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hypertrophiccardiomyopathy.Cardiacinvolvementmayoccasionallyprecede
theonsetofneurologicmanifestations.266Cardiacsymptomsarepresentin
approximatelyone-thirdofthepatientsandconsistmainlyofexertionaldyspnea,
palpitations,andangina.Clinicalfindingsofcardiacdiseasearenotpresentin
everycase.Whentheyare,theyincludesystolicmurmursattheleftsternal
borderandapex,togetherwiththirdandfourthheartsounds.Thepulsemay
havearapidupstroke.Evaluationoftheseverityofheartdiseasebyphysical
examinationisoftendifficultbecauseofthepresenceofscoliosisandthelackof
consistentcardiovascularsigns.Interestingly,thedegreeofcardiacinvolvement
appearstocorrelatewiththesizeoftheGAArepeatofthesmalleralleleorwith
themeansizeoftherepeatsinbothalleles.267
Pathologicstudiesrevealcardiacdilationwithventricularhypertrophy.
Histologicallythereisadegenerationofmyocardialcellswithmyocardial
fibrosis.Intracellulargranulardepositsofcalciumandironareseen.Itis
hypothesizedthatiron-catalyzedmitochondrialdamagemayleadtothe
pathologicfindingsinthemyocardium.268Electrocardiographicchangesare
presentinovertwo-thirdsofpatients,andtheyprogressinrelationtothe
durationofthedisease.ThemostfrequentchangesinvolvetheSTsegmentsand
Twaves.Thesearenonspecificandarepresumablycausedbyrepolarization
disturbancesfromtheunderlyingmyocardialfibrosis.Signsofventricular
hypertrophyarealsofrequent,andright-orleft-axisdeviationiscommon.
Arrhythmiasarenotfrequent.Whenpresent,theyincludesupraventricularand
ventricularprematurebeats,supraventriculartachycardia,atrialflutter,andatrial
fibrillation.269
Thepresenceofscoliosismakesradiographicevaluationoftheheartdifficult.
Heartsizeisusuallynormal.Mostpatientshaveanabnormalechocardiogram.
Themostcommonanomaliesreflectthepresenceofasymmetricconcentric
hypertrophiccardiomyopathy.Thereisanincreaseinleftventricularwalland
septalthickness.Asymmetricseptalhypertrophyisseenonoccasion.270
Impairedleftventricularfunctionhasalsobeenshownechocardiographically
andmaybetheendstageofthecardiomyopathicprocess,asreducedfractional

shorteningoftheleftventricleiscommon.Thesystolicfunctionoftheposterior
wallismoreseverelyaffectedthanthatoftheseptum.Abnormaldiastolic
functionmayantedatesystolicabnormalities.Interestingly,aconstantfeatureis
delayinmitralvalveopening.
Theclinicalcourseismarkedbysteadilyprogressivedeterioration.Cardiac
failure,whichappearslateinthecourseofthedisease,hasapoorprognosisand


isoftenapreterminalevent.MostpatientswithFriedreichataxiadiefrom
cardiaccauses.Heartfailureaccountsforhalfofthedeaths.Cardiacarrhythmias
andrespiratorycomplicationsaretheothermajorcausesofdeath.
Althoughconventionalmethodsfortreatinghypertrophicanddilated
cardiomyopathyarefrequentlyemployed,newertherapeuticoptionsforpatients
withFriedreichataxiahavecometolightinrecentyears.Idebenone,afreeradicalscavenger,wastestedunderthehypothesisthatironoverloadleadsto
damageofiron-sulfurcluster–containingenzymes,whichmayleadtothe
damageseeninthemyocardium.271Althoughthetreatmentremainssomewhat
controversialandisnotuniversallyaccepted,severalsmalltrialsshowa
consistentbenefitintermsofreductionofcardiacmassandimprovementin
function.272,273

