ImagingImaging PediatricPediatric LeukodystrophiesLeukodystrophies

JonathanJonathan AA PhelanPhelan MSMS IVIV1 && LisaLisa HH LoweLowe MDMD2 1Kansas City University of Medicine and Biosciences 2Department of Radiology, Children’s Mercy Hospital and Clinics and2The University of Missouri-Kansas City LearningLearning objectivesobjectives

1.1. DistinguishDistinguish betweenbetween normalnormal andand abnormalabnormal whitewhite mattermatter inin childrenchildren 2.2. FormulateFormulate anan approachapproach toto whitewhite mattermatter disordersdisorders inin childrenchildren 3.3. RecognizeRecognize thethe findingsfindings ofof commoncommon whitewhite mattermatter problemsproblems inin childrenchildren IntroductionIntroduction zz WhiteWhite mattermatter (WM)(WM) disordersdisorders inin childrenchildren areare extensive,extensive, complexcomplex andand challengingchallenging toto learnlearn ImportantImportant CellCell OrganellesOrganelles

LysosomeLysosome (garbage(garbage disposaldisposal unit)unit)

PeroxisomePeroxisome (oxidation(oxidation && catalationcatalation))

MitochondriaMitochondria (power(power house)house) LysosomalLysosomal disordersdisorders MitochondrialMitochondrial dysfunctiondysfunction MetachromaticMetachromatic LeighLeigh diseasedisease leukodystrophyleukodystrophy MELASMELAS KrabbeKrabbe’’ss diseasedisease KearnsKearns--SayreSayre MucopolysaccharidosesMucopolysaccharidoses syndromesyndrome GangliosidosesGangliosidoses PeroxisomalPeroxisomal disordersdisorders UnknownUnknown metabolicmetabolic defectdefect ZellwegerZellweger syndromesyndrome PelizaeusPelizaeus--MerzbacherMerzbacher NeonatalNeonatal ALDALD AlexanderAlexander’’ss diseasedisease XRXR adrenoleukodystrophyadrenoleukodystrophy CanavanCanavan diseasedisease PathophysiologyPathophysiology ofof WMWM disorders:disorders: generalgeneral conceptsconcepts

FaultyFaulty genegene

StructurallyStructurally abnormalabnormal proteinprotein

EnzymeEnzyme defectdefect

MetabolicMetabolic blockblock PathophysiologyPathophysiology ofof WMWM disorders:disorders: generalgeneral conceptsconcepts AccumulationAccumulation ofof abnormalabnormal productsproducts ƒƒ InterfereInterfere withwith normalnormal neuronalneuronal functionfunction InsufficientInsufficient normalnormal biochemicalbiochemical productproduct ƒƒ EssentialEssential toto metabolismmetabolism ofof neurons/myelinneurons/myelin ƒƒ InjureInjure otherother organsorgans (lung,(lung, heart,heart, liver,liver, kidney)kidney) SecondarySecondary effecteffect onon CNSCNS ƒƒ ToxicToxic toto neurons/myelinneurons/myelin TreatmentTreatment optionsoptions WMWM disordersdisorders

Supportive,Supportive, symptomaticsymptomatic SubstrateSubstrate deprivationdeprivation BoneBone marrowmarrow transplanttransplant EnzymeEnzyme replacementreplacement GeneGene therapytherapy NeuralNeural stemstem cellcell transplantationtransplantation WhatWhat areare thethe obstaclesobstacles toto learninglearning pediatricpediatric WMWM disorders?disorders?

ManyMany classificationsclassifications systemssystems andand mostmost areare notnot usefuluseful forfor imagingimaging OrganelleOrganelle basedbased BiochemicalBiochemical basedbased ClinicalClinical syndromesyndrome HistochemicalHistochemical stainingstaining patternpattern OtherOther obstaclesobstacles toto learninglearning pediatricpediatric WMWM disordersdisorders VariousVarious formsforms zz SingleSingle vs.vs. multiplemultiple enzymeenzyme defectsdefects VariousVarious presentationspresentations zz InfantInfant vs.vs. juvenilejuvenile vs.vs. adultadult PresentPresent -- nonspecificnonspecific OverlapOverlap -- imagingimaging AdvancedAdvanced casescases looklook alikealike 60%60% nevernever getget aa DxDx HowHow cancan wewe overcomeovercome thesethese obstacles?obstacles?

