in

ChaPlolg2 Hypoglycenia

allv it is 1st evident n older children. nsulin concentration

inaooropriarelv levatedat the time of documenred y

elviimii; *ith non-hyperinsulinernichyroglycemia. pla

insulinconcentrationshouldbe <5 puiml and no higher

administrationof insulinas a {orm of child abuse Muncha

by prory syndrome), SeeChapter 36'2.] Provocative ests

rolbutamideor leucine r€not necessaryn infants;hypoglyc

92.7) .The measurement f serum GFBP-1concentrationmay

diagnosehyperinsulinemia. he secretionof IGFBP-I is acinhibited by insulin; IGFBP-1 concentrationsare low du

hyperinsulinism-inducedypoglycernia.n patientswith spneousor fasting-induced ypoglycemiawith a low insulin (ketotichypoglycemia, ormal fastilg), IGFBP-1coflc€ntra

are significantly higherThe differential diagnosis of endogenoushyperinsul

includes di{fuse p-cell hyperptasiaor focal p-cell microadenThe distinction between hese wo major eotities s imPo

becausehe former, f unresponsiveo medical herapy, eq



66 0 PABT I Metabolic iseases

TYPE

tpcrad(

IflPOGTY(ETIIA/

MA(flIXOMIA IIYPERITISUIINITIIA

P,esrntb h ltrlodecelewrcn 5tCa)5oweeb i e

ASS0OATIDtllllftL, ntJm $I0 R[(0t1tr,ltttDtDFAMILY 8t0(Hti{Gt,0R t rDtcfl. SuRGt(AtHIsTORYMOLT(UIARtfI(TS MOITOTAIIATURTsMI}IAGTMEI.ITPfNOA(H

Ne_oatve ItURl/KN6)

MLrtalions0talwaysiCentiReddifu5ehyperpla5ia

Los5Fraero4go5itynmicrc,rdenom,Iouj

l !5Ue

6enerallypooI

niy resp0nd

benero

man0

0ldZoXrCe

l:rld pai(reiteatl]rJl

l -a3l t rodc9 rr5rn i

nlde miirljdderomi

iulr.rtd !t%

5uLto:3anarealedo.l))'

!urqery5Lrlinot eqIed

hrtd pan(rei redcn!ni l f

nreotG anrllmeE 5)uqe

luju3 lol e(jLco

Nolrerommend,.d

Pn(XNo

[rrelenr

Gu3ded;db

nel i tu5derelcp

ofFatie

nvpo!1apeAh[npanrral

riTmftne

shohsq

nui i in- d rus

n/perptlil]irded

[xrrlent

L{celleri

Fr(eentlol

fyp0qr/r

ai50iat€

enbr)o'a

tumo15!!1hepitob

tun

retes5e

domrnart

Autc5omil

Be.l( h

wecemann

5ln0i0tne

[onqerild

d sdrderslgyrolEnon

Presen,lbrrth sel/eren 5tdaysor'rcekiflitu

LlnurLl2 [lcdera(enletsuallyprtnan0tage

'Jnu5Lral ll0dpr,ttcnietsualypcll m0 laqe

Pre5eillbirt[ Mcderate,sNmaneousrcJoivrsosi6mo Fage

Nol 5ua l\,loderare/onseto5iI moofage

tUlJKa6) (o[sa uinityeaturen Poortome puiat0n5

6fu(0kdie cvariig) None Verymd 0\omea5e5qene ex(elent

Gluiamale ModesiypeBfitrnoftmiiVeq 0rd0'lehydrcgena'e e)((elent

(activalnq)

Dupiratinll/mpdntnqva(mgloi5a,onphalorele,oodn hromo5ome hemlhypeffiophyl l c l5 l

Po5live

Po5:1ve

Neqalve

NeQate 6ood htTtann0!esuppernenr

Phosphomanro5e Hepatomeliltvomitng,i50meE5eefr:enc! intractableanhed

l lear totrrl pilncreelectom\i dcspite which hypoglycellra tnavpcrsistor rLabetesmcllitusmav ensueat somc irtcf frme.Bv corri r r r t . t . r . : l , t . l r r r , ' r n r . d iaqno 'eJ p r r , , l ' . r r r r re l r ' ' i n r r , r , l ' e r . r

nvch pcnnif loc:rlrzed urarivc esectionwith subscqLrentormdlghLcosc rctaLroLisrn.Lrour 509/oof rhe au<rsomal recessi\r )r

spordclic orms of neonatal/ inlhlt i le h1'perinsulinisnrre dre roiocal n-icroaclenonas, rhich ma,v be t l ist ingLrishedrorn rh cclif fuse orn by thr lirttcrn of insulin responsc o sclectivensulin

secretirgoguesLniusctl nto irn arrery suppl,ving fhc pirncreas '!.ithsrmpling viu rhe heparic vein. Positror enission tomographv(Pt-l scannnlf l) sinq 18 f luoro L <1opa an disringLrishhe diffuseform (ulifornr lluorrscence hroughorLt hc pl crcas) ion fhc

5U85TMTIS6lurosPireeiacytirdrl(eloft5L3ataltu l ca (

HoRMollt5lnrutntortl5ol.lrohftromoneihl.crine,hyrod-stimutingFrmoner3F3P

'6 urdgdr,l rqlkq rhm mumf I mq V r M'M!:r!rc0fte0n

! bebreoi|1erq(iqondmiii{,m0n iem9l!(seol>40mg/d: lifl gu{dgongMndther'me

rf hy".0911{em,rnqy 5uqq6tia hypernlulmrir tre wt zdeqeareepdtk ['(o,;enores ndnh(rglirdEe.o,t s4mei I dnm0nlis eel'alrd 100-100,M, i3'der rrivarg mlbrm ot gidamal€

6igP , n5!ln l€oroMh'?r1rndinqorerr

locrl fomr (iocal uprakc <rf 8lluoro I- clopaand localizcdrescence)Scc rig. :,123.].

