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MATERNAL PHENYLKETONURIA-CHRONOLOGY OF THE DETRIMENTAL EFFECTS ON EMBRYOGENESIS AND FETAL DEVELOPMENT: Pathological Report, Survey, Clinical Application
Robert 0. Fisch, MD, Barbara Burke, MD, John Bass, MD, T. Bruce Ferrara, MD, and Angeline Mastri, MD 0 Departments of Pediatrics, Laboratory Medicint. and Pathology, and Pediatric Neurology, University of Minnesota Medical School. Minneapolis, Minnesota 55455
11 Maternal phenylki~tonuria (I'KlJ} is likely t o hurw detrimental e f frcts on embryogenesis and fcjtal d(~vc1oprnent. Manifestations in the offspring include spontaneous abortion, various congenital malformations, intrautrrinc growth re tardation, and micrucc~phaly. The t ime at which the metabolic abnormalities induccl pathologic cmbryogenc~sis can be documented by knowing the t ime o f the devclopmr~nt of specifically damaged organ systems. This review reveals that, while thc most recognized congenital malformations occur in the heart, the most c o m m o n abnormality is growth inhibition occurring throughout pregnancy. The organ systrm most commorily aff(,cted by this growth inhibition is the brain, rcsulting in a high incidencc of micrcjncephaly. I t appears that maternal phenyl- kiptonuria interfrrc .~ with appropriate fe tal growth and that this cffcct occurs during the cntirr course of pregnancy and has no tissue specificity. This information can bc bo th informativr t o pathologists and uscJful to clinicians.
K E Y WORDS: maternal phrnylk~tonun'a, datrimrntal i.mhryugrnrsir.
INTRODUCTION
Mothers with phenylkctonuria (PKU), rcgardless of their intclligencc, have previously been observed t o have a high incidence of abnormalities in their offspring. Thcsc previously rcported abnormalities include mental retardation' intrautcrinc and extrauterinc growth retardation with micro- ccphaly,* congenital heart d i s c a ~ c , ~ spon taneous abortion^,^ various addi- tional malformations: and a higher incidence o f PKC' than cxpected.' The incidencc of these aberrrations in maternal PKU progeny appears to be correlated with the maternal concentration o f serum ph~ny la l an ine .~
A recent example o f a malformed infant born to a mother with PKU at the University of Minnesota Hospitals initiated an analysis of prcviously
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tlocirmentetl abnormalities in the offspring of PKU mothers. This report cmphdsiles the rrlationship between the effect o f phenylketonuria on different organ s)'stcms during embryogenesis and the development of nidformations.
CASE REPORT
.4 39-\vcek-Kestatioii female infant was admitted to th r Selvborn Intcnsive Care Unit at the University o f Minnesota IIospitals because of c.!.anosis. ' Ihe mothci- \vas ;I 22-year-old primigravatia who was diagnosed ;IS having PKU (serum phenylalanine 22.2 mg/dl) at 6 months o f age, tollo\ving i i n onset o f petit ma1 seizures. The mother was on dietary therap). until 9 years o f age. IIer I Q was 67, and she was graduated from high school with special tutoring. One maternal sibling with PKU was cspilcpric and severely rcstarded. Two additional siblinss bvithout PKU had 1 cii rn ing disc )rde 1-5.
PI-cgnanc), was uncomplicated. 'The mother bvas sccn for routine prcnatal visits, received no dietary restrictions, and gained 20 pounds (lilt-ing pregnant).. Labor and delivery were uncomplicated. Apgar scorcs uerc 5 at both 1 and 5 min. The baby's weight was 2600 2 (25th pcrccntilc), length was 48 cm (25th percentile), and occipital-frontal head ciI-ccimfercncc was 30 cm (more than 2 standard dcviations below the mean). Significant tindings on physical examination included marked c-).anosis and decreased peripheral pulses. An initial arterial blood gas ~-cvc;ilcd 'I Pa02 o f 18 torr. An echocardiogram demonstrated aortic \.al\.cilar atrcsia with a hypoplastic left ventricle. The infant deteriorated d c y i t c medical support , and i t was felt that an at tempt a t surgical palliation o f her Icsion \ \odd be unsuccessful. She siibscquently expired, d t 2 days o f age. Laboratory data obtained prior t o her death included a serum phenylalanine 01' 1 . 1 ing/dl and a serum tyrosinc o f 1.1 mg/dl.
