ClinicalPresentationAllsixpatientsweredeliveredvaginallyattermOnehadp - PDF document

ClinicalPresentationAllsixpatientsweredeliveredvaginallyatterm.Onehadperinataldepressionwithlow1and5minuteApgarscores(2/5).Theotherfivepatientshadcraniofacialdysmorphism,pro-foundhypotonia,neonatalseizures,andweaktendon,sucking,andswallowingreflexes,notedonthefirstdayoflife.Twoofthepatientsre-quiredreintubationbecauseofaspirationre-latedtotheimpairedswallowingreflex.Headsizewaswithin2standarddeviations(SD)ofnormalinallsixpatients.Congenitalglaucomawasdiagnosedinthreeofthepatientsandtwohadcongenitalcataracts.Hepatomegalywaspresentinfourpatients.Twohadcontracturesattheelbowsandfeet.Bilateralcubitusvalguswaspresentinoneinfant.Cardiacabnormalitieswerepresentintwopatients,includingapatentductusarteriosusandsmallatrialseptaldefectinoneandaventricularseptaldefectintheLaboratory,Electroencephalographic,andRadiologicFindingsPlasmalevelsofverylongchainfattyacidsweretestedinthreepatientsandwereincreasedwithamarkedelevationofC24:C22(range,1.8to2.1;normal,0.8)andC26:C22(range,0.4to0.7;normal,0.01).Analysisofurineinfourpatientsrevealedelevatedlevelsofdicarboxylicacidsanddihydroxycholestanoicacid.Inthreeofthepatients(theonlythreesotested),cul-turedfibroblastsshowedadecreaseinplas-malogensynthesisenzymeandamarkedin-creaseinverylongchain(greaterthan22carbons)fattyacids.Electroencephalographic(EEG)resultswereavailableinfourpatientsandshowedmultifocalspikesanddiffusebackgroundslowinginall.Plainradiographsofthepatellawereobtainedinthreepatients.Allshowedpatellarstippling.MRResultsAllpatientshaddiminishedmyelinationanddysplasticcortexthatinvolvedessentiallyallofthecerebrum;thecorticalregionaffectedmostdramaticallywasfromtheposteriorsylvianre-gionupwardtotheposteriorfrontalandparietallobes(Figs1and2).OnT1-weightedMRim-ages,diminishedhighsignalintensitywaspresentintheposteriorlimbsoftheinternalcapsulesintwopatientsandnormalhighsignalwascompletelyabsentfromthecapsulesintheotherfour(Fig1B).NolowsignalwaspresentinthecerebralwhitematteronT2-weightedim-agesinanyofthepatients;thisincludestheposteriorportionsoftheposteriorlimbsoftheinternalcapsules,whichexhibitlowsignalinhealthyneonates(Fig2B).SomehighT1signalandlowT2signalwaspresentinthedorsalbrainstem,mostlikelyrepresentingacombina-tionofmyelinationofthemedianlongitudinalfasciculusandmediallemnisciandnormalgraymattersignalofthebrainstemnuclei(Fig1C)(1).Inaddition,lowsignalintensitywaspresentinthesuperiorcerebellarpeduncles(Fig1C).Theentiretyofthecerebralcortexwasabnor-malinallpatients.Thenatureofthecorticalabnormalitydifferedindifferentpartsofthebrainandtheextentofabnormalitydifferedamongpatients.Inthetemporallobes,thecor-texhadnormalthicknessbutthegyralpatternwasabnormal;insome,thesulciweretooshal-lowandthegyritoofew(Fig1C),whileinothersthecortexappearedmicrogyric(Fig2B).Intheperisylviancortex,theappearancewasthatofmoretypicalpolymicrogyria,withmultiplesmallgyriandirregularityofthecortical±whitematterjunction(Fig2B).Theanteriorportionsofthefrontallobeshadamicrogyricappear-ance(Figs1Dand2BandC).Inthreepatients,theperirolandiccortexwasthickenedandshowedanareaofwhitematterintensity,simi-lartotheªcell-sparseºzoneseeninclassicallissencephaly(2),betweenat