ILrsulil-sccrcfng macroailenomls are rare in chilclhooc

rnay be diaenoscdprcoperafii 'elyvi a CT or MRL The pialcr'cis o1 insulin alrrc, holvever,cannoc disringuish he lfomenti(ncd cntit ics.Th e diffuse or nricroaclelomarousorlttislet cell hypcfplasia ep resert a vnrietv of eeleric defects essible or abnorrralit ics n the erdocrine pancreas haracterizaLronomous ls l in secrctiol fhat is nor appropnarelv rcclu'hen blood glucose decliles sponfarreousl] ' r in resporsprovocafi\.emaneuvers lrch as fasfins (scc abies 92,r- a||d8). Cllinical, riochcmical, nd moleculergeneticapplo:rchespermit classilic.rt ionoI congeniral h,vpcrinsulinisnr. ornterrnednesidioblasrosis,nt o disrincrcnrit ies. 'ersisrcnr vpesulincmic hypoglycemiaoI infancy (PHHI) nray lre nherircdsporadic, s sclcre, ancl s causedby lrrutirf ions Lr hc rcgulaof rhe porassium hannel ntimately nvolved r Lrsulin sccrcby chepancrearicB ccll (Fig. 92 2). Nororally, glucose ntrv

th ep

cell s enahledb-v hc non insulin-rcsponsive lucose rporter GLL-l' l-2.On enfry, glucose s phosphorylateclo li luc5 phosph.ate by rhr cnz,-rne glucr>kinase, enabling gluc

I ilypedn!u[[emiapasmansu,n2 lJ/mL]r2 |]ypofaftyacidemiapaifidree tlya(ids 15 flmo,/l)I HypoketonempldgmaFlrydrcxybutyrdte:<2] mmo/i)

4 lnappropflaielly{emrie5p0n5poqlucagon,:! iV decqucoie40m_q,/dll*Cependron en5i!iryfnrdn5s?lfmn5hnlqLd lomron 5.ilE0d DN,ral: ypqtFrma. nfdn15rid Le0niIEl5refiq ]VA d 0,):

ladwn\hrytd ed,P\it)ehn,\\8aunder.?002p l5 l59



A(UT[SYMPTott'lSRESIIIT

su5pe{tyFllniulinemiar alty dd xidande{KLfpre*nt,uspetfetothcnnone

hotm|]neeasLlreremsnTabk2-5

piruilaryi5ed5e,rboth.dm ohospal or omonaest g nd elloimaEng

pignentdtnhdrenaailuE);5hlurend eurcqlc 1alu5il0itrrysea5e)

when cLrleymplorxsrcsent

b Pituitary-adrenauntton slngrqrn,nein5ulintmu,ltone5t nd akd

syn0lome,e(

Pancreatic Ce

Gl!cose

Chaplergz HyPoglycemia

rLlarions.nofabl,v Arabic and Ashkenazi Jervish communi

u,here r nay reachan incidence rI bout 1/2,500,comparedu

the sporadic ates n rhe generalpopulation of =1/-50,000. h

auroiomal recelsive forms of PHHI t,vpicaliv Presenf in

/Glulamale

//

+GDH

a-Ketoglutarate

oo

srMuLArEp_./

-r$:

"rf\{'l'N\

BESTING

gL'=:a



062 PABT t MetabolicDiseases

(0 DfloN

N0[naHypern!rnerniaK:tolir'yprgre|r

futly (d.rd;. lisol:rl l lrD0pilurdr5mddrcna5Jfliren.ytzimeetcenti

ilur:D5eiorpiataleebi herrroiploryla$

hucos?,6 rphc5pl'alajeGl aaicfn J

Fludolr ntoeran(e

IIYPOGTYGMIA

0Reautrc4l5ewTe

severe{hm[5ed ea

5everc,ith

miJsedeal,4oderdteithmi55ec eals

te\,e,ethm$edmea

Severeon5lanl

Modetule! lh astng

[lildmoderire

!everewith5inq

Aiier lkormkpadurt5

Aftertuctose

URINARYI(ETO5OR TDUONGUGARs

00rcrcnuraH

iemnularci0nura-êlonuna(erorLrda+(,oto,ruda+[etonJla+0 Ketones;ii)+0 K."tonei;ir)+

HEPATOMEGALY

0ll

c

0 o+Abnornawr ufr:oltct-H

Deta50|ei . (0ndl00ardid$!ednI iete(c 'abq:e] idJndf te5F5tn! t } 'ma]h( f0df f6e;1

irnrnediete neu-Lrorn eriocl irs nracros()rlic reu,horns r,r ' irh aweighr >,1.0 g and scvere ecLrrreltf )r persisreLrtvpoglycernia

manifesting,n lhcinit iLrl

ours or days of l if i.(, lucosc

infusionsas hJgh rs 1.5-20 /k/min and frerluent cec[ngs ail ro rnain

rail cuglvccmra.Diazoxide, vhich:rcrsbv opening, r '" channels(see ig. 92-2). fajls o concrolhy|.Tog)vcerniaclequarelv. omato

stlrrirr. \,hich nlso opels K111 nd inhibrts c;rlciunr 1ux,mav bepa r t ia l l y i i cc f i vc n =50 i ' , o f L ra f ien t sseeFrg .92 -2 ) . -a lc iL rn r

channcl hLocLin.e gents have had rncorsistcnr cticcts. \\ iheLrallecrerlparicnrsarc Lrnrcsporrsiveo thesemelsures.pancrcatcc

tonry is st ronglv rec()rnrrendedt) avoid thc long rcr r neurolt>gic

secluclac i hr poglvccrria. i surgerl is Llnderfaken. rcopcrarire(i l or N{RI f irclv rcvcalsat isoiafedaden()[r.r,\,LrLchvould rhcnpcrmit locrl fcsccrior).lrttaoperativeuLtrasonogrphv mav rden

tif,va small irrpllplble acienona,pernirung local rcscction.Ad e

lomls ofren present in lare inlancv or earlr chilclhood.