HaveHave anan approachapproach toto imagingimaging ofof WMWM leukodystrophiesleukodystrophies BeBe familiarfamiliar withwith commoncommon autoimmuneautoimmune && infectiousinfectious disordersdisorders thatthat maymay affectaffect WMWM inin childrenchildren KnowKnow thethe keykey historyhistory && imagingimaging patternspatterns usefuluseful toto formulateformulate aa limitedlimited differentialdifferential diagnosisdiagnosis OutlineOutline

NormalNormal developmentdevelopment LeukodystrophiesLeukodystrophies ƒƒ SubcorticalSubcortical WMWM ƒƒ DeepDeep WMWM DisordersDisorders withwith lacklack ofof WMWM myelinationmyelination NonspecificNonspecific WMWM disordersdisorders NormalNormal developmentaldevelopmental anatomyanatomy andand pitfallspitfalls thatthat simulatesimulate diseasedisease

WMWM signalsignal changeschanges withwith ageage AdultAdult appearanceappearance atat 1818 momo -- 22 yearsyears MyelinationMyelination progressesprogresses backback toto frontfront AssessAssess myelinationmyelination withwith MRIMRI TerminalTerminal myelinationmyelination zoneszones zz PeriatrialPeriatrial andand subcorticalsubcortical WMWM LackLack ofof myelinationmyelination cancan mimicmimic WMWM diseasedisease NormalNormal milestonesmilestones myelinationmyelination

BrainBrain regionregion T1T1 T2T2 Middle cerebellar peduncle, BirthBirth BirthBirth –– 2mo2mo post limb internal capsule Anterior limb internal 22--33 momo 77--1111 momo capsule, centrum semiovale Splenium corpus callosum 33--44 momo 44--66 momo Genu corpus callosum 44--66 momo 55--88 momo Occipital white matter, 44--77 momo 1111--1515 momo peripheral Frontal white matter, 77--11mo11mo 1414--18m18m peripheral •T1 used < 6 mo, T2 used > 6 months Newborn 5 months

Normal progression of myelination

8 months T2 nb 5mo 8mo

T2 12mo 18mo 24mo NormalNormal terminalterminal myelinationmyelination zoneszones

1818--momo--malemale withwith normalnormal brainbrain NormalNormal variantvariant thatthat cancan persistpersist intointo adulthoodadulthood HowHow dodo wewe approachapproach pediatricpediatric WMWM disorders:disorders:

AskAsk somesome questions!questions! 1.1. AreAre therethere anyany usefuluseful symptoms?symptoms? ƒ Head size: Macrocephaly ƒ WM symptoms: Spasticity, hyperreflexia, ataxia ƒƒ OtherOther organs:organs: liver,liver, msk,msk, renal,renal, eye,eye, earear 2.2. IsIs thethe disorderdisorder primarilyprimarily WM,WM, graygray mattermatter oror both?both? 3.3. IsIs itit primarilyprimarily SUBCORTICALSUBCORTICAL oror DEEPDEEP whitewhite matter?matter? SubcorticalSubcortical vs.vs. Deep?Deep? Note the region of sparing in the subcortical WM region

Note the abnormal signal in the WM extends to the subcortical U fiber region ApproachApproach toto pediatricpediatric WMWM disordersdisorders OtherOther questions:questions: 1.1. DistributionDistribution -- anterior,anterior, posterior,posterior, both?both? 2.2. SubcorticalSubcortical oror deepdeep WMWM cysts?cysts? 3.3. ThalamicThalamic involvement?involvement? 4.4. BrainstemBrainstem involvement?involvement? 5.5. DelayedDelayed oror lacklack ofof myelination?myelination? 6.6. LeadingLeading edgeedge ofof enhancement?enhancement? 7.7. CorticalCortical dysplasia?dysplasia? 8.8. ElevatedElevated NAA,NAA, lactatelactate oror otherother peakspeaks onon MRS?MRS? ImagingImaging techniquetechnique WMWM disordersdisorders