hinouterlayerofgraymatterandathinnerinnerlayerofgraymatter(Fig2CandD).Intwoofthesepatients,themedialoccipitallobesweresimilarlyaf-fected(Fig2C).Theinnersurfaceoftheinnerlayerwasslightlyirregular.Inallthreeofthesepatients,anabnormallydeepperirolandicsul-cuswaspresentbilaterallyintheregionofthethickenedcortex(Fig2D).Cystswerepresentatthecaudothalamicnotchinallpatients.ThesewerebestseenonthesagittalT1-weightedimages(Fig2A)andcoronal3DFTgradient-echoimages(Fig1A).Thecystswereisointensewithcerebrospinalfluid(CSF)onallimagingsequencesandwerenotvisibleonaxialimages.Noabnormalitiesweredetectedinthebrainstemorcerebelluminanyofthepatients.AninterestingfindingwassignificantT1shorteningintheglobipalladianddorsalmes-encephalon,intheabsenceofnormalT1short-1164BARKOVICHAJNR:18,June1997 eningintheposteriorlimboftheinternalcap-sule,inonepatient(Fig1AandB).Reviewofthechartshowedthatthispatienthadhyper-bilirubinemiaassociatedwithhepaticfailureatthetimeoftheMRstudy.AutopsySpecimenSeveralphotographswereavailableofasin-glecoronalbrainsliceoftheonepatientinwhomanautopsywasperformed.Thephoto-graphsclearlyshowedthebilateralgerminolyticcysts(Fig3).Thegyralanomaliesandhypo-myelinationwerenotwellseenonthephoto-graphs.Nomicrotomespecimensorspecialstainswereavailableforreview.Peroxisomesaresmallcellularorganellesthatcontainmultiplecompoundsthatarees-sentialfornormalgrowthanddevelopmentoftheorganism.Thebiochemicalfunctionsthattakeplacewithinperoxisomesincludetionofaspecificsetoffattyacidsandfattyacidderivatives,synthesisofether-phospholipidsandplasmalogens,-oxidationofphytanicacid,andbiosynthesisofcholesterol(3±6).Al-thoughperoxisomesweredescribedin1954(7),theirfunctionandimportanceinnormaldevelopmentwasnotdiscernedforanumberofyearsafterward(8,9).Thefunctionoftheseorganellesandtheroleoftheirmalfunctioninthecausationofdiseasehavebeensubstantiallyclarifiedoverthelasttwodecades(4,6,10,11).Peroxisomaldisordersarenowclassifiedintothreemaingroups(Table1).Patientswithdis-ordersofgroupAhaveabnormal-appearingperoxisomeswithageneralizedlossofperoxi-somalfunction;theunderlyingdefectisbe-lievedtobeaninabilitytoimportintotheper- Fig1.MRfindingsinapatientwithmultifocalmicrogyriccortexandhepatic,Coronal3DFTgradient-echoimageshowsabnormalhyperintensity(blackar-)intheglobuspallidusbilaterallyandgerminolyticcysts(whitearrows)inthecaudothalamicgroovebilaterally.,Axialspin-echo500/15(repetitiontime/echotime)imageshowshyperinten-sityoftheglobuspallidusbilaterally()andabsenceofnormalhyperinten-sityoftheposteriorlimboftheinternalcapsule.Thesubacutesubduralhema-tomaisaremnantfromvaginaldelivery.,Axialspin-echo3000/120imageshowshypointensityinthesuperiorcere-bellarpeduncles()anddorsalpon-tinetracts,indicatingmyelinationinthosestructures.Asimplifiedgyralpatternispresentinthetemporallobes.,Axialspin-echo3000/120imageshowsanabnormalmicrogyricpatternintheperirolandic(openarrows)andpre-frontal(solidarrows)regions.AJNR:18,June1997ZELLWEGERSYNDROME1165 oxisomecertainproteinsthataresynthesizedinthecytoplasm(6,12).PatientswithdisordersofgroupBhavenormal-appearingperoxisomesbutlossofmultipleperoxisomalfunctions.Pa-tientsclassifiedingroupCh