Disringuishrng Lrcnvccn ocal and diffusc cascs oi persistent

hvperinsulinismha s bccn artcnrprcd n sevcrai vars. Preopera-rivcll. , ranshcpirt ic (rrtnlvcin cathctcri?irt ion nd selecrirepan-

crearicveDousSaLIplir lg () neasure ilsulin rnav localizc a focal

lcsion rom th e stcp up in insulin colcelfration rt a speciiic ite.

Selective athcrerizariol of arterial branchessupplying the pan

creas, ollo\cd br infusion of a sccrct:rgoglrcLrch s crlciunr an dporral veill srrrrplrrrg or insulrn concenlriloon ertenal srimuLa

fi()n-venous arnplrlgl rna,vocalizca lcsion.Both eppfoaches r 'e

highlr- invasr"e. restricted o speclalized enfers. rnd not Lrri-

iorrrly sr.rccessfuln clist inguishing he loca fronr the diffrLsc

iorms. l8F llbc)cd I clopa cornbined wirh Pt.T scuniLrg is :r

pornisirg, rncani t() disrin[juish hc iocal frorn rhc c]if fuse esions()f hrferinsulinrsrnLrnresponsivco mcdicdlmlrnaecrrcnt Fig.92

.1). I-hc'gold

sranciard" cmarns rltraopcr.t iyc histologicchar

ilcrcri7.lcio11.iffusc h,rperilsulinisll is chdrrcferireclbv lrr14e

cclls \.\, ithrbrrornally

large rtuclei,whereas ocrl ddenomat()Lls

l cs ions l sp l r r y m i l l i r nd nonn. l B ce l l nL rc lc i - l r hoL rgh URI

nrutilf l()ns.rc prcscLrfn both 11pes, hc focal lcsio s alisc bv arnrrcll) irrr)sr rI rrrit terrally lnprinredgrou'rh inhrbrtorygelre ll

nrtefnal chronlos()rne 1p il associ:rf iorlwith pafcrlrxl rr:rlrs

orission f a nruritcd .S{-iR or K|16- 2 prrcrnrl chr'onr' :rsomeI pr.

ThLrs hc rrrcrl iofm representsa cloLrble rt ()ss oi nrarenlal

rcpress()r nd trrnsrlrission f a pitcrnel nrrrrrrt ion.-ocalercision

of focal . ldenonraftrusslercelL yperpl:rsiir csulfsLr 11cr.Lrcvirh

lrrt lc or no rccurrc rrcc- or rhe clif iuse ofnr, rrcrr tofrl resection

oi 8.5-90'11,i thc p.rrcrc.s s rcconrrncrrrled.hc rcer rotal pan-

crcilfccrorrr\ reqrrired k)r rhe diffuse hi'perplasric lcsions is ,

hor,r 'ever,ifel rss()ciatcd "vithpcrsistcnfhvpoglr'ccrrirr virh rh e

later dcr.clopmcnrof hypelglvcenril or frank. irsLrLiu cquirurg

diabctcs ncllitus.

Further resecrion i thc rcm:riningpancrcirsnril)_ ccisionbe necessar,vi hypogli.ccmil recurs alld cannot be cortt()l le

medrcaimcaslrrcs, uch rs the Llsroi somdtostafinor diazoxLxpcricnccdpcdiatric sLrrgeorsn rnedical cntersequippeprovide dre ncccssnrvl)rL1)pcrafivend posropcrlt ire care, drrosticev.rlLrafxxr! ncl rnanagernent hoLrlcl crform srrgersonrepaticnrswh o hlve beeu managcd rcdically,hyperil lsrmi a and ht po.qLvcemLaegrcssover nonths. This is siurilarvhat oc.Lrrs n childlcn wirh rhe h,vperlnsulincrnicyL.og[1

sccn n Beckuith-Wiedenann syndronc.It hvpoglrccrrria sr rrrrrrifests ern'ccn3 ancl 5 rn o oI ag

later a rherapeutic rlal rLsing redicelapproaches virh dieic1e.onatosratin, lnd freqnent ccdings au be rtteDfted fo

to 2-4 wk. l 'arlurc to marntain clll l l lcerriit with()ut undcsir

side effecrs rom the drugs miy pronrpt the leecL irr surg

Sone successn suppressrngnsulirr clcase lld c()rrecnngh,

gJlcernia n pirt ients ii ith PHHI has been reporrcd vi th thc

ol rhc long-rcting som:lt(rstafirr nalog octreofLde.Most casneolaral PHHI ,rrcsporaciic; amllial fornts pennit !,cncti ' : oselingon rhe L.asis f anncrpared utosonral ecessivenherita