USUS && CTCT -- limitedlimited rolerole zz USUS –– screenscreen macrocephalymacrocephaly inin developmentallydevelopmentally normalnormal childrenchildren zz CTCT –– abnormalabnormal areasareas usuallyusually hypodensehypodense MRIMRI –– ImagingImaging modalitymodality ofof choicechoice ƒƒ RoutineRoutine brainbrain ++ GadoliniumGadolinium MRSMRS –– JustJust dodo it!it! ItIt maymay helphelp you.you. zz TETE 30msec30msec && 270msec270msec zz MultivoxelMultivoxel nicenice toto comparecompare samplesample volumesvolumes inin normalnormal && abnormalabnormal regionsregions Begin with……

SubcorticalSubcortical WhiteWhite MatterMatter leukodystrophiesleukodystrophies

CaveatCaveat:: nearlynearly allall havehave somesome graygray mattermatter involvementinvolvement…………

Approach according to Barkovich JE. Pediatric Neuroimaging 4th ed. FirstFirst discussdiscuss SUBCORTICALSUBCORTICAL whitewhite mattermatter disordersdisorders WithWith macrocephalymacrocephaly:: 1.1. IfIf yes,yes, consider:consider: AlexanderAlexander && CanavanCanavan diseasedisease 2.2. ++ subcorticalsubcortical cystscysts,, thinkthink of:of: vanvan derder KnappKnapp diseasedisease 3.3. ++ ataxiaataxia && decreaseddecreased myelinationmyelination thinkthink of:of: VanishingVanishing whitewhite mattermatter diseasedisease

Approach according to Barkovich JE. Pediatric Neuroimaging 4th ed. CanavanCanavan diseasedisease

SpongiformSpongiform leukodystrophyleukodystrophy AutosomalAutosomal recessive,recessive, AshkenaziAshkenazi JewsJews AspartoacylaseAspartoacylase deficiency;deficiency; ChromosomeChromosome 1717 Presentation:Presentation: hypotoniahypotonia withwith headhead laglag inin firstfirst fewfew weeksweeks ofof lifelife,, followedfollowed byby macrocephalymacrocephaly && seizures,seizures, thenthen spacticityspacticity RapidRapid progressionprogression DeathDeath 22nd yearyear ofof lifelife CanavanCanavan diseasedisease

HxHx:: 22--monthmonth--oldold hypotonichypotonic femalefemale Imaging:Imaging: CTCT HypodenseHypodense ƒ Subcortical WM ƒ Globus pallidi ƒ Thalami ƒ Extreme capsule ƒ Claustra

Image from Barkovich JE. Pediatric neuroimaging 2005 CanavanCanavan diseasedisease

Imaging:Imaging: MRIMRI hypointensehypointense T1T1 && hyperintensehyperintense T2T2

DiffuseDiffuse subcorticalsubcortical P WMWM GP GlobusGlobus pallidipallidi withwith normalnormal putaminaputamina InternalInternal && externalexternal capsulescapsules inin rapidrapid casescases CanavanCanavan diseasedisease RestrictedRestricted diffusiondiffusion inin WMWM acuteacute diseasedisease ADCADC DWIDWI CanavanCanavan diseasedisease MRSMRS –– Marked elevation NAA peak SpecificSpecific forfor CanavanCanavan diseasedisease

