Fran D Kendall M DFran D. Kendall, M.D. · E d i di d h di b t llitEndocrine disorders such as diabetes mellitus ... Pbl t i ll itht hProblems ... 1 in 90 individuals is diagnosed

Fran D Kendall M DFran D Kendall M DFran D. Kendall, M.D.Fran D. Kendall, M.D.Virtual Medical Practice, LLCVirtual Medical Practice, LLCBiochemical Genetics, PediatricsBiochemical Genetics, PediatricsBiochemical Genetics, PediatricsBiochemical Genetics, Pediatrics

Metabolic, Mitochondrial & Inherited DisordersMetabolic, Mitochondrial & Inherited Disorders

© Copyright 2010 Fran D Kendall. All rights reserved

To provide basic background information onTo provide basic background information onTo provide basic background information on To provide basic background information on Mitochondrial Disease, its clinical features, Mitochondrial Disease, its clinical features, diagnosis, treatment, prognosis, inheritance and to diagnosis, treatment, prognosis, inheritance and to discuss its association with Fatty Acid Oxidationdiscuss its association with Fatty Acid Oxidationdiscuss its association with Fatty Acid Oxidation discuss its association with Fatty Acid Oxidation Defects and Autistic Spectrum Disorders (ASD).Defects and Autistic Spectrum Disorders (ASD).


WhatWhat are Mitochondria?are Mitochondria?

What is Mitochondrial Disease?What is Mitochondrial Disease?


Smallest functioning unit Smallest functioning unit of our bodiesof our bodiesof our bodiesof our bodies

Many cells together Many cells together make up tissuesmake up tissuesmake up tissuesmake up tissues

Many sheets of tissues Many sheets of tissues make up our organsmake up our organsmake up our organsmake up our organs


L d i id b dL d i id b d Located inside our body Located inside our body cellscells

Composed of an innerComposed of an inner Composed of an inner Composed of an inner and outer membraneand outer membrane

The energy producing The energy producing gy p ggy p gpathway is the pathway is the respiratory chainrespiratory chain

The respiratory chain The respiratory chain consists of 5 complexes consists of 5 complexes (groups of chemicals) (groups of chemicals) (g p )(g p )that produce ATPthat produce ATP


Oxygen & phosphate Oxygen & phosphate used to make energyused to make energy

Composed of five Composed of five complexes or groups of complexes or groups of chemicals with a total ofchemicals with a total ofchemicals with a total of chemicals with a total of ~90 subunits~90 subunits

Energy packets areEnergy packets are Energy packets are Energy packets are known as ATPknown as ATP


Found in 1 in 4,000 Found in 1 in 4,000 i di id li di id lindividualsindividuals

Caused by an Caused by an lt ti ilt ti ialteration in our alteration in our

inherited blueprintinherited blueprint

R lt i d dR lt i d d Results in decreased Results in decreased energy production energy production and localized or and localized or widespread problemswidespread problems


There are hundreds of genes involved in coding There are hundreds of genes involved in coding for the various proteins and other compoundsfor the various proteins and other compoundsfor the various proteins and other compounds for the various proteins and other compounds involved in OXIDATIVE PHOSPHORYLATION or involved in OXIDATIVE PHOSPHORYLATION or mitochondrial energy productionmitochondrial energy production

These genes are contributed by two sets of These genes are contributed by two sets of inherited genetic materialinherited genetic material

Nuclear genes are inherited from both parents andNuclear genes are inherited from both parents and Nuclear genes are inherited from both parents and Nuclear genes are inherited from both parents and contribute the vast majority of the information contribute the vast majority of the information needed for energy production needed for energy production

Mitochondrial genes are inherited EXCLUSIVELY Mitochondrial genes are inherited EXCLUSIVELY through mom and contribute the remaining through mom and contribute the remaining informationinformation


Approximately 850 proteins are encoded for by the nuclear Approximately 850 proteins are encoded for by the nuclear mitochondrial genes in comparison to 13 by the mitochondrial genes in comparison to 13 by the mitochondrial DNAmitochondrial DNAmitochondrial DNAmitochondrial DNA

Many of these proteins are responsible for the control of Many of these proteins are responsible for the control of electron transport chain structure and function and assemblyelectron transport chain structure and function and assembly

Nuclear genes encode 36 subunits of complex I, all 4 Nuclear genes encode 36 subunits of complex I, all 4 subunits of complex II, 10 subunits of complex III, 10 subunits of complex II, 10 subunits of complex III, 10 subunits of complex IV and 14 subunits of complex Vsubunits of complex IV and 14 subunits of complex V

AutosomalAutosomal recessive inheritance of nuclear gene defects is recessive inheritance of nuclear gene defects is probably the most common etiology of pediatric patients with probably the most common etiology of pediatric patients with mitochondrial disorders.mitochondrial disorders.