,\ 2nd iorm oi farril i l l PHHI suggests utosomal domininhcritancc, Lrechnical eatures enrl () bc lcssscr,efe, nc looi hypog,lvceLlJas nosr likcJ1',brrr rrot exclusLvell-,r> obcvond thc rnrrnediatc crvborn period errclusuall]. bclondper' iod ) i \t 'eanilrgat aLraveragcaec rr onset of dbouf I rrbirth, rnlcnrsornia s rlr 'clv obsen'ed. urd responsc o cli ir?ois alnrosr Lnifbnn.Thc lrrit ial presenretionLral be dclal'cd

rarely occLrr s ldte as l0,vr, ulrlcssprovokecl bi 1:rstinggeneoc bisjs ior rhis .rurosornaldonrinant f ' :rrrnha s ror b

cleli learedrt is nor alu,rlr l inked ro Kl16-2l-lt iR1. Howcver

activrt ing nutati(r1 in ,5lucokrrrases transrnitcedrt ln eut

r n , r l J , , r ' r 'r l r ' r n . r r r . , r J n r r l \ r i r r u r \ \ l r e \ ( r ) t . F e n r r ' ('

sellng or-a j0'] l rceurrence arccan bc

given oriuture

of|spr

A .lrcl iornr of per-srstenrllHI i\ .rssociared it h mild

asymptonaric hypcrammonemia, usualLr as a sporadic oc

rcnce. althotlgh dominarrr inhcrirancc occurs, Itresentafrrrrorc likc rhe i lLrtosonrirl onrinant for-nr han the aut()s

recessi\.eofrn Dier ancl Ji:rzoxidecorlrrol symptonls. )Lrtp

crcatcctonrl nrrlv be ncccssir\r n sor'ne ases. hc associarrhl.perrnsuLiLrLsrrnd lrvperammolemia s calLscd y err rnhc

or dc novo girirrof funcfion f iLrfation rrl the enz)ine gLuta

dehvdrrrgellasc.he result ing ncrcrsc ll glutarrrirte)xid:lf i(

the p,rncrcntic ccll rrrses he ATP conccntrrrior ancl,hcnce

rario of ATP:,{Dl \\ 'hichclosesK.r-rr,elcling o membranede

la r i za t ion , a l c i rLn rn f lux . nd nsu l in cc rc r ionscc ig - 92 2

rhc livcr, hc cxccssrvc xidation oi it lutarndfc o [] kcroglt it i

nriry gcnerare lnrnronir alrd divelt glLrtnmdte Ionr lr



Chapter92| Hypoglycemi

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occurs il ntluv oi thcsc infirnrs- )if fuse rslcr ccll hvp.cr-plasia

occLrrs!l ini.rrltswirh hvpoglrcenli,r ' lhe dr.tgrrosrrcnd dlcrr-

I

\Yilnrs t luuor, heplrobirrstonre. rclrrnrI carcir]olri l, gonadttrL)nre. :rndrhebdonl,voslrcotrit . Ihis o"'crgro*'rh synclror

tufc5 rrd paltcrnsof transmrisir)rr. vpogllcemia ma,v eso

\!ccl\ to mollths of meclical heraP\- )ancreatic escction

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ro,rrr l p. rrcri . rt i t is{ t l r l r r r r ' r . L: \ \ \l (^\ Jl , ndmrl pl rnrt tet i . ns

n . r r o r o a l l S l : l ) O P . \ u r r i l c n : t l ) r l r r r e r c . r t i c h c . r . l r ' t h c o t r s t r r r r r i

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664 PABT r ilelabolicDisoases

and hypoglycemia seeChapter87,5).Thesedisordersare oftenunderdiagnosed,One entity associatedwith hyperinsuLnemichypoglycemia s caused by phosphomannosesomerasedefi-ciency,and clinical improvement ollowed supplemental reat-mentwrth oral mannose t a doseof 0.17g/kg six timesper day.

After the 1s t 12 mo of life,hyperinsulinemic tates re uncom-mon unril isletcell adenomaseappear sa cause fter hepatientis several earsof age.Hyperinsulinemia ue o isletcell adenomashould be consideredn any child 5 yr or older presenringwithhlpoglycemia.The diagnosticapproach s outlined n Tables92-

7 alnd92-8. Fasting or tp to 24-36 hr usuallyprovokeshypo-glycemia; coexisting hyperinsulinemiaconErms the diagnosis,provided hat factitiousadminislrationof insuhnby the parenrs,a form of Munchausen yndromeby proxy, is excluded.Occa-sionally,provocaciveestsmay be requrred.Exogenously dmin-istered nsulin can be distinguished rom endogenousnsulin bysimultaneousmeasurement f C-peptide concentration. f C-peptide levels are elevated,endogenous nsulin secretion sresponsibleor the hypoglycemia;f C peptide evelsare ow butinsulinvaluesarehigh,exogenousnsulinhas beenadministered,perhapsas a form of child abuse. slet cell adenomas r this ageare treatedby surgicalexcision; amrl ial multiple endocnneade-nomatosrsype iVermer syndrome) houldbe considered. nti-bodies o rnsulin or the insulinreceptor insulinmrmeticacrion)are also rarely associatedwith hypoglycemia,Some tumors

produce rnsulinJike growth facors, therebyprovoking hypo-glycemiaby interactingwith the nsulinreceptorThe asrute lin-ician must alsoconsider he possibilrry f deliberate r accidentalingestionof drugs such as a sulfonylureaor relaced ompoundthat stimulalesnsulinsecretion.n suchcases,nsulinand C-peDtide oncentratio[s n blood will beelevated.nadvertenr ub-iriiution of an insulin secretagoguey a drspensrngrror shouldbe consideredn those aking medicationswho suddenlydevelopdocumented ypoglycemia.

A rare form of hyperinsulinemichypoglycemia has beenreported after exercrse. 0hereas glucose and insulin remainunchanged n most people after moderate,short-termexercise,rare patientsmanifesrseverehvpoglycemrawith hyperinsuline-mia 15-50 min after rhe samestandardized xercise. his {ormof exercise-inducedyperinsuhnism ay be caused y an abnor-

mal responsivenessf p-cell nsulin releasen responseo pvru-vategenerated uring exercise.