NAA

Cr T1 CanavanCanavan diseasedisease

T2 T2

Spongiform leukodystrophy AlexanderAlexander diseasedisease FibrinoidFibrinoid leukodystrophyleukodystrophy RosenthalRosenthal fibersfibers onon histologyhistology MutatedMutated GFAPGFAP (glial(glial fibrillaryfibrillary acidicacidic protein)protein) PresentationPresentation macrocephalymacrocephaly 11st yearyear ofof life,life, developmentaldevelopmental delay,delay, failurefailure toto thrivethrive 33 subgroups:subgroups: z Infantile – most common; death in 2-3 year of life z Juvenile – 7-14 years – ataxia & spasticity z Adult – present like juvenile Dx:Dx: analysisanalysis ofof GFAPGFAP genegene Prognosis:Prognosis: DeathDeath firstfirst yearyear ofof lifelife AlexanderAlexander diseasedisease HxHx:: 22 yearyear oldold male,male, macrocephalymacrocephaly && ataxiaataxia ImagingImaging:: CTCT HypodenseHypodense subcorticalsubcortical WMWM FrontalFrontal ContrastContrast enhancementenhancement –– ƒƒ AdjacentAdjacent toto frontalfrontal hornshorns

ƒƒ CaudateCaudate headsheads Image from Barkovich JE. Pediatric neuroimaging 2005 AlexanderAlexander diseasedisease MRMR imagingimaging criteriacriteria accordingaccording toto vanvan derder Knapp:Knapp: SubcorticalSubcortical WM,WM, frontalfrontal lobelobe predominancepredominance ContrastContrast enhancmentenhancment ofof graygray andand WMWM structuresstructures (esp(esp adjacentadjacent toto frontalfrontal hornhorn tipstips andand ventricularventricular trigones)trigones) BrainBrain stemstem abnormalitiesabnormalities AbnormalAbnormal basalbasal ganglia,ganglia, thalamithalami DWIDWI -- increasedincreased waterwater motionmotion (bright(bright onon ADCADC map,map, darkdark onon DWI)DWI) MRSMRS –– lowlow NAANAA +/+/-- elevatedelevated myomyo--inositolinositol

van der Knapp MS, et al. AlexaAlexandenderr disease: Diagnosis with MR imaging. AJNR 2001;22:541-52 AlexanderAlexander diseasedisease Bright,Bright, anterioranterior subcorticalsubcortical toto periventricularperiventricular WM,WM, basalbasal gangliaganglia && thalamithalami

Image courtesy of Mauricio Castillo, MD AlexanderAlexander diseasedisease vanvan derder KnappKnapp dzdz oror MegalencephalicMegalencephalic leukoencephalopathyleukoencephalopathy withwith cystscysts ImagingImaging:: AbsentAbsent myelinmyelin inin subcorticalsubcortical WMWM SparedSpared deepdeep WMWM andand basalbasal gangliaganglia SubcorticalSubcortical cystscysts inin posteriorposterior frontalfrontal andand temporaltemporal lobeslobes DWIDWI –– increasedincreased diffusiondiffusion (dark(dark onon DWI,DWI, brightbright onon ADCADC map)map) MRSMRS –– nonnon--specific;specific; lowlow NAANAA levelslevels vanvan derder KnappKnapp dzdz oror MegalencephalicMegalencephalic leukoencephalopathyleukoencephalopathy withwith cystscysts VanishingVanishing whitewhite mattermatter diseasedisease

FamilialFamilial childhoodchildhood ataxiaataxia withwith diffusediffuse CNSCNS hypomyelinationhypomyelination ChromosomeChromosome 33 Presentation:Presentation: RelapsingRelapsing--remittingremitting periodsperiods ofof progressiveprogressive ataxiaataxia && spasticspastic diplegiadiplegia DxDx criteria:criteria: initialinitial motormotor andand mentalmental (a)(a) developmentdevelopment isis nl,nl, (b)(b) chronicchronic episodicepisodic neuroneuro deterioration,deterioration, (c)(c) cerebellarcerebellar ataxiaataxia && spasticityspasticity (d)(d) MRIMRI showsshows symmetricsymmetric WMWM signalsignal ofof CSFCSF LabLab screening:screening: elevatedelevated glycineglycine inin thethe CSF,CSF, serumserum andand urineurine Prognosis:Prognosis: deathdeath 22nd decadedecade VanishingVanishing whitewhite mattermatter diseasedisease WMWM graduallygradually lookslooks thethe samesame asas CSFCSF

