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presentearlyinlife,andprogressionisthenrapid.Characteristicallythereareno
faciallinesandtheeyelidsareveryweak.Wingingofthescapulasisseenwhen
thearmsareabductedandthereisamarkedthoracolumbarlordosis.Affected
musclesincludetheneckflexors,theserrateandpectoralmuscles,bicepsand
tricepsintheupperlimbs,thehipflexors,andtheanteriortibialmuscles;inthe
latestages,thequadricepsandsartoriusinthelowerlimbsarealsoaffected.
Retinalvasculopathyisalsofrequentlyseen.Theserumlevelsofcreatinekinase
arenormaloronlymildlyelevated.Theprecisemolecularmechanismfor
expressionhasnotbeenelucidated,butpatientsareknowntohavealarge
deletioninvolvingtheqarmofchromosome4.Nogenehasbeenidentifiedin
thisregion;thereforevarioushypotheseshavebeenpresentedtoexplainthe
mechanismwherebythisdeletioninducesclinicaldisease.252
Ventricularfunctionisnotaffected.However,supraventriculartachycardiahas
beenreportedwithafrequencyhigherthanthatofthegeneralpopulation.253
Sinusnodedysfunction,abnormalAVnodeorinfranodalconduction,andeasily
inducibleatrialfibrillation/flutterhavealsobeenreportedwithanincidenceof
27%ofthepatientpopulationstudied.254

Emery-DreifussMuscularDystrophy
Emery-Dreifussmusculardystrophytypicallypresentsbetween5and15years
ofage.ItcanbeinheritedinanX-linkedrecessivefashionorinanautosomal
dominantorautosomalrecessiveform.Thebicepsandtricepsaremoreseverely
affectedthanthedeltoidmuscle.Theperonealsaremoreinvolvedthanthe
proximalmusculatureofthelegs.Contracturesgenerallydevelopattheelbows,
posteriorcervicalmuscles,andtheAchillestendon.Pseudohypertrophyis
absent.Creatinekinaselevelsare3to10timesabovenormal.Progressionis
veryslow,andthephysicallimitationsareminimal.Thereisnormalintellectual
function.
TheX-linkedformisduetoadefectinthegeneencodingemerin,anuclear
envelopeproteinthatplaysaroleintheregulationofmanycellularand
nucleolarprocesses.However,itsroleinthepathogenesisofmuscledamagehas

notbeelucidated.Theautosomaldominantformisduetodefectsinthelamin
A/Cgene,similartolimb-girdlemusculardystrophytypeIb.Again,theroleof
laminA/Cmutationsinthedevelopmentofthemyopathyisnotclear.The
recessiveformisalsoduetodefectsinthegeneencodinglaminsAandC.255
Howandwhydefectsinthesamegenecancausedominantandrecessiveforms


ofthediseaseremainstobediscerned.
Cardiacinvolvementisoftenmanifestbyatrialarrhythmiasand
atrioventricularblock.Anydegreeofatrioventricularblockcanbepresent,anda
slowjunctionalescaperhythmiscommon.Severesinusbradycardiaorsinus
arrestisseenandmayalsorequirepacemakerimplantationduetotheincreased
riskofsuddendeath.256“Atrialparalysis,”withtheabsenceofPwavesandan
inabilitytoelectricallypacetheatrium,isseen.Ventricularfunctionisusually
normal,butprogressiveleftventriculardysfunctionwithfibrousinfiltrationof
themyocardiumcanbeseen,257andcardiactransplantationhasbeenemployed
forend-stagedisease.258Patientswithbradycardiamayhaveahypertrophied
anddilatedleftventricle,probablyasacompensatoryphysiologicresponse.
ElectrophysiologicstudiesshowprolongedH-Vintervalsand,onsome
occasions,acompleteabsenceoftheHispotential.Thisfinding,togetherwith
theveryslowjunctionalescaperhythms,suggeststhatthemyopathicprocess
extendsintotheatrioventricularconductionaxis.Thehighriskofsuddendeath
inthisvarietyofmusculardystrophymakesearlyrecognitionimportant,since
insertionofaventricularpacemakerinpatientswithbradycardiawillimprove
survival.