avenormal-ap-pearingperoxisomesandlossofasingleperox-isomefunction(4).ZellwegersyndromefallsintogroupA,alongwithneonataladrenoleukodystrophy,infantileRefsumdisease,and,accordingtosomebutnotallauthors,hyperpipecolicacidemia(4,13).PatientswithclassicZellwegersyndromeareidentifiedinthenurserybytypicalcraniofacialdysmorphia(highforehead,largeanteriorfon-tanel,hypoplasticsupraorbitalridges,epican-thalfolds,midfacehypoplasia),ocularanoma-lies(cataracts,glaucoma,cornealclouding,pigmentaryretinopathy),severehypotonia,neonatalseizures,andhepatomegaly.Allofourpatientshadsomedegreeofcraniofacialdys-morphism;however,ocularanomalieswerepresentinonlythreeandhepatomegalyinfour.Affectedpatientsusuallysurviveforlessthan1year;indeed,fourofourpatientshavediedandtheothertwo,bothofwhomarelessthan14monthsold,aredeteriorating.NeuropathologicexaminationofthebrainsofpatientswithZellwegersyndromeshowthatthegyriareªtoonumerous,toosmall,andtoobroadº(14).AccordingtoEvrardetal(15),thesmallnumerousgyridonotrepresenttruepolymicrogyria,butmerelytoomanygyriwithadecreasedamplitude.Allourpatientshadre-gionsofgyrithatweretoonumerousandtoosmall(Figs1Dand2B±D).Abnormaldeepsulci(ªcleftsº)havebeendescribedinthesylvian(16)andparietal(17)regions.Wenotedsuchcleftsinfourofourpatients(Fig2CandD).FewreportsoftheMRappearanceofthebrainsofpatientswithZellwegersyndromehavebeenpublished;ourMedlinesearchrevealedonere-portinwhichvanderKnaapandValk(18) Fig2.PachygyricandpolymicrogyricMRappearanceinasinglepatient.,Sagittalspin-echo600/11imageshowsagerminolyticcyst()inthecaudothalamicgroove.Notelackofnormalsulcationinfrontallobes(straightarrows,Axialspin-echo3000/120imageshowsapaucityofmyelinintheposteriorlimboftheinternalcapsule.Inaddition,microgyriccortex(ispresentinthefrontal,temporal,andinsularcortices.,Axialspin-echo3000/120ataslightlyhigherlevelthanmacrogyriinthemedialrightoccipitallobe(openarrow)andintheperiro-landicregions(solidarrows).Theanteriorfrontalcortexremainsmicrogyricatthislevel.,Axialspin-echo3000/120atahigherlevelthanshowstheappear-anceoftwolayersofgraymatter(thicksolidarrows)withinterveninglayerofwhitematterintensityintheperirolandicandparietalregions.Theinnersurfaceoftheinnerlayerofgraymatter(thinsolidarrows)appearsirregularinsomeregions.Largeperirolandicinfoldingsofcortex(openarrows)arepresentbilaterally.Muchoftheremainderofthecortexappearsmicrogyric.1166BARKOVICHAJNR:18,June1997 describeasinglecaseofZellwegersyndromeintheirarticleonMRimagingofperoxisomaldis-orders.Theircaseshowssomeincompletefron-talsulcationandperirolandicpolymicrogyria,similartothatinthepatientinFigure1.Thisbringsupaninterestingfindinginoursixpa-tientswiththissyndrome:namely,markedvari-ationintheextentandappearanceofcorticalabnormalities.Thisvariationwasseenbothwithinthesamepatientandacrossthepatientpopulation.Somecorticalregionshadnormalorslightlydiminishedthicknesswithanirregu-larmicrogyricpatternconsistingofmultipleshallowsulciseparatingsmallgyri;thisappear-ancewasseenintheanteriorfrontalandperi-sylviancortexinallpatientsandinthetemporallobesofsome(Figs1Dand2B±D).Inotherareas,thecorticalthicknessappearednormalbutthegyriwerebroadand