T2 FLAIR

Image from van der Knapp. Magnetic Resonance of myelination and myelin disorders ApproachApproach toto SUBCORTICALSUBCORTICAL whitewhite mattermatter disordersdisorders WithoutWithout macrocephalymacrocephaly?:?: GalactosemiaGalactosemia –– alsoalso involvesinvolves liverliver KearnsKearns SayreSayre –– especiallyespecially ifif globusglobus palliduspallidus isis involvedinvolved GalactosemiaGalactosemia

AutosomalAutosomal recessiverecessive DefectiveDefective conversionconversion ofof glucoseglucose toto galactosegalactose z Galactose-1-phosphate-uridyl transferase Presentation:Presentation: newbornsnewborns oror youngyoung childrenchildren withwith signssigns ofof increasedincreased intracranialintracranial pressurepressure andand vomitingvomiting Untreated:Untreated: severesevere liverliver diseasedisease && mentalmental retardation,retardation, seizures,seizures, choreoathetosischoreoathetosis Rx:Rx: dietarydietary restrictionrestriction ofof galactosegalactose Prognosis:Prognosis: variesvaries GalactosemiaGalactosemia FLAIR ImagingImaging:: CTCT –– nonspecificnonspecific lowlow densitydensity WMWM MRIMRI –– delayeddelayed subcorticalsubcortical WMWM myelinationmyelination onon T2T2 (nl(nl onon T1);T1); zz OccasionalOccasional WMWM focalfocal lesionslesions andand latelate atrophyatrophy zz MRSMRS -- normalnormal

Image from Barkovich JE. Pediatric neuroimaging KearnsKearns SayreSayre MitochondrialMitochondrial disorderdisorder DxDx requiresrequires externalexternal opthalmoplegia,opthalmoplegia, retinitisretinitis pigmentosapigmentosa andand onsetonset ofof neurologicneurologic dysfunctiondysfunction << 2020 yearsyears z +/- protein in CSF, heart block & cerebellar ataxia Imaging:Imaging: abnormalabnormal WMWM early,early, atrophy,atrophy, laterlater basalbasal deepdeep graygray mattermatter z CT - WM hypodense with calcifications z MRI -subcortical WM, globus pallidus z DWI - restricted diffusion z MRS – non-specific increased lactate & low NAA KearnsKearns SayreSayre SubcorticalSubcortical WMWM ++ sparedspared deepdeep WMWM ++ GlobusGlobus palliduspallidus

Image from Barkovich JE. Pediatric neuroimaging Next……

DeepDeep WhiteWhite MatterMatter LeukodystrophiesLeukodystrophies

Caveat:Caveat: nearlynearly allall havehave somesome graygray mattermatter involvementinvolvement………… ApproachApproach toto DEEPDEEP WMWM disordersdisorders

THALAMICTHALAMIC involvement?:involvement?: KrabbeKrabbe diseasedisease GMGM 11 GMGM 22 ƒƒ TayTay--SachSach diseasedisease ƒƒ SandhoffSandhoff diseasedisease KrabbeKrabbe diseasedisease GloboidGloboid cellcell leukodystrophyleukodystrophy LysosomalLysosomal enzymeenzyme deficiencydeficiency ƒƒ galactogalacto--sylceramidesylceramide betabeta--galactosidasegalactosidase MultipleMultiple mutationsmutations (chromosome(chromosome 14)14) Presentation:Presentation: 33--66 mos,mos, hypertonia,hypertonia, irritable,irritable, fever,fever, developmentaldevelopmental delay,delay, poorpoor feeding,feeding, opticoptic atrophy,atrophy, opsomyoclonusopsomyoclonus && hyperacusishyperacusis Dx:Dx: enzymeenzyme assayassay WBC/skinWBC/skin fibroblastsfibroblasts DeathDeath inin firstfirst fewfew yearsyears KrabbeKrabbe diseasedisease CTCT isis characteristic:characteristic: zz HyperdenseHyperdense thalami,thalami, hypodensehypodense deepdeep WMWM