AUTOPSY FINDINGS
I'crtinent findings a t autopsy included the presence of both growth I ctai-dation and microcephaly as noted clinically. The brain wcighcd 195.4 s pi-ior t o fixation (expected weight =349 ? 36 g). Organ weights other than that o f the brain were within normal limits for the body sizc. I)ccI-c.;ised numbers o f renal lobules were present, b u t thc numbers were n o t in the hypoplastic: range.
'The infant had a hypoplastic left heart syndrome with levocardia, tiorma1 atrial and visceral situs, normal atrial-ventricular and ventricular-atrial 1-clationships, and an intact ventricular septum. Aortic valvular atresia and
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MATERNAL PHENYLKETONURIA 451
a d1,splastic stenotic mitral valve representing in essence an atretic mitral valve were found together with an intact atrial septum (so-called premature closure o f the foramen ovale6). ‘The left atrium thus ended blindly, having received all of the pulmonary veins as usual. Its lining MW noted t o be pittcd with what was thought t o be the dilated openings of Thcbesian veins representing avenues of egress o f blood from the left a t r i ~ m . ~ ~ ~ A search f o r an o in a1 c) us p u 1 monar y vc n ( )u s connect i o ns , a 1 ev oa t r i oc a r ti i 11 a1 vein, a venous communication between pulmonary and systemic veins, anti coronary s inusdeft atrial window revealed n ~ n e . ~ - ’ ~ A pcrsistent left superior vena cava entered the coronary sinus but had no communication with the pulmonary veins or left atrium. The coronal-). sinus cntcrcd thc right atrium, which was dilated. As anticipated, because o f the pulmonar), venous obstruction, thee were both pulmonary venous and arterial hyper- sensitive changes present in the lung, the latter being manifest by major medial hypertrophy o f pulmonary muscular arteries and b!. premature muscle development in acinar pulmonary arteries. Pulmonary lymphatic channels were niodcrately dilated. The pulmonary trunk was \vide, and a widely patent ductus arteriosus supplied the entire vascular tree. l h e ascending aorta was hypoplastic. There was no endocardia1 fibroclastosis o f the hypoplastic left ventricle.*
The brain shoived no gross abnormalities. On microscopic. cxamination, the cerebral cortex was well developed and normal in architecture and ccll density in both lobes. IIistologic evaluation o f the basal ganglia, thalamus, cerebellum, and brainstem also revealed normal ccll density with no unusual findings. E:xamination o f the spinal cord revealed no gross o r histologic defects. Myelination in all areas o f thc cerebrum, cerebellum, brainstem, and spinal cord corresponded t o published standards for full-term infants.*’
METHODS AND RESULTS
All reports o f fetal congenital malformation related t o maternal PKU, regardless of diet o r phenylalanine concentration during pregnancy, prior t o April 1984 were reviewed. A summary of each rcportcd malformed organ systcm was catalogued along with the time of embryologic develop- ment of each respective system. These data are presented in ‘Table l.22-27
Evaluation o f the data reveals that cardiovascular anomalies are quantitatively more prevalent than others. However, all organ systems show evidence o f some developmental defect. A s cxpected, most o f the
*Jesse E. Edwards, MD, linited-Children’s Hospital, St. Paul, Minnesota, examined thc cardiovascular specimen from this casc in consultation, and he concurs with thc gross and microscopic findings.
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MATERNAL PHENYLKETONURIA 455
obscrved malformations are those originating in the first trimester, since development of most organ systems is largely completed by the end of the first 12 weeks of gestation. However, the dctrimental effect of hyper- phenylalaninemia is not restricted to any specific time during prc'gnancy but may have a deleterious effect throughout gestation, resulting particularly in growth retardation of the brain (Fig. 1 ) . Somatic growth is also compromised in many of these infants. While the presence of abnormalities is high in PKU offspring, they are not uniformly present, and some infants have been said to have had normal development following birth.