flat(Fig1C).Inaddition,threepatients(Fig2D)hadcorticalregionsthatappearedquitesimilartothatseenintype1lissencephaly(19);athinoutercorti-callayerwasseparatedfromathickerunderly-inglayerofgraymatterbyacell-sparsezone(Fig2CandD).However,theinnersurfaceoftheinnergraymatterlayerhadaslightlyirreg-ularcontour,incontrastwiththesmoothcon-tourseenintype1lissencephaly.Ourfindingsaresupportedbythepathologicfindingsre-portedbyFriede(20),whostatedthatsomecorticalareasinZellwegersyndromearetypicalofpachygyriaandothersaretypicalofpolymi-Theothermajorneuropathologicfindingthathasbeenreportedisthatofseverelyabnormalmyelination.Thisappearstobeprimarilyahy-pomyelination,incontradistinctiontodysmyeli-nationordemyelination(21).Itisspeculatedthatthelackofmyelinationresultsfromthelackofformationofplasmalogens,whichareama-jorcomponentofthenormalmyelinmembrane(4,21).Anotherfactormaybetheabundanceofverylongchainfattyacids;itisthoughtthatthepresenceofverylongchainfattyacidsinmembranephospholipidsmightdestabilizetheaffectedmembrane(22),inthiscasemyelin.Impairedcholesterolbiosynthesis(anotherper-oxisomalfunction)mayalsoaffectmyelinfor-mation.TheMRimagesinourstudyclearlyshowedimpairedmyelination:theT1andT2shorteninginlocationscharacteristicofearlymyelinationwasdiminishedinthecerebrumofallthepatients.Oneofourpatients(Fig1AandB)didhavesomeT1shorteninginthecere-brum;however,theT1shorteningwasintheglobipalladi,nottheinternalcapsule.Onfur-therinvestigation,itwasfoundthatthepatientwashyperbilirubinemicfromhepaticdysfunc-tion,anothermanifestationofZellwegersyn-drome.Theoretically,onemightbeledawayfromthecorrectdiagnosisbymisinterpretingthisT1shorteningasmyelination.However,be-causetheventrolateralthalamiandtheposte-riorlimboftheinternalcapsulemyelinateear-lierthantheglobuspallidus(23),onedoesnotseemyelinationintheglobuspallidusintheabsenceofmyelinationintheventrolateralthal-amusandposteriorlimboftheinternalcapsuleintheneonatalbrain.Inaddition,hypoxic-isch-emicinjury,whichcancausehyperintensityof Fig3.Coronallycutgrossautopsyspecimenshowsthebilat-eralgerminolyticcysts().Thesulcalappearanceisdifficulttodetermineonthissingleslice.Classificationofperoxisomaldisorders GroupA:Deficiencyofperoxisomeswithgeneralizedlossofperoxisomalfunction1.Cerebrohepatorenal(Zellweger)syndrome2.Neonataladronoleukodystrophy3.InfantileRefsumdisease(4.Hyperpipecolicacidemia)GroupB:Lossofmultipleperoxisomefunctions(peroxisomes1.Rhizomelicchondrodysplasiapunctata2.ZellwegerlikesyndromeGroupC:Lossofsingleperoxisomefunction(peroxisomespresent)1.X-linkedadrenoleukodystrophyandvariants2.Acyl-CoAoxidasedeficiency(pseudo-NALD)3.Bifunctionalenzymedeficiency4.Peroxisomalthiolasedeficiency(pseudo-Zellweger)5.Dihydroxyacetonephosphateacyltransferasedeficiency6.Alkyldihydroxyacetonephosphatesynthasedeficiency7.Di-andtrihydroxycholestanoicadidemia8.Glutaryl-CoAoxidasedeficiency9.HyperoxaluriatypeI10.AcatalasemiaAJNR:18,June1997ZELLWEGERSYNDROME1167 theglobuspallidus,alsocauseshyperintensityoftheventrolateralthalamus(24);suchhyper-intensitywasnotpresentinthiscase.Thus,themostlikelycauseoftheglobuspallidushyper-intensityinthiscasewastheknownhyperbil-irub