ArthrogryposisMultiplexCongenita
Thisconditionpresentswithjointcontracturesatbirthinatleasttwodifferent
areasofthebody.Atypicalpresentationincludesequinovarusdeformitiesofthe
feet,abductedhips,incompletelyextendedkneesandelbows,pronatedforearms,
andclawhands.Themajorityofthoseaffectedhaveaneurogeniccausewith
patchylossofanteriorhorncells,althoughsomecasesarecausedbyprimary
myopathicdisorders.Theymayresultfromenvironmentalfactorsormay
demonstrateafamilialpropensity.
Theheartisrarelyinvolved.Areportofthemyopathicformofarthrogryposis
multiplexcongenitarevealedcongenitalheartdiseaseinone-quarterofthe

patients.274Thesecasesresultedfromconsanguineousparents,andfiveofsix
withcongenitalheartdiseaseresultedfromonepairing.275Patencyofthearterial
duct,congenitalaorticstenosis,andmitralstenosishavebeenreported.276,277

HereditaryMotorandSensoryNeuropathy
(PeronealMuscularAtrophy,Charcot-MarieToothDisease)
Thehereditarymotorandsensoryneuropathiesareadiversegroupofdisorders
typicallyinheritedinanautosomalorX-linkeddominantfashion.Linksto
defectsinconnexinsandotherSchwanncellproteinsarewelldescribed.278They
arepredominantlyamotorneuropathyproducingatrophyandweaknessofthe


distalmuscles.Thisdeterminesthetypical“invertedbottle”appearanceofthe
legs.Bilateralclubfootisafrequentassociation.Thehandandforearmmuscles
mayalsobeinvolved.Thereisadecreaseorlossofthedeeptendonreflexes.
Electromyographicstudiesshowslowingofnerveconductionvelocityorsigns
ofdenervation.
Thecardiacinvolvementhasclassicallybeenrelatedtosupraventricular
arrhythmiasandconductionsystemabnormalities.Sicksinussyndrome,right
bundlebranchblock,completeheartblock,Wolff-Parkinson-Whitesyndrome,
atrialfibrillation,andatrialflutterhavebeendescribed.279,280Ithasbeen
postulatedthatthereisaprimarydegenerationoftheconductionsystemrather
thanchangessecondarytoacardiomyopathy.281Inadditiontodysrhythmias,left
ventricularhypertrabeculation/noncompactionhasbeenreportedinapatient
withCharcot-Marie-ToothdiseasetypeIAandaduplicationdefecton
chromosome17involvingtheperipheralmyelinprotein22.282TheRoussy-Lévy
syndromeisaphenotypicvariantofCharcot-Marie-ToothtypeIAandshares
manyfeatureswiththisdisease.283Dilatedcardiomyopathyhasalsobeen
reported.284

SpinalMuscularAtrophyTypeIII(Juvenile
SpinalMuscularAtrophy,Kugelberg-Welander
Syndrome)
Juvenilespinalmuscularatrophyappearsinchildhoodoradolescence.Initiallyit
ismanifestbyweaknessandatrophyoftheproximallimbmuscles,whichis
laterfollowedbydistaldisease.Theusualpresentationiswithdifficultyin
walking,climbingstairsandliftingthearms.Fasciculationisseeninhalfof
thoseaffected.Theclinicalcourseisslowlyprogressive.Thereisevidencefrom
electromyographyandmusclebiopsytoindicatelowermotorneurondisease.
Somepatientshaveanassociateddilatedcardiomyopathy,althoughthismaybe
secondarytoassociatedrespiratorydisturbances.285Rhythmdisturbancesare
veryfrequentandincludeatrialprematurebeats,atrialfibrillation,atrialflutter,
andadvanceddegreesofatrioventricularblock.Somepatientsrequirethe
implantationofapacemaker.286TheECGfrequentlyshowsafinetremoronthe
isoelectricline,whichrepresentsfasciculationscharacteristicofthisdisease.287
Thesyndromeistransmittedinautosomalrecessivefashionandisduetodefects
inthesurvivalmotorneuron1(SMN1)gene.288Theinfantileformofspinal