Images from Barkovich JE. Pediatric neuroimaging and van der Knapp MR of Myelination and Myelin disorder KrabbeKrabbe diseasedisease MRMR imaging:imaging: zz NonspecificNonspecific abnormalabnormal deepdeep WMWM,, postpost limbslimbs internalinternal capsule,capsule, cerebellarcerebellar WMWM && nucleinuclei zz ThalamiThalami involvedinvolved laterlater zz CranialCranial nervenerve && caudacauda equinaequina enhancementenhancement zz DWIDWI –– earlyearly reducedreduced diffusion,diffusion, laterlater increasedincreased zz MRSMRS –– MostMost abnormalabnormal inin infants.infants. ElevatedElevated myomyo-- inositol,inositol, creatinecreatine (CR),(CR), reducedreduced NAA,NAA, +/+/-- lactate;lactate; z Juvenile - less severe MRS z Adult - mild decrease in NAA & mild elevations of Cr & myo-inositol KrabbeKrabbe diseasedisease MRI:MRI: T2T2 brightbright deepdeep WMWM cerebrumcerebrum && cerebellum,cerebellum, thalamusthalamus

Image from van der Knapp. MRI of myelin disorders KrabbeKrabbe diseasedisease DeepDeep cerebralcerebral ++ cerebellarcerebellar WMWM brightbright ++ sparedspared subcorticalsubcortical WMWM

Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC KrabbeKrabbe diseasedisease GMGM 11 gangliosidosisgangliosidosis

RareRare lysosomallysosomal disorderdisorder DeficientDeficient activityactivity ofof betabeta--galactosidasegalactosidase ChromosomeChromosome 33 ThreeThree forms:forms: Infantile,Infantile, childhood,childhood, adultadult InfantileInfantile -- mostmost commoncommon z Dysmorphic facial features, osseous dysplasias, hepatosplenomegaly, hypotonia, mental retardation early childhood (between 1-5 years), seizures, spasticity z Death in a few years ChildhoodChildhood && adultadult formsforms –– moremore slowlyslowly progressiveprogressive dysarthria,dysarthria, ataxia,ataxia, myoclonus,myoclonus, normalnormal facies,facies, nono hepatosplenomegalyhepatosplenomegaly GMGM 22 gangliosidosesgangliosidoses (Tay(Tay--SachsSachs && SandhoffSandhoff disease)disease)

Autosomal recessive sphingolipidosis Deficient hexosaminidase (2 parts) z Isoenzyme A – Tay Sachs disease z Isoenzyme A & B – Sandhoff disease Accumulation of GM2 ganglioside causes damage Clinical & imaging findings are similar for TSD & SD Presentation: z Infant with hypotonia, psychomotor retardation z Late first year - spasticity, weakness, dystonia, ataxia, then macrocephaly, abnormal movements, seizures z After 3-10 years severe dementia & bed ridden GM1GM1 &GM&GM 22 (Tay(Tay--SachsSachs && SandhoffSandhoff disease)disease) gangliosidosesgangliosidoses ImagingImaging nearlynearly identicalidentical forfor GM1GM1 && GM2GM2 CTCT–– earlyearly hyperdensehyperdense thalamithalami && hypodensehypodense WMWM,, latelate atrophyatrophy MRIMRI ––T2T2 brightbright periventricularperiventricular WMWM zz TayTay--Sacchs:Sacchs: PosteromedialPosteromedial thalamithalami T2T2 brightbright withwith reducedreduced diffusiondiffusion zz Sandoff:Sandoff: BasalBasal gangliaganglia isointenseisointense withwith WMWM LateLate stagestage atrophyatrophy cerebralcerebral andand cerebellarcerebellar hemisphereshemispheres GMGM 11 gangliosidosisgangliosidosis Imaging appearance: Nonspecific WM & same as GM2 CT- Hypodense WM, late atrophy MRI–T2 bright WM

Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC GMGM 22 (Tay(Tay--SachsSachs && SandhoffSandhoff disease)disease) gangliosidosesgangliosidoses

DiffuseDiffuse atrophyatrophy HypoattenuatedHypoattenuated WMWM HyperdenseHyperdense atrophicatrophic thalamithalami