inerma.Itisimportanttobeawareofthepossibilityofhepaticdysfunctioninaffectedne-onatesandtointerprettheMRstudyonlyafteracquiringadequateclinicalinformation.Subependymalgerminolyticcystsarebe-lievedtoresultfromhemorrhageintoandsub-sequentlysisofthetelencephalicsubependy-malgerminalmatrix(20).Thesecystscanoccuranywherealongthewallsofthelateralventricles,butaremostcommonlyseenintheregionoftheganglioniceminenceofthegermi-nalmatrix,thelastportionofthegerminalma-trixtoinvolute.Theganglioniceminenceislo-catednearthejunctionofthecaudateheadandthethalamus,aregionknownasthecaudotha-lamicnotch.Thecystsarenonspecificwithre-specttopathogenesisandhavebeendescribedinpatientswithcongenitalheartdisease,con-genitalorneonatalinfection,prenatalhemor-rhage,andlacticacidemia,aswellasinthosewithZellwegersyndrome(25±27).Althoughtheyarenonspecific,thesecystshaveachar-acteristicappearance(Figs1A,2A,and3)andcanbeausefulfindinginpatientswithsus-pectedZellwegersyndrome,astheyareeasilydetectedbytransfontanelsonography(25±27)andMRimaging.Incontrast,theother,morespecific,findingsofhypomyelinationandcorti-calmalformationcanbedetectedonlywithMROtherreportedneuropathologicfindingsinZellwegersyndromeincludeabnormalolivarynuclei,cerebellarhypoplasia,andmigrationaldefectsofthecerebellarPurkinjecells(13,14).NoneoftheseabnormalitieswasobservedonourMRstudies.ThemaindisorderfromwhichZellwegersyn-dromemustbedifferentiated,accordingtomostchildneurologytexts(13),isneonatalad-renoleukodystrophy(NALD).AlthoughsomeauthorsconsiderZellwegersyndrometobedis-tinctfromNALD,othersbelievethetwodisor-dersarepartsofacontinuum.Powers(21)andNormanetal(14)pointoutthatZellwegerpa-tientshavehypomyelination,whereasNALDpatientshavedemyelinationwithinflammatorycellsandfoamymacrophagesinthewhitemat-ter.Inaddition,thecorticalmalformationsseeninZellwegerpatientsaredescribedasmorecommonandmoreseverethanthoseinNALDpatients.Kelleyetal(28)haveproposedcrite-riatodiscriminateZellwegersyndromefromNALD,suggestingthatNALDpatientshavead-renalatrophy,cerebraldemyelination,systemicinfiltrationoflipid-ladenmacrophages,andel-evatedlevelsofsaturatedverylongchainfattyacids,whereasZellwegerpatientshavechon-drodysplasia,glomerulocystickidneydisease,centralnervoussystem(CNS)dysmyelination,andaccumulationofbothsaturatedandunsat-uratedverylongchainfattyacids.Whilethesearestrongarguments,otherauthorsareequallyconvincinginsuggestingthatNALDisjustamilderphenotypeofthesamedisease(13,29).Moser(13)pointsoutthatpatientswithZell-wegersyndrome,NALD,andinfantileRefsumdisease(whichhealsoconsiderspartofthesamespectrum)canallhavethesamegeno-type.ThisviewofaspectrumofphenotypicexpressionissupportedbytheobservationofNormanetal(14)thattheseverityofinflam-matorychangesseeninthecerebralwhitemat-terofpatientswithZellwegersyndromeseemstoincreasewiththedurationofsurvivalafterbirth.Thus,itmaybethatpatientssaidtohaveZellwegersyndromehavepoorsurvivalbe-causetheyhaveseverecorticalmalformationsandconsequentepilepsy;becausetheirsurvivalisshort,thewhitemattershowslittleinflamma-torychanges.Thosepatientswithlessercorticalmalformationspresumablysurvivelongerandhavemoreinflammatorychangesinthew