Nesidioblascosisas also rarely beenreported after bariatricsurgery or obesiry

END0CRINEEFICIENGYypoglycemia ssociated i!h endocrinedeficiency s usually causedby adrenal insufficiencywith orwirhour assocratedrowth hormonedeficiency seeChapters 58and 576). In panhypopituitarism, solatedadrenocorticorropichormone (ACTH) or growth hormonede6cienc,.',r combinedACTH deliciency lus growth hormonedeficiency,he incidenceof hypoglycemias as high as20%. In the newbornperiod,hypo-glycemiamay be the presenting eatureof hypopituitarism; nmales,a rnicrophallusmav provide a clue to a coexistentdefi-crencyof gonadotropin,Newborns with hypoprtuirarismoften

havea form of "hepaticis"and the syndromeof septo-optic ys-plasia.When adrenaldiseases severe, s in congenitaladrenalhyperplasia ausedby cortisol syntheticenzymedefects, drenalhemorrhage, r congenitalabsence f the adrenalglands,distur-bances n serum electrolyteswith hyponatremiaand hyper-kalemiaor ambiguous enitalsmay provide diagnostic lues seeChapter577). n older children, ai lure of growth should suggesrgrowth hormonedeficiencv. yperprgmentationmay provide heclue to Addlson diseasewith increased CTH levelsor adrenalLrnresponsivenesso ACTH owing to a defect n the adrenalreceptor or ACTH. The frequentassociation f Addison diseasein childhood wich hypoparathyroidrsmhypocalcernia),hronicmucocutaneous andidiasis, nd other endocrinopathies houldbe considered. drenoleukodystrophy hould also be considered

in the differential diagnosis of primary Addison disease n ochildren (seeChapter 86.2).

Hypoglycemia in cortisol-growth hormone deficiency maycaused by decreasedgluconeogenic enzymes with conisol dciency, rncreasedglucose utilzation due to a lack of the antanistic effects of growth hormone on insulin action, or failurestrpply endogenousgluconeogenic substrate In the form of alanand lactate with cornpensatory breakdown of fat and generaof ketones. Deficiency of these hormones results in reduced coneogenic subsrrate, which resernbles he syndrorne of ket

hypoglycemia. Investigaron of a child with hypoglycemia, thfore, requires exclusion of ACTH-cortisol or growrh hormdeficiency and, if diagnosed, its appropriate replacement wcortisol or growth hormone.

Epinephrine deficiency could theoretically be responsiblehypoglycemia. Urinary exctetron of epinephrine has been dimished n some patients with spontaneous or insulin-induced hyglycemia in whom absence of pallor and tachycardia was anoted, suggesting that f ailure of catecholamine release,duea defect anywhere along the hvpothalamic-autonom

adrenomedullary axis, might be responsible for the hyglycemia. This possibrlrty has been challenged, owing to the raof hypoglycemia m patients with bilaceral adrenalectomy, pvided that they recei.'e adequate glucocorricoid replacernent,because drminished epinephrine excretion is found in norm

pa ents witb repeated insulin-rnduced hypogll'cemia. Manythe patients described as having hypoglycemia with failure of nephrine excretion fit the criteria for ketoric hypoglycemia.

Glucagon deficiency in infants or children may rarely be aciated with hypoglycemra.

SUBSTfiATE IMITED

Ketotic Hypoglycemia.This is the most commor form of ch

hood hypoglycemia, This conditron usually presents betweenages of 18 mo and 5 yr and remits spontaneously by the age8-9 yr Hypoglycemic episodes typically occur during periodsintercurrent illness when food intake is limited. The clahisrory is of a child who eats poorly or completely avoids evening meal, is diflicult to arouse from sleep the followmorning, and may have a seizuaeor be cornatose by midmo

ing. Another common presentatio[ occurs when parents sleepand the affected chrld is Lrnable o eat breakfast, thus prolong

the overnieht fasr.

At the time of documenred hypoglycemra, rhere is associa

ketonuria and keronemia; plasma insulin concentrations

appropriately low, <5-10 pU/mL, thus excluding hyperinsulimia. A ketogenic provocative diet, formerly used as a diagno

!est, is not essential to establish the dragnosis because ast

alone provokes a hypoglycemic episode with ketonemia

ketonuria within 12-18 hr in susceptible individuals. Normchrldren of similar age can withstand fasting wirhout hvglycemia developing during the same period, although e

normal children may acquire these features by 35 hr of fascinChildren with ketotic hypoglycemra have plasma alanine c

cenffatiols that are markedly reduced in the basal state after

overrught fast and dechne even further with prolonged fastAlanine, produced in muscle, is a major gluconeogenlc precur

Alaoine is the only amino acid that is significantly lower in thchildren, and infusions of alanine (250 mg/kg) produce a ra

rise in plasma glucose wrthout causing significanr changes

blood lactate or pyruvate levels, ndicating that the entire glu

neogenic pathway from the level of pyruvace is intact, but tthere is a deficiency of substrate. Glycogenolytic pathways

also intact becauseglucagon induces a normal gly'cemic espo

in affected children in the fed state, The levels of hormones tcounter hypoglycemia are appropriately elevated, and insulin

appropriately low.The etiology of kerotic hvpoglycemia may be a defect in a

of the complex steps involved in protein catabolism, oxidat



deaminatron of amino acids, transamination, alanine synrhesis,

or alanine efflux from muscle. Children with ketotic hypo-

hypoglycemJa-

GLYCOGENTOBAGE ISEASE. eeChapter 87.1.