DISCUSS I0 N
There are many gcnetic variations o f hyperphenylalanemia. One of the variations is based on the differences in concentrations of phenylalanine48.4q 'I'hc available data suggest that the higher the concentration of maternal serum phenylalaninc during pregnancy, the higher the incidence of abnor- malities in the o f f s p r i ~ i g . ~ ~ ~ ~ ~ ~ ~ ~ ~ For example, the most commonly reported abnormality in the offspring of PKU mothers is microcephaly. The incidence of microcephaly is 2.7% in the normal p o p ~ l a t i o n . ~ ' Infants born to PKU
AFFECTED ORGANS
- BrainGrowth
-- Sornati Growth ---- Cardiovascular
Spleen
Chert Cavity
LunO
I 9
.._ ............ _ _ _ _ -.-.- - Gastrointestinal Tract
bw Urimary Tract - Ear
Eye =---
-..- Oral Cavity
000 Extremitas
o--o Neural Tube and Spine
FIGURE 1 . Thc organ systems of the fetus that arc dctrimentally affcctcd by maternal PKU prcscnted in chronological ordcr suggest that ( 1 ) thc rffcct has no organ sprcificity and (2) the anomalies occur during the rntirc course of thc prcgnancy. Numbers indicate monthyl duration of the pregnancy.
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456 R . 0. FlSCH ET AL.
mothers with blood phenylalaninc levels >20 mg/dl have a 73% incidence of microccphal).. This incidence of microcephaly decreases to 34% with levels between 16 and 19 mg/dl and t o 33% with levels between 11 and 13 mg/dl, but is reported to be 44% with levels between 3 and 10 mg/dl.' As o u r case indicates, thc affected infants exhibit n o gross malformations o r histologic abnormalitirs o f brain development b u t have brains that are disproportionatcl), small c.omparcti t o agc-matched normals, indicating that inpaired brain growth has occurred. Similarly, the incidence o f malformation o f the ciirdiovascular system in this setting is reported t o be 14% if thc concentration o f maternal blood phenylalaninc is over 20 mg/dl, 17% i f i t is between 16 m d 19 mg/dl, 13% i f i t is between 11 anti 13 mg/dl, and none i f i t is tintier IO ing/tII.'-'O
Although incrcascd conccntration of maternal serum phen),lalaninc and coiiconiitarit metabolitcs o r the deficiency o f tyrosine" have been proposed a 4 rcspc)nsiblc f o r the microcephaly and decreased birth size found in the offspring o f mothers \vith PKU, there is n o consensus on the exact mcchanism 1)). which the inability t o oxidize phrnylalanine t o tyrosine disrupts normal embr)fogenesis and fetal growth. T h e conccntration o f phcn).lalanine in the amniotic fluid from mothers with PKU has been found t o bc 3 5 times greater i hicii bu t this is no t reflected proportionately in thc fctal blood.
'I'hcre is considcrat)lc evidcncc that an cxc(:ss o f either 21 single amino ;i<.id o r o f several amino acids produces a variety o f detrimental metabolic conscqucnccs, bu t thcsc arc usually direct toxic effects. An amino acid irnbal;incc produced hy c.xcessivcly large amounts o f methionine, cystinc, o r glycinc. may have inhibitory effects on growth similar t o amino acid dct'icicnc). in rats, but phenylalaninc has relatively little ~ f f e c t . " ~ ~ ' I)cc-r.cased levels o f other amino acids ma)- play a role in abnormal cmbq.ogcnesis and in growth inhibition in the Ictus. Phenylalanine t lcpr iut ion o f rat dams leads t o severel). damaged fetuses with only a slight (20%) drop in fetal plienylalanine b u t an 80% d r o p in fctal tyrosine lcvels.s6 Kt:duced in tc,slinal absorptioin of t r y p t o p h a ~ i , ' ~ valinc," a r g i n i n ~ , ~ ~ Ieucinc, ar id tryosine60 and a relatively gcncra l ixd hypoamino acidemia6' have been ot)sct-vcd in untreated PKl.'s. Tyrosine deficiency experimentally produced in pregnant rats causes a severe inhibition o f tubulin s).nthesis in brain.62 ' I ' \ i I ) i r I i i i is thc major struc.tura1 protein in the brain cell.
T h e high incidenc c o f microcephaly and the absence of specific brain malformations in cil'fspring of mothcrs with I'KU indicates that the inhibitory effect o n brain drvelopment is no t related t o an insult a t a spccific timc during gestation but occiirs secondary t o a general developmental fai lui . t r that is present throughout pregnancy.