hitematter;thesepatientsareconsideredtohaveOtherdifferentialconsiderationsinthisgroupofpatientsaretheperoxisomalbifunctionalen-zymedefect(BFD)(30),acyl-CoAoxidasede-ficiency(pseudo-NALD)(31),andperoxisomalthiolasedeficiency(pseudo-Zellweger)(32);patientswithallthesediseaseshaveneonatalcoursesandmanyphenotypicmanifestationsthataresimilartothosewithZellwegersyn-drome(4).Congenitalmusculardystrophiesthatareassociatedwithbrainmalformations(Walker-Warburgsyndrome[33,34],Fuku-yamacongenitalmusculardystrophy[35,36],Santavuorimuscle-eye-braindisease[37±39],andothermusculardystrophieswithbrainin-volvement[40,41])arealsodiagnosticconsid-erationsfromanimagingperspective,asallthesedisordershavemalformationsofcorticaldevelopmentassociatedwithabnormalmyeli-nation.Wewereunabletofindanypublished1168BARKOVICHAJNR:18,June1997 MRbrainimagesofBFD,pseudo-NALD,orpseudo-Zellweger.However,onewouldexpectBFDtohavegreatneuroradiologicsimilaritytoZellwegersyndrome.PublishedbrainautopsyfindingsinBFDshowhypomyelinationandbi-lateral,symmetriccorticalmalformationsintheperirolandicandsylvianregions.Microscopicexaminationrevealedpachygyriaandunlay-eredpolymicrogyriawithpoordemarcationofthecortexandunderlyingwhitematter(42).ThesefindingsaresimilartothoseinourcasesofZellwegersyndrome.Moreover,thesesimi-laritiessuggestthattheperoxisomalbifunc-tionalenzymeisinsomewayrelatedtotheprocessesofneuronalmigrationandorganiza-tion.IncontrasttothefindingsinBFD,autopsyfindingsinapatientwithpseudo-Zellwegersyn-dromerevealedhypomyelinationbutanormalcerebralcortex(32);mostabnormalitieswereinthecerebellum.Findingsonaheadcom-putedtomographic(CT)scanofpseudo-NALDwerereportedtobenormal(43).MostofthecongenitalmusculardystrophiescanbedifferentiatedfromZellwegersyndromeclinically,inthatmostaffectedpatientsarenotassickintheneonatalperiod;donothavethetypicalZellwegerfacies;donothavehepatic,renal,oradrenaldysfunction;anddonothaveneonatalseizures.Theonecongenitalmusculardystrophythatmaybeaccompaniedbypro-foundhypotoniaandseizuresintheneonatalperiodisWalker-Warburgsyndrome.PatientswiththisdisordercanbedifferentiatedfromthosewithZellwegersyndromebyusingMRimagingtodetectthemanyassociatedCNSanomaliespresentinWalker-Warburgpatients,includinghydrocephalus,ocularanomalies(typically,persistenthyperplasticprimaryvitre-ous),corpuscallosalhypogenesisoragenesis,andlissencephalyinvolvingtheentiretyofthecerebrum(19).IncontrasttothosepatientswithWalker-Warburgsyndrome,changesofmusculardystrophyarenotpresentonmusclebiopsyspecimensofpatientswithZellwegersyndrome.Finally,thepresenceofgerminolyticcystshasnotbeendemonstratedinWalker-Warburgsyndromeandmaybeausefulfeatureinestablishinganimagingdiagnosis.AlthoughwedidnothaveCTscansorsono-gramstocomparewiththeMRstudiesofourpatients,itappearsthatMRimagingshouldbetheneuroimagingstudyofchoiceintheassess-mentofpatientswithsuspectedZellwegersyn-drome.MRimagingistheonlytechniquethatcanshowthesometimessubtlecorticalmalfor-mationsandhypomyelinationthatarecrucialinmakingthediagnosis.Althoughgerminolyticcystscanbedetectedbysonographyandper-hapsbyCT,theyare,bythemselves,nonspe-cificasdiscussedearlier.Insummary,wehavedesc