Affected untreated children manifest growth {ailure' mental

continuous gastric feeding. The dayome feedings are given eve

34 hr: 60-70L of the calories as carbohydrate low in fructo

an d qalactose, 2-15% of rh e caloriesas protein, an d 15-25%

of th*e alories as fat. At night, a small nasogastric cube s passed

1.87o as safflower oll, and 9 2o/" as crystalline amino acids

(\rivonex,Novartis Nutrit ion, St. Lours Park MN 55416). Noc-

Chapter 2 I HYPoglycomia

turnal cornsrarch therapy is also beneficial. Transtenr noctur

hypoglvcemia is not completely prevented, and renal glomeru

dysfuncrion plus formation of hepatic adenoma lemain seli

complications, Liver transplantacion offers promrse of long-te

cufe,

defects have been described. Hepatomegaly, excessivedepositof gLycogen n liver, growth retardation, and occasional svmp

maiic hypoglycemia occur A dret hrgh in Prot€in and reduce

cholamines, are appropnately elevated or normal, and ins

levels are appropriarely low. The liver is nor enlarged. Prot

rich feedings at frequent rntervals result in dramatic cltn

improvement, rncluding growth velociry This condition mim

the syndrome of ketotic hvpoglvcemia aod should be considein the differential diagnosis of that syndrome

DISOBOEBSFGTUCONEOGENESIS

provokedbv inhibrt ion ol glycogenolysis. lrco8enol)cr s em

inracr,an d glucagonelrerts normal glycemic e\ponse n the

but not rn rhe fasted, state. Accordingly, affected individuals h

Clinical features simulare those of rype I glycogen sco

disease.Hepatomegaly n individuals with fructose-1,5-di

phatase deficiency is due to hpid storage talhet than glyco

storage. Lactic acidosis, ketosis, hyperliprdemra, and hy

uricemia occur; their pathogenesis s related to the severiq'

durarion of hypoglycemia and lhe resultant lorv levels of ins

and high levels of counter-regulatory hormones. Therapy

these infants, consistrng of a diet high in carbohydtates 15excluding fructose, which cannot be utilzed), lorv in pro

(12%), an d normal in far composrtion (32%), ha s perm

normal growth and developmenr- Continuous nocturnal pr

sion of calories rhrough rhe intragastric infusion svstem descr

earlier for tvpe I glycogen storage disease s also applicabl

children with fructose 1,6-diphosphatase de6cienc,v. Duintercurrent illnesseswith vomiting, intravenous glucose inlu

is necessaryo preventsevere ypoglycemia.

Oelects n Fatty Acid Oxidalion (See Chapter861.The impor

role of fattl acid oxidation in maintaining gluconeogene

underscored by examples oI congeniral or drug-induced de

rn fatry acid metabolism that may be assocratedwith fa

hypoglycemia-

Various congenitaI enzymadc deficrencies ausrng defective

nitine or fatty acid merabolism occur. A severe and relar

common form of fasting hvpoglycemia with heparomegall',

diomyopathv, and hvpotonia occurs with long and med

chain faty acid coenzyme-A dehydrogenase deficrency (LC

and IvICAD). Plasma carnitine leveLsare low, ketones ate



666 r PARTX Melabolicoise8ses

present in urine, but dicarboxylic aciduria is present. Clinically,pacients rvith acyl CoA dehydrogenase deficiency present with aReye-like syndrome (see Chapcer 358), recurrent episodes ofsevere fasting hypoglycemic coma, and cardiorespiratory arrest(sudden nfant death syndrome-like events).Severehypoglvcemiaand metabolic acrdosiswithout ketosis also occur in oatients withmulriplea.rl ( oA dehydrogenase isorder' . HypuroniaJ eizures,and acrid odor are other chnical clues, Survival depends onwhether rhe deiect, are 'evere or mildi diagnosrs s eirablishedfrom scudies of enzvme activlty ln liver biopsy tissue or rn cul-

tured fibroblasts from affected patients. Tandem mass spectrom-etry can be employed for blood samples , eyen those on frlterpaper, tor screening of congenital inborn errors. The frequencyof this disorder s ar leasr1/10,000*15,000birrhs. Avoidanceoffasting and supplementation with carnitine mav be lifesaving inthese patients lvho generally present in infancl'.

Interference with {artv acrd metabolism also underlies thefasting hypoglycemia associated with Jamaican vomiting sick-ness,with atractyloside, and with rhe drug valproate. ln Jamaicanvomiting sickness, he unripe ackee fruit contains a water-solubletoxin, hypoglycin, which produces vomiting, CNS depression,and severe hypoglycernia. The hvpoglvcemic acciviry of h1'po-glycin denves from its inhibition of gluconeogenesissecondary toits interference vvith the acyl CoA and carnitine mecabolism essen-tial for rhe oxidarion of long-chain fatty acids, The disease rs

almosc torally confined to Jamaica, where ackee forms a stapleof the diet for the poor. The ripe ackee fruit no longer containsthis toxin. Atldctlloside rs a reagent that inhibits oxidative phos-

phorylation in mitochondria by preventing the rranslocation ofadenine nucleotides, such as ATP, across he mitochondrral mem-brane. Atractyloside is a perhvdrophenanthrenic glycoside

derrved from Atractyls gummrfera. This plant rs found in rhe

Medicerranean basin; ingesrron of this "thistle" is associatedwith

hvpoglycemia and a syndrome similar to Jamaican vomiting sick-

ness, The anticonvulsalt drug valproate is associated with sideeffecrs, predominantly in young infants, which include a Rer.e-like syndrome, low serum carnitlne levels, and the porential forfasting hypoglycemia. In all these conditions, hypoglvcemra is zol

associated uith ketonu/u,Acute Alcohol Intoxication. The liver metabolizes alcohol as a

preferred fuel, and generalion of reducrng equivalents during theoxidation of ethanol alters the NADH:NAD ratio, which is essen-

tial for cerrajn gluconeogenic steps. As a result, gluconeogenesis

is impaired and hypoglycemia ma,v ensue if glycogen stores are

depleted by starvation or by pre-existing abnormalities in gl1'co-

gen metabolism. In toddlers who have been unfed for some cime,

even the consumptioo of small quantities of alcohol can precipi-

late rhese events. The hypoglycemia promptly responds !o intravenous glucose, which should ahr.ays be considered in a childrvho presencs nitiaLly rvith coma or seizure, after taking a blood

sample to determine glucose concentration. The possrbilit,vof the

child's ingesting alcoholic drinks must also be considered if there

was a preceding adulr evening parq'. A careful history allows the

diagnosis to be made and may avoid needlessand expensive hos-

pitalizacionaod investigation.