Inherited e cl si el thro gh the maternal lineInherited e cl si el thro gh the maternal line Inherited exclusively through the maternal lineInherited exclusively through the maternal line

Circular molecule, a number of copies in each Circular molecule, a number of copies in each mitochondriummitochondrium (5(5--10 copies typical)10 copies typical)

16,569 bases or pieces and 37 genes, all known and 16,569 bases or pieces and 37 genes, all known and sequencedsequenced

Encodes for 22Encodes for 22 tRNAstRNAs, 13 polypeptides of the respiratory, 13 polypeptides of the respiratory Encodes for 22 Encodes for 22 tRNAstRNAs, 13 polypeptides of the respiratory , 13 polypeptides of the respiratory chain and 2 ribosomal RNAschain and 2 ribosomal RNAs

13 polypeptides include 7 subunits of complex I, 1 subunit of 13 polypeptides include 7 subunits of complex I, 1 subunit of complex III, 3 subunits of complex IV and 2 subunits of complex III, 3 subunits of complex IV and 2 subunits of co p e , 3 subu ts o co p e a d subu ts oco p e , 3 subu ts o co p e a d subu ts ocomplex Vcomplex V

All subunit of complex II are nuclear encodedAll subunit of complex II are nuclear encoded

M t t dM t t d tDNAtDNA b t i i t ith ildb t i i t ith ild Mutated Mutated mtDNAmtDNA may be present in varying amounts with wild may be present in varying amounts with wild type DNA (type DNA (heteroplasmyheteroplasmy))




Central Ner o s s stem (Brain) problems incl ding hearing andCentral Ner o s s stem (Brain) problems incl ding hearing and Central Nervous system (Brain) problems including hearing and Central Nervous system (Brain) problems including hearing and vision loss, developmental delays including AUTISM AND vision loss, developmental delays including AUTISM AND AUTISTIC FEATURES, loss of function, seizures, weaknessAUTISTIC FEATURES, loss of function, seizures, weakness

Cardiac (heart) complications such asCardiac (heart) complications such as cardiomyopathycardiomyopathy (enlarged(enlarged Cardiac (heart) complications such as Cardiac (heart) complications such as cardiomyopathycardiomyopathy (enlarged (enlarged heart) and rhythm problemsheart) and rhythm problems

Liver diseaseLiver disease

Kidney problems such as renal tubular dysfunctionKidney problems such as renal tubular dysfunction

Chronic fatigueChronic fatigue

E d i di d h di b t llitE d i di d h di b t llit Endocrine disorders such as diabetes mellitusEndocrine disorders such as diabetes mellitus

Gastrointestinal issues such as chronic constipationGastrointestinal issues such as chronic constipation

Autonomic dysfunction such as irregular heart rate and bloodAutonomic dysfunction such as irregular heart rate and blood Autonomic dysfunction such as irregular heart rate and blood Autonomic dysfunction such as irregular heart rate and blood pressure and temperature instability with heat intolerance.pressure and temperature instability with heat intolerance.


Typical brain changes suggestive of Leigh disease or Typical brain changes suggestive of Leigh disease or abnormalities in white matterabnormalities in white matter

Persistent, significant elevations in lactate (especially if Persistent, significant elevations in lactate (especially if in the brain) and other specific biochemical featuresin the brain) and other specific biochemical features

Problems in many body systems suggestive of Problems in many body systems suggestive of mitochondrial diseasemitochondrial disease

St f il hi t f it h d i l diSt f il hi t f it h d i l di Strong family history of mitochondrial diseaseStrong family history of mitochondrial disease



Abnormalities in mitochondrial Abnormalities in mitochondrial structure/size/shape/number on tissue biopsystructure/size/shape/number on tissue biopsy

Enzymatic abnormalities on testing of the energy Enzymatic abnormalities on testing of the energy producing system (respiratory chain or electron producing system (respiratory chain or electron t t h i )t t h i )transport chain)transport chain)

Specific DNA changes that cause mitochondrial diseaseSpecific DNA changes that cause mitochondrial disease