ribedtheMRim-agingfindingsinsixpatientswithcerebrohepa-torenal,orZellweger,syndrome.Althoughtheimagingappearancevariesslightlyfromcasetocase,thecombinationofhypomyelination,dif-fuselyabnormalgyrationthatismostsevereintheperisylvianandperirolandicregions,andgerminolyticcystsinthecaudothalamicgrooveshouldallowconfidentdiagnosisofthisdisorderintheproperclinicalsetting.1.MartinE,KrassnitzerS,KaelinP,BoeschC.MRimagingofthebrainstem:normalpostnataldevelopment.2.BarkovichAJ,KochTK,CarrolCL.Thespectrumoflissenceph-aly:reportoftencasesanalyzedbymagneticresonanceimaging.AnnNeurol1991;30:139±1463.VandenBoschH,SchutgensRBH,WandersRJA,TagerJM.Bio-chemistryofperoxisomes.AnnRevBiochem4.WandersRJA,SchutgensRBH,BarthPG.Peroxisomaldisorders:areview.JNeuropatholExpNeurol1995;54:726±7395.KrisansSK.Theroleofperoxisomesincholsterolmetabolism.AmJRespCellMolBiol1992;7:358±3646.LazarowPB.Peroxisomestructure,functionandbiogenesis:hu-manpatientsandyeastmutantsshowstrikinglysimilardefectsinperoxisomebiogenesis.JNeuropatholExpNeurol1995;54:720±7.RhodinJ.Correlationofultrastructuralorganizationandfunctioninnormalandexperimentallychangedproximalconvolutedtu-bulecellsofthemousekidney.Stockholm,Sweden:AktiebolagetGodvil;19548.SinghI,MoserAB,GoldfischerS,MoserHW.Lignocericacidisoxidizedintheperoxisomes:implicationsfortheZellwegercere-brohepatorenalsyndromeandadrenoleukodystrophy.ProcNatlAcadSc1984;81:4203±42079.GoldfischerS,MooreCL,JohnsonAB,etal.Peroxismoalandmitochnodrialdefectsinthecerebro-hepato-renalsyndrome.1973;182:62±6410.MoserHW,MihalikSJ,WatkinsPA.Adrenoleukodystrophyandotherperoxisomaldisordersthataffectthenervoussystem,in-cludingnewobservationson-pipecolicacidoxidaseinprimates.BrainDev1989;11:80±9011.NaiduS,MoserAE,MoserHW.Phenotypicandgenotypicvari-abilityofgeneralizedperoxisomaldisorders.PediatrNeurol12.BravermanN,DodtG,GouldSJ,ValleD.DisordersofperoxisomeHumMolGenet13.MoserHW.Peroxisomaldisorders.In:BergBO,ed.PrinciplesofChildNeurology.NewYork,NY:McGraw-Hill;1996:1233±124814.NormanMG,McGillivrayBC,KalousekDK,HillA,PoskittKJ.Congenitalmalformationsofthebrain:pathologic,embryologic,clinical,radiologicandgeneticaspects.Oxford,England:OxfordUniversityPress;1995:223±307AJNR:18,June1997ZELLWEGERSYNDROME1169 15.EvrardP,CavinessVSJ,Prats-VinasJ,LyonG.ThemechanismofarrestofneuronalmigrationintheZellwegermalformation:anhypothesisbaseduponcytoarchitectonicanalysis.ActaNeuro-1978;41:109±11716.VolpeJJ,AdamsRD.Cerebro-hepato-renalsyndromeofZell-weger:aninheriteddisorderofneuronalmigration.ActaNeuro-17.deLeoÂnGA,GroverWD,HuffDS,Morinigo-MestreG,PunnettHH,KistermacherML.Globoidcells,glialnodules,andpeculiarfibril-larychangesinthecerebro-hepato-renalsyndromeofZellweger.AnnNeurol1977;2:473±48418.vanderKnaapMS,ValkJ.TheMRspectrumofperoxisomal1991;33:30±3719.BarkovichAJ,GressensP,EvrardP.Formation,maturation,anddisordersofbrainneocortex.AJNRAmJNeuroradiol423±44620.FriedeRL.DevelopmentalNeuropathology.2nded.Berlin,Ger-many:Springer;198921.PowersJM.Thepathologyofperoxisomaldisorderswithpatho-geneticconsiderations.JNeuropatholExpNeurol1995;54:710±22.vanderKnaapMS,ValkJ.Myelinandwhitematter.In:vanderKna