Salicylate Intoxication (SeeChapter5Sl.Both hypergh'cemia andhypoglycemia occur rn children with salicylare intoxication.

Accelerared urrlizarion of glucose, resulting from augmentarion

of insulin secretion by salicylares,and possible interference with

gluconeogenesis may contribute ro hypoglycemia. Infants are

more susceprible chan are older children. Momtoring of bloodglucose levels with appropriate glucose infusion in the event ofhypoglycemia should form part of the therapeutic approach co

salicylate inroxrcatron ln chlldhood. Ketosrs may occur.

Phosphoenol Pyruvate Caftorykinase Deliciency. Deficiency ofthis rateJimicing gluconeogenic enzyme is associated vr.rthseverefascing h1'poglycemia and variable onset after birth. Hypo-glvcemia may' occur within 24 hr aher birth. and defecrive glu-

coneogenesis from alanine calt be documenled rn vrvo. Liver,

kidnel and myocardium demonsrrate atqv infiltration,atrophy of th optic nerveand vrsual cortex may occur.Hyglycemiamay eprofound.Lacrateand pvruvareevelsn plahavebeennormal, but a mild metaboli acidosrsmay be preThe fatty rnfiltrationof variousorgans caused ,v ncreasemation ol acetylCoA, u.hichbecomes vailableor fattv acidthesis.Diagnosisof this rare enrity can be made,"l.rth erronlr through appropriare nzymaric erermrnarionrn biopsymaterial.Avoidance f periodsof fasring hrough reqfeedingsich in carbohydrare houldbe helpful because lyc

synthesis nd breakdownare ntact.PyruvateCalboxylase eficiencySeeGhapter 7). This is

dominanclya drsease f the CNS characterized y a subanecrotizing ncephalomvelopathynd high evelsof blood acand pyruvate.Hypoglycemia s not a prominent eatureof syndrome,presumably ecause luconeogenesisrom precuother than alanine emains ntact, and theseprecursorsbythe p)'ruvatecarboxylase tep.The utilization of alamneasas lactate hrough pyruvatecannot proceed,however,so tsubstrates ccumulate n blood, and modesthypoglycemiaresultduring fastrng.AffectedpatieotsLrsually ie of progreCNS disease.

OTHER ]IIZYMEEfECTSGalactosenia Galactose-1-Phosphateridyl TransferaseD

ciencyl. eeChapter 7.Fructosentolerancetructose-l-PhosphateldolaseDeficie

[SeeChapter 71, cute h,vpoglycemias due to the inhibiciofructose-1-phosphate f glycogenolysis ia the phosphorsyscem nd of gluconeogenesist rhe evelof fructose-1,5-diphatealdolase.Affected ndivrdualsusually earn spontaneto eliminate ructose rom their diet.

DEFECTSN GTUCOSERAI{SPOBTERSGLIJT-IDeficiencv. wo infancswith a seizuredisorderw

found to have ow cerebrospinalluid (CSF)glucose oncetions despilenormal plasma glucose.LactateconcentratioCSF were also lolri suggesting ecreased lycolvsis ather tbacterial infection, whjch causes ow CSF glucosewith h

lactare.The erythroq/te glucoseuanspofter was defective,gescing simrlardefect n the brain glucose ransporter espble for the clinical eatures.A ketogenicdiet reduced he sevof seizures y supplying an allernatesourceof brain fuel bypassedhe defect n glucoseransport.

GLUT-2 eficiency. hildren vichheparomegal,v,alactosenerance, nd renal ubular dysfuncrion Fanconi-Bickel yndrohave been shown to have a deficienc,v f the GLUT-2 glucransponer f plasmamembranes,n addition o Lver and kidtubules, GLUT2 is also expressedn pancreaticp cells.Hethe chnical manifesradonseflect mpairedglucose elease liver and defective ubular reabsorptionof glucoseplus ppharuria nd aminoaciduria.

SYSTEMIC ISOBDERS.everal ystemic isordersare assoc

wirh hypoglycemia n inlants and children.Neonaral sepsoften associated ith hypoglycemia, ossiblyas a resultof dimished caloric intake wi rh rmpaired gluconeogenesis. imnechanismsmay apply to the hypoglvcemia ound in sevmalnourishednfantsor thosewichseveremalabsorption,Hyviscositywith a central hematocritol >65"/o s associatedhvpoglycemian at least10-157" of affecred nfancs. alcipamalaria has been associatedwirh hyperinsulinemia nd hyglycemia.Hean and renal ailure havealsobeenassociatedhypoglycemia, ut the mechanism s obscure. nfants and cdren with Nisseo undoplicat ion,a relativelycommonproceused to ameliorate gastroesophagealeflux, frequently han associated dumping" syndrome .ith hypoglvcemia,Cacteristic features nclude srgnificanthyperglycemraof up



500 mg/dl 30 minutes postprandiallv and severe hypoglvcemia

(aleraie 32 me./d in oni .eriesl 1.5-3-0hr larer. hc earlvhvper-

elycem"ia ha.e r\ associaredwirh brisk an d excessivr nsulin

i. i.rr" ,hl cau\e\ rhe rebound hypogllcemia 6lucagon

responseshave been inappropriatel]- low ir some. Although the

oh is io loe jcmechan j \ms re no r l lways c lea r l yapparent , nd

anemore"drearmenrs or alwavselfective'acarbose, n inhibtlor

of glucose absorption, has been reported ro be successflrl n one

small series.