Complex I nuclear gene mutations Complex I nuclear gene mutations (NDUFV1,NDUFV2, NDUFS1, NDUFS3, (NDUFV1,NDUFV2, NDUFS1, NDUFS3, NDUFS4 NDUFS6 NDUFS7) present ithNDUFS4 NDUFS6 NDUFS7) present ithNDUFS4, NDUFS6, NDUFS7) present with NDUFS4, NDUFS6, NDUFS7) present with variable phenotypes for example NDUFV1 variable phenotypes for example NDUFV1 patients with patients with leukodystrophyleukodystrophy and and myoclonicmyoclonic

il NDUFS1 ithil NDUFS1 ith h t ih t i i t ii t iepilepsy; NDUFS1 with epilepsy; NDUFS1 with hypotoniahypotonia, seizures, ataxia , seizures, ataxia and and ptosisptosis; NDUFS4 & NDUFS7 with Leigh ; NDUFS4 & NDUFS7 with Leigh diseasedisease

Complex IV assembly gene mutations (SURF1, Complex IV assembly gene mutations (SURF1, SCO1, SCO2, COX10 and COX15) present with SCO1, SCO2, COX10 and COX15) present with variable phenotype including Leigh disease invariable phenotype including Leigh disease invariable phenotype including Leigh disease in variable phenotype including Leigh disease in SURF1SURF1


MELAS (Mitochondrial MELAS (Mitochondrial EncephalomyopathyEncephalomyopathy Lactic Lactic (( p y p yp y p yAcidosis and Stroke Like Episodes) due to Acidosis and Stroke Like Episodes) due to tRNAtRNA3243 3243 mtDNAmtDNA mutationmutation

MERRF (MERRF (MyoclonicMyoclonic Epilepsy and Ragged RedEpilepsy and Ragged Red MERRF (MERRF (MyoclonicMyoclonic Epilepsy and Ragged Red Epilepsy and Ragged Red Fibers) due to Fibers) due to tRNAtRNA 8344 mutation8344 mutation

NARP (NARP (NeurogenicNeurogenic muscle weakness, ataxia, muscle weakness, ataxia, (( ggretinitis retinitis pigmentosapigmentosa) due to mutation at base 8993) due to mutation at base 8993

KearnKearn Sayre Syndrome (onset before age 20 Sayre Syndrome (onset before age 20 years with progressive externalyears with progressive external ophthalmoplegiaophthalmoplegiayears with progressive external years with progressive external ophthalmoplegiaophthalmoplegiaand and pigmentarypigmentary retinal degeneration plus other retinal degeneration plus other symptoms including heart block, elevated CSF symptoms including heart block, elevated CSF protein orprotein or cerebellarcerebellar ataxia) due to mitochondrialataxia) due to mitochondrialprotein or protein or cerebellarcerebellar ataxia) due to mitochondrial ataxia) due to mitochondrial DNA deletionDNA deletion


Quite variable but typically progressive over timeQuite variable but typically progressive over time

M ti t f di biliti d lM ti t f di biliti d l Many patients face severe disabilities and early Many patients face severe disabilities and early deathdeath

P bl t i ll ith t hP bl t i ll ith t h Problems typically worsen with stressors such as Problems typically worsen with stressors such as illness and surgeryillness and surgery


Symptomatic Symptomatic –– treat existing problemstreat existing problems

PreventativePreventative early detection of associatedearly detection of associated Preventative Preventative –– early detection of associated early detection of associated problemsproblems

Therapeutics very limited and include use of highTherapeutics very limited and include use of high Therapeutics very limited and include use of high Therapeutics very limited and include use of high dose Coenzyme Q10dose Coenzyme Q10


AutosomalAutosomal Recessive Inheritance Recessive Inheritance © Copyright 2010 Fran D Kendall. All rights reserved

Maternal InheritanceMaternal Inheritance© Copyright 2010 Fran D Kendall. All rights reserved

AutosomalAutosomal Dominant formsDominant forms

SporadicSporadic

XX li k dli k d XX--linkedlinked


High dose Coenzyme Q10 & creatine trialsHigh dose Coenzyme Q10 & creatine trials

Additional treatment trialsAdditional treatment trials

Basic science to expand knowledge ofBasic science to expand knowledge of Basic science to expand knowledge of Basic science to expand knowledge of mitochondrial functionmitochondrial function


Fatty acidFatty acid Fatty acid Fatty acid oxidation oxidation defects aredefects aredefects are defects are considered considered energyenergyenergy energy disordersdisorders



SeizuresSeizures MyopathyMyopathy CardiomyopathyCardiomyopathyy p yy p y Developmental delaysDevelopmental delays Failure to thriveFailure to thrive Failure to thriveFailure to thrive Exercise intoleranceExercise intolerance HypotoniaHypotonia