apMS,ValkJ,eds.MagneticResonanceofMyelin,Myelina-tion,andMyelinDisorders.2nded.Berlin,Germany:Springer;23.HasegawaM,HoudouS,MitoT,TakashimaS,AsanumaK,OhnoT.Developmentofmyelinationinthehumanfetalandinfantcerebrum:amyelinbasicproteinimminohistochemicalstudy.BrainDev1992;14:1±624.BarkovichAJ,WestmarkKD,FerrieroD,SolaA,PartridgeC.Perinatalasphyxia:MRfindingsinthefirst10days.AJNRAmJ1995;16:427±43825.MitoT,AndoY,TakeshiteK,etal.Ultrasonographicalandmor-phologicalexaminationofsubependymalcysticlesionsinma-turelyborninfants.26.RusselIMB,vanSonderenL,vanStraatenHLM,BarthPG.Sub-ependymalgerminolyticcystsinZellwegersyndrome.1995;25:254±25527.ShackelfordGD,FullingKH,GlasierCM.Cystsofthesubependy-malgerminalmatrix:sonographicdemonstrationwithpathologic28.KelleyRI,DattaNS,DobynsWB,etal.Neonataladrenoleukodys-trophy:newcases,biochemicalstudies,anddifferentiationfromZellwegerandrelatedperoxisomalpolydystrophysyndromes.AmJMedGenet1986;23:869±90129.vanderKnaapMS,ValkJ.Zellwegercerebrohepatorenalsyn-drome,neonataladrenolekukdystrophy,andinfantileRefsumdis-ease.In:vanderKnaapMS,ValkJ,eds.MagneticResonanceofMyelin,Myelination,andMyelinDisorders.2nded.Berlin,Ger-many:Springer;1995:110±12030.WatkinsPA,ChenWW,HarrisCJ,etal.Peroxisomalbifunctionalenzymedeficiency.JClinInvest31.Poll-TheBT,RoelsF,OgierH,etal.Anewperoxisomaldisorderwithenlargedperoxisomesandaspecificdeficiencyofacyl-CoAoxidase(pseudo-neonataladrenoleukodystrophy).AmJHum1988;41:422±43432.GoldfischerS,CollinsJ,RapinI,etal.Pseudo-Zellwegersyn-drome:deficienciesinseveralperoxisomaloxidativeactivities.JPediatr33.WilliamsRS,SwisherCN,JenningsM,AmblerM,CavinessVSJ.Cerebro-oculardysgenesis(Walker-Warburgsyndrome):neuro-pathologicandetiologicanalysis.34.DobynsWB,KirkpatrickJB,HittnerHM,RobertsRM,KretzerFL.Syndromeswithlissencephaly.2:Walker-Warburgandcerebraloccularmuscularsyndromesandanewsyndromewithtype2AmJMedGenet35.AidaN,TamagawaK,TakadaK,etal.BrainMRinFukuyamacongenitalmusculardystrophy.AJNRAmJNeuroradiol17:605±61436.FukuyamaY,KawazuraM,HarunaH.Apeculiarformofcongen-italmusculardystrophy:reportoffifteencases.PaediatrUnivers1960;4:5±837.SantavuoriP,LeistiJ,KruusS.Muscle,eyeandbraindisease:anewsyndrome.Èdiatrie(Suppl)38.SantavuoriP,SomerH,SainioK,etal.Muscle-eye-braindisease.BrainDev39.ValanneL,PihkoH,KatevuoK,KarttunenP,SomerH,SantavuoriP.MRIofthebraininmuscle-eye-brain(MEB)disease.1994;36:473±47640.TrevisanCP,MartinelloF,FerruzzaE,etal.Divergenceofcentralnervoussysteminvolvementin2Italiansisterswithcongenitalmusculardystrophy:aclinicalandneuroradiologicalfollow-up.EurNeurol1995;35:230±23541.PiniA,MerliniL,TomeÂFMS,ChevallayM,GobbiG.Merosin-negativecongenitalmusculardystrophy,occipitalepilepsywithperiodicspasmsandfocalcorticaldysplasia:reportofthreeItal-iancasesintwofamilies.BrainDev1996;18:316±32242.KaufmannWE,ThedaC,NaiduS,WatkinsPA,MoserAB,MoserHW.Neuronalmigrationabnormalityinperoxisomalbifunctionalenzymedefect.AnnNeurol1996;39:268±27143.KyllermanM,BloomstrandS,ManssonJE,ConradiN,HinmarshT.Centralnervoussystemmalformationsandwhitematterchangesinpseudo-neonataladrenoleukodystrophy.1989;21:199±2011170BARKOVICHAJNR:18,June19