T h c neural plate is clearly demarcated at 16 days' gestation, and a faint
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MATERNAL PHENVLKETONURIA 457
neural groove with early neural folds is evident by 18 days. This complex development continues throughout gestation. At approximately 6 months’ gestation, the primary fissures and sulci begin to appear. Secondary sulci develop a t approximately 8 months’ gestational age, and tertiary sulci are present a t approximately 9 months. ‘The brain weight increases from about 70 g a t approximately 24 weeks’ gestation to 250 g a t 32 weeks’ and approximately 380 g a t 40 weeks’ gestation.63964 When the brain growth spurt begins in the middle of gestation, the adult number of neurons has already been largely a c h i e v ~ d . ~ ’ At birth, only a small fraction of the total myelin is p r ~ s e n t . ~ ’ * ~ ~ As our case report indicates, the lack of malformation, the normal myclination, and normal histologic appearance indicate that the development of the central nervous system progresses normally in PKU offspring but that overall brain growth is impaired. Micrencephaly may be a reflection o f the deficit in the total number of cells, a feature that is not detectable in routine brain examination, even though cell density appears normal in all areas o f brain examined. Although the mechanism involved in brain growth inhibition is unknown, previous experimental work in rats has shown a reduction in total DNA, RNA, and protein in fetal brains subscqucnt to the administration of excessive phenylalanine and alpha- mcthylphenylalanine, which is an inhibitor o f phenylalanine h y d r o ~ y l a s e . ~ ~ It is again not a ccrtainty whether the defects were caused by phenylalanine excess, tyrosine deficirncy, or some effects of alpha-methylphenylalanine itself.
The incidence o f different malformations and the inhibitory impact on both brain and somatic growth suggests that the metabolic abnormality caused by maternal PKU phenylketonuria docs not have organ specificity. Because microccphaly and growth retardation are more common than various other malformations, one can conclude that the common pathologic effect of maternal PKU is also not time-specific during pregnancy. This may have a considerablc clinical importance, for if there is not a specific time during pregnancy that the fetus can be protected, whatever factor causes these problems, it is probably not an increased phenylalanine o r any of its metabolites, for dietary restriction at any particular time during pre<gnancy has only limited, i f any, value. Large numbers o f physically and mentally
preconccptual dietary treatment has been utilized in these mothers, even then abnormalities occurred among their ~ f f s p r i n g . ~ ’ , ~ ~ The withholding of phenylalanine as therapy is relatively ineffective, but it is reported that tryosinc added to the maternal diet during pregnancy” docs prevent abnormalities, lending credence ot the tyrosine deficiency theory of phcnylketonuria.
The presence in an infant o f the constellation of fetal and neonatal
handicapped children have been born to treated m o t h c r ~ . ~ ~ ~ ” ~ ~ ~ ’ ~ ~ Alth ough
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;~ l ) i~u rma l i tics notcd i n 1 his stud). should alcrt clinicians and pathologists t o t111, possil)ilit) o f rn;itcrnal I'Kt;. Gro\\.th retardation, micwct.ph;il>-, and c 1 ) I I gcn i t al c;ir di ovasc iiI;i1- an r ) ma1 ics rep rcsen t t h c com mon c s t ;i bc r r;i t i ( )ns Ioiind in m,ircrn,il PKL.. '['his suggcsts that the lack o f t).rosinr cniiscd b\. the I.iiliii-c 01 thc mothcr norinally t o oxidizc phenylalanine t o tyrosine Ind) lead [ ( I J dcficicnc). o f t ) I osiric huppl). to the fetus. This is consistent with thc gc.nc. 1x1 t h (*( 1 I T t ical ap p i-;i( w h t c) PI( I: 'O and M' i th th c Icp ( ) r tcd con f i 1-m ;I t i o n o t that appro,[ch the successful prcvcntion o f fetal damage b y fccding t!.i.osinc t o thc mothcr throiighoiit prcgniincy. O u r s t u d y suggcsts that cvcn / H . ~ ~ c * I - siicccss might I) ( , obtained \vith tyrosine supplcmcnt t o thc P K L mc )tIici. prioi- t o concept ion.
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Rcceivsd Dgccmber 7 , 1984 Hmisc,d uer.rion accepted March 1, 1986
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