Andersons pediatric cardiology 1561
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noted.Dilatedcardiomyopathyisanearlymanifestation,with70%ofpatients
withBarthsyndromehavingcardiomyopathybefore1yearofageandevidence
ofcardiomyopathyrelatedtoBarthhasbeenseenasearlyas18weeks’
gestation.161,162Responsetostandardheartfailuretreatmentisgood,butcardiac
transplantationhasbeenreportedinrefractorycases.163Suddendeathhasalso
beenreported;thismaybeduetotheincreasedriskofventriculararrhythmias
independentoftheseverityofcardiomyopathyandmayrequireimplantationof
adefibrillator.164Deathtypicallyresultsfrominfectiouscomplicationsorfrom
cardiacdisease.
PropionicAcidemia
PropionicacidemiaisararemetabolicdisorderduetoadeficiencyofpropionylCoAcarboxylase,anenzymeinvolvedinthecatabolismofvaline,leucine,
isoleucine,methionine,threonine,cholesterol,andfattyacids.Genemutations
mappedtochromosomes3and13havebeendescribed.165Diagnosisis
suspectedbyanalysisofurinaryorganicacids,withelevationsofpropionate,
propionylglycine,andmethylcitrate.Confirmationofthediagnosisrestswith
demonstrationofreducedactivityofpropionyl-CoAcarboxylaseinskin
fibroblasts.Thereisawidespectrumofclinicalpresentations,fromsevereearly
onsetofthediseaseinthefirstdaysoflifetorelativelymildformspresentingin
adulthood.Patientsdevelophypoglycinemia,hyperammonemia,hypoglycemia,
anddeficitsinthecentralnervoussystem,particularlyintimesofmetabolic
stresssuchasoccurswithminorinfections.Cardiomyopathyandsuddendeath
arerelativelyfrequentlatecomplications.166Thelattermaybeduetoan
increasedprevalenceofprolongationoftheQTintervalinthesepatients,a
phenomenonseenmorefrequentlywithage.167Becauseofthis,regular
electrocardiographicscreeningisnecessary.Wheninvolved,theheartis
typicallydilatedwithdepressedfunction,althoughhypertrophyisalsoseen.168
Poorventricularcontractilitycancomplicateacutemetaboliccrises,andpatients
presentingwithencephalopathyshouldbeassessedforleftventricularsystolic
dysfunction.Oneseriesfoundthat23%ofthosesurvivinginfancydeveloped
dilatedcardiomyopathyatanaverageageof7years.Thedevelopmentwas
independentofapparentdiseaseseverityandfrequencyofmetaboliccrises.In
twopatientstreatedwithlivertransplantation,thecardiomyopathywas
reversed.169Thepreciseetiologyofthecardiomyopathyisnotknown,but
disorderedcarnitinemetabolismandtoxicityofbyproductsinthemetabolic
pathwayofpropionyl-CoAcarboxylaseareleadingsuspects.Treatmentconsists
ofrestrictionofproteinandsupplementationwithL-carnitineandantibiotics.
MethylmalonicAciduria
Methylmalonicaciduriaisclinicallysimilartopropionicacidemiaandisduetoa
deficiencyofmethylmalonyl-CoAmutase.Itcanalsobeduetodefectsin
adenosylcobalamin,itscofactor.170Theenzymeisrequiredforthemetabolism
ofvaline,leucine,isoleucine,methionine,andthreonineandyieldssuccinylCoAforthetricarboxylicacidcycle.Deficiencycanleadtodilated
cardiomyopathy,althoughthepathogenesisisnotknown.171Somepatients,who
likelyhaveresidualenzymaticactivityorwhosediseaseistheresultofdefective
ordeficientcofactor,canrespondfavorablytosupplementalcyanocobalamin.
Thosewithdeficiencyoftheenzymeitselfaremanagedonalow-proteindiet
withcarnitinesupplementation.Despitetherapy,however,theriskofmetabolic
crisisduringacuteillnessesremainshigh.Hepatocyte-directedgenedeliveryhas
beenshowntocorrecttheenzymaticactivityinvitroandmayholdpromiseasa
futurecorrectivetherapy.172
DisordersofFattyAcidMetabolism
Theheartutilizesfattyacidsforenergyproductionbyconvertinglong-chainfree
fattyacidstolong-chainacyl-CoAviaacyl-CoAsynthetase.Theseacyl-CoA
compoundsarethentransferredintothemitochondria,wheretheyaredegraded
toproduceacetyl-CoAforuseinthetricarboxylicacidcycle.
Carnitine-acylcarnitinetranslocasemediatesentryoffattyacyl-CoA
compoundsintomitochondria.Deficiencyoftenresultsinearlydeathdueto
severemetaboliccollapsewithencephalopathyandhypertrophic
cardiomyopathy,althoughpatientswithmildervariantscanpresentlater.
Treatmentwithmedium-chaintriglyceridesandcarnitinesupplementationcan
potentiallyavertthesevereneurologicoutcomesusuallyassociatedwiththis
disease.173
CarnitinepalmitoyltransferaseIIconvertsacylcarnitinebacktoacyl-CoAfor
β-oxidationonceithascrossedtheinnermitochondrialmembrane.Deficiencyof
thisenzymeleadstononketotichypoglycemiawithseizures,hepatomegaly,and
hypertrophiccardiomyopathy.Milderformscanpresentlaterwithfastingor
duringperiodsofmetabolicstress.Treatmentconsistsofalow-fatdiet,
supplementationwithmedium-chaintriglycerides,carnitinesupplementation,
andavoidanceoffasting.174
Theacyl-CoAdehydrogenasesmediatethereactionsyieldingacetyl-CoA
fromacyl-CoAcompoundsofvaryinglengths.Theseenzymesarereferredtoas
short,medium,long,andverylongacyldehydrogenases.Deficiencyofanyof
thesecanyieldageneralizedmyopathyalongwithnonketotichypoglycemiaand
cardiomyopathy.175