DIAGiIOSISNDDIFFEREI'ITIALIAGNOSIS

Table92 8 lists he pertinentclinical and iochemical indings n

rhe commonchildhooddisordersassocia d with hypoglycemia

5exes.

suggescsyperinsulinemia r a defect n fatry acid oxidarion' In

moit othet caos.tof hypoglycemia, rth the exceptionof galac-

tosemiaand fructose ntolerance, etonemiaand kelonuria are

Dresen tt rhe rme, ' i as t ing ypog lycemia .t the imeof rhe

irvpog.lvcemia.erumshouldbe obrained or determinarioni

h,rrm"onesnJ \ubslrares,ollowedby repeatedmeasurement

afteran intramuscularr intravenousnjecnon f glucaSon, s

rapidlv by the histo lnadvertentor deliberatedrug ingestion

and ertors n dispen g medrcineshouldalsobe considered.

When the history is suggestive, ut acuresymptoms re not

present,a 24-36 hr supervisedast can usuallyprovok hypo-

Chapterg r Hypoglycemia

e l l cem iaand reso l \ e he ques t ion f hype r rn ' l i nema or o

iondicion* L5ee able q2 8) . Such a fasr is conrraindicated

fatty acid oxidatron defect is suspected;ocher approaches suc

mass randem spectrometry or molecular diagnosis, or b

shor:ld be considered. Becauseadrenal insuffrciency may mi

necessary,

ln the presence of hepacomegaly and hvpoglycemia, a

sumptil'e diagnosis o[ the enzyme defect can otten be m

through the clinical manifestations, Presenceof hyperlipidem

acidoJis, hyperuricemia) resPonse to glucagon in the fed

expertise available only in cerrain rnstirutions,

TREATMENT

somatostalln alogs.

Treatment acute symptomatic neonatal ot infant h

gl,vcemia inc des intravenous administtatron of 2 mUkg

D1n w, follo ed by a conrinuous rnfuslon of glucose a

8 mg/kg/min, djusting rhe rate to mainrain blood glucose l

In the normal range. If hvpoglycemic seizuresare presenl' s

recommend a 4 mUkg bolus of D16 !(/.

The managemenr of persistent neonatal or infanrile h

glycemia rncludes rncreasing he rare of intrarcnolrs glucose

sion to 10-15 mg/kg/min or more, if needed. This may requ

central venous or umbilical venous catheter to adminis

h-vperromc 15-25% glucose solution. If hyperinsulinemi

present, it should be medically managed itiall,v with diazo

and lhen somatostarin analogs or calciu channel blocke

hvpoglvcemra is unresponsive to intravenous glucose plus

zoxide (maximal doses up to 25 mg/kg/day) and somastos

analogs, surgery via partial or near-total pancreatectom; sh

be considered.

Oral diazoxrde, 10-25 mg,&gi24hr given in divided d

every 5 hr, may reverse hyperrnsulinemtc hypoglycemra but

alsoproducehirsutism,edema,nausea, yperuricemia, lect

disrurbances, advanced bone age, IgG deliciencl', and, ra

tive in controlling hyperinsuhnemrc hvpoglycemia in pat

v' ith islet cell disordersno t causedby genecicmutations in

channel and rslet cell adenoma. Octreotrde is adrninistered

cutaneously very 6-12ht in dosesof 20-50 pg in neonate

young infanrs. Potencial bur unusual cornphcations include

growth due ro inhibition of growth hormone release,pain a

injection site, vomrtrng, drarrhea, and hepatic dysfun

(hepatit is,cholelithiasis).Octreocide s usually employed

temporizing agent for various periods before subtotal pancre



668 PABTX Metabolic iseases

tomy for KArpchannel disorders. ft mav be parricularly useful forthe rreatment of refracrory hvpoglycemia despite subtotal pan-createctomy. Tcrtalpancreacectomy s not oprimal therapy, owingto the risks of surgery,permanent diabetes mellitus, and exocrinepancreatic insufliciencl'. Conrinued prolonged medical therapywjrhour pancreatic resection if hypoglycemia rs controllable isworthu'hile becausesome children have a soontaneous resolution, , i t he hype r rnsu l rnemiclpog l ' cem ia .Th is ' hou ld be ba lancedagainst the risk of hypoglycemia-induced CNS rnjury and rhe toxlcll,vor orugs,

PROGNOSIS

The prognosis is good in aslmptomatic neonaces with hypo-glycemia of shorr duration. Hypoglycemia recurs rn 10-15o% ofinfants afcer adeoLraLereatment. Recurrence is more common iflntravenous fluids are extravasared or discontinued too raoidlv

beforeoral teedine.are well t .r lerated.Children in whom keL.rrichypoglvcemia latir develops have an rncreased rncidence ofneonatal hypoglvcemia.

The prognosis for normal inrellectual function must be guarded

because prolonged, recurrent, and severe symptomatic hypogl_v-cemias associaled u'rrh neuroLogic sequelae. Sympcomatic

infants wrrh hvpoglycemra, particularl). low-birthweighc infants,those with persistent hyperinsulinemic hvpoglycemia, and infants

of draberic mothers, have a poorer prognosis for subsequent

normal intellectual development than asympromatic infants do.

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