CentronuclearMyopathy
Thisuncommonmusculardisorderischaracterizedbyptosis,strabismus,
generalizedmusclewastingandweakness,andabsentorreduceddeeptendon
reflexes.Developmentaldelayanddysarthriaarecommon.Adilated

cardiomyopathyhasoccasionallybeenobserved,andcardiactransplantationhas
beenperformed.259PatientshaveaprolongedPRintervalandasuperioraxison
theECG.Thediagnosisisbasedonclinicalfindings,raisedlevelsofcreatinekinaseinblood,evidenceofamyopathyonelectromyography,andatypical
histologicpicture.Thisconsistsofcentrallocationofthenucleus,withvariation
ofmusclefiberdiameterandatendencyforpredominanceoftype1fibers.
Inheritanceisvariable.TheX-linkedformisusuallythemostsevereformand
involvesthegeneencodingmyotubularin.Anautosomalrecessiveformseemsto
haveamildercourse,althoughpatientsstillpresentinchildhood.Finally,the
autosomaldominantformismilder,withpatientsreachingadulthoodbeforethe
onsetofsymptoms.


NemalineMyopathy
Thenemalinemyopathiesaresonamedbecausemusclespecimensdemonstrate
rodswithinthemyocytes.Thisgroupofclinicallyheterogeneousdisorderscan
resultfromdefectsinvolvingactin,troponin,myosin,ortropomyosin.Although
theskeletalmusclesarepredominantlyinvolved,casesofhypertrophicand
dilatedcardiomyopathyarebecomingincreasinglyevident.Themainfocusison
theα-actingene,ACTA1,inwhichnumerousdefectshavebeendescribed.260
Patientscanhaveaverymildcourseofskeletalmuscleweaknessorsevere,
lethalneonataldiseaseleadingtorespiratoryfailure.Hypertrophic
cardiomyopathyismorecommonlyseen,261butdilatedformsof
cardiomyopathyhavealsobeenreported.262

FriedreichAtaxia
Friedreichataxiaisararespinocerebellarneuromyelopathyoccurringin
approximately1to2per40,000.Thediseaseisinheritedinanautosomal
recessivefashion,andmostcasesareduetohomozygosityforanexpanded
GAAtripletonchromosome9q13.263Thisgeneencodesfrataxin,aprecursor
proteinthatmaybeinvolvedinthematurationandassemblyofironandsulfur

proteinsofthemitochondriaandcytosol.264Childrenpresentaroundtheageof6
years.Themostfrequentearlysymptomisanabnormalgait.Neurologicsigns
includetheataxicgait,absenttendonreflexes,incoordination,andapositive
Rombergtest.265Lowerlimbweaknessandmuscularatrophyarecommon,as
aredysarthriaandlossofvibrationandpositionalsenseandextensorplantar
responses.Somepatientshavenystagmus.Thepresenceofbrisktendonreflexes
makesthediagnosisofFriedreichataxiaveryunlikely.Skeletalinvolvementis
common,withclubfeetandscoliosisamongthemostfrequentmanifestations.
Apartfromtheclinicalaspectsofthedisease,nerveconductionstudiesare
essentialtosupportthediagnosis.Motorconductionvelocityisnormaland
sensoryconductionisabsentormarkedlyreduced.Sinceclinical,ECG,and
radiographicexaminationsoftheheartarenonspecificfortheevaluationof
cardiacinvolvementinFriedreichataxia,anechocardiogramisnecessaryin
everypatient.
Theheartisinvolvedinaveryhighpercentageofpatients,andcardiac
symptomsareanintegralpartoftheclinicalspectrumofthedisease.Most
usually,theheartexhibitsasymmetric,concentric,andslowlyprogressive