Low Low carnitinecarnitineE h l l iE h l l i id i SCAD d iid i SCAD d i EthylmalonicEthylmalonic acid in SCAD and some mito acid in SCAD and some mito disordersdisordersEl t d CPKEl t d CPK Elevated CPKElevated CPK

Elevated lactate in LCHAD and mito disordersElevated lactate in LCHAD and mito disordersff Nonspecific long chain abnormalities on Nonspecific long chain abnormalities on

acylcarnitinesacylcarnitines in mito due to secondary FOD in mito due to secondary FOD disturbancedisturbancedisturbancedisturbance


Vitamin cofactor supplementationVitamin cofactor supplementation Carnitine supplementationCarnitine supplementation Avoidance of fastingAvoidance of fasting Avoidance of fastingAvoidance of fasting Avoidance of offending compounds in FOD Avoidance of offending compounds in FOD

d it ( ith f t di t b )d it ( ith f t di t b )and some mito (with fat disturbance)and some mito (with fat disturbance) Aggressive treatment of Aggressive treatment of intercurrentintercurrent illnessesillnesses Preventative care (i.e. flu shots)Preventative care (i.e. flu shots)


A ti d MitA ti d MitAutism and MitoAutism and Mito


A complex neurobiological disorder that typically A complex neurobiological disorder that typically lasts throughout a person’s lifetime, is a part of a lasts throughout a person’s lifetime, is a part of a group of disorders known as autism spectrum group of disorders known as autism spectrum disorders (ASD) and affects the ability to disorders (ASD) and affects the ability to communicate and relate to otherscommunicate and relate to others

Also associated with rigid routines and repetitive Also associated with rigid routines and repetitive behaviorsbehaviors

1 in 90 individuals is diagnosed with autism1 in 90 individuals is diagnosed with autism 1 in 90 individuals is diagnosed with autism 1 in 90 individuals is diagnosed with autism making it more common that pediatric cancer, making it more common that pediatric cancer, diabetes and AIDS combineddiabetes and AIDS combined

Occurs in all racial ethnic and social groups and isOccurs in all racial ethnic and social groups and is Occurs in all racial, ethnic and social groups and is Occurs in all racial, ethnic and social groups and is 4 times more likely to affect boys than girls.4 times more likely to affect boys than girls.

An underlying diagnosis is established in only An underlying diagnosis is established in only 2% 2% -- 36% of cases36% of cases


One 2005 population based study in PortugalOne 2005 population based study in Portugal One 2005 population based study in Portugal One 2005 population based study in Portugal suggested that 7.2 out of 100 patients with suggested that 7.2 out of 100 patients with ASD have an underlying ASD have an underlying mitomito disorder. disorder.

A 2007 study by the same group revised their A 2007 study by the same group revised their population figures and noted 4.1 out of 100 population figures and noted 4.1 out of 100 patients with autism had underlying patients with autism had underlying mitochondrial disease.mitochondrial disease.Alth hAlth h itit t b ft b f Although Although mitomito appears to be a rare cause of appears to be a rare cause of autism, it is one of the more common definable autism, it is one of the more common definable causes of ASDcauses of ASDcauses of ASD. causes of ASD.


One study evaluated five patients with ASD andOne study evaluated five patients with ASD andOne study evaluated five patients with ASD and One study evaluated five patients with ASD and family histories of mitochondrial DNA diseases.family histories of mitochondrial DNA diseases. Three patients had isolated autistic features and twoThree patients had isolated autistic features and two Three patients had isolated autistic features and two Three patients had isolated autistic features and two

had additional neurological findings.had additional neurological findings.

Two patients had the common MELAS A3243G Two patients had the common MELAS A3243G ppmutation.mutation.

One patient had One patient had mtDNAmtDNA depletion.depletion.


WeissmanWeissman et al reported the association of ASDet al reported the association of ASDWeissmanWeissman et al reported the association of ASD et al reported the association of ASD with the with the mtDNAmtDNA A4295G mutation in a 15 year A4295G mutation in a 15 year old with a number of other neurological findings old with a number of other neurological findings g gg gincluding hearing loss.including hearing loss.


Overall these various studies indicate that whileOverall these various studies indicate that whileOverall, these various studies indicate that while Overall, these various studies indicate that while likely a rare cause of ASD, mitochondrial likely a rare cause of ASD, mitochondrial disease can be considered when associated disease can be considered when associated with other neurological complications and/or a with other neurological complications and/or a family history of mitochondrial disease.family history of mitochondrial disease.



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Fran D Kendall M DFran D. Kendall, M.D. · E d i di d h di b t llitEndocrine disorders such as diabetes mellitus ... Pbl t i ll itht hProblems ... 1 in 90 individuals is diagnosed