Image courtesy of M Castillo, MD; UNC-Chapel Hill, NC ApproachApproach toto DEEPDEEP whitewhite mattermatter disordersdisorders NoNo THALAMICTHALAMIC involvement:involvement: IsIs therethere brainstembrainstem (corticospinal(corticospinal tract)tract) involvement?:involvement?: XX--linkedlinked adrenoleukodystrophyadrenoleukodystrophy ifif ponspons andand medullamedulla MapleMaple syrupsyrup urineurine diseasedisease ifif internalinternal capsule,capsule, cerebralcerebral pedunclepeduncle andand dorsaldorsal ponspons AdrenoleukodystrophyAdrenoleukodystrophy

RareRare peroxisomalperoxisomal disorderdisorder ChromosomeChromosome 2828 mutationmutation (300+(300+ mutations)mutations) AcylAcyl--CoACoA synthetase,synthetase, peroxisomalperoxisomal membranemembrane transporttransport proteinprotein (prevents(prevents longlong chainchain fattyfatty acidacid breakdown)breakdown) CNS,CNS, adrenal,adrenal, testestestes 22 mainmain forms:forms: z Classic X-linked type is most common z Adrenomyeloneuropathy – presents in adults with predominant brainstem & spinal cord disease RareRare neonatalneonatal form:form: AR,AR, multiplemultiple enzymeenzyme deficienciesdeficiencies ClassicClassic XX--linkedlinked ALDALD

BoysBoys 55 –– 1212 yearsyears oldold LearningLearning difficultiesdifficulties (ADHD),(ADHD), impariedimparied vision,vision, gaitgait oror hearing,hearing, abnormalabnormal pigmentationpigmentation skinskin (adrenal(adrenal insufficiency),insufficiency), 10%10% seizures,seizures, adrenaladrenal crisis,crisis, comacoma ProgressionProgression isis rapidrapid DDx:DDx: NoneNone withwith appropriateappropriate historyhistory z Acyl CoA oxidase deficiency – similar imaging, but history differs; 2 year old girls & boys delayed cognitive & motor development XX--linkedlinked ALDALD Imaging: Several characteristic patterns All have confluent symmetric deep WM with leading edge enhancement (inflammatory reaction) z Posterior - 80% z Anterior - 15% z Unilateral hemispheric – rarely z Restricted to internal capsules Pons & medulla CT – low density, MRI – T1 and T2 prolongation relaxation times, increased diffusion MRS (may be abnormal prior to visible changes on MRI) – decreased NAA, increased choline, glutamine/glutamate, decreased myo-inositol, +/- lactate XX--linkedlinked ALDALD Hx:Hx: 66--yearyear--oldold boyboy withwith SNHLSNHL Pons, medulla, posterior deep WM, leading edge enhancement

T2 T1 T1+Gd XX--linkedlinked ALDALD

PosteriorPosterior (85%)(85%) distributiondistribution isis mostmost commoncommon NoteNote 33 zoneszones:: BurnedBurned outout InflammatoryInflammatory DemyelinatingDemyelinating XX--linkedlinked ALDALD Hx:Hx: 1212 yearyear oldold malemale withwith ataxiaataxia && ADHDADHD AtypicalAtypical frontalfrontal distributiondistribution (15%)(15%) MRSMRS –– elevatedelevated glutamine/glutamateglutamine/glutamate && lactatelactate MapleMaple syrupsyrup urineurine diseasedisease (MSUD)(MSUD)

Rare,Rare, heterogenousheterogenous groupgroup ofof disordersdisorders withwith abnormalabnormal oxidativeoxidative decarboxylationdecarboxylation ofof branchedbranched chainchain fattyfatty acidsacids 55 clinicalclinical phenotypesphenotypes –– correlatecorrelate withwith degreedegree ofof enzymeenzyme activityactivity z Classic MSUD – present week of life 1 with vomiting, dystonia, seizures, and die in a few weeks without treatment z Other forms MSUD are less severe, present in later childhood with metabolic crisis MapleMaple syrupsyrup urineurine diseasedisease (MSUD)(MSUD)

Imaging classic MSUD: Sonography – echogenic periventricular WM, basal ganglia & thalami CT & MRI – very characteristic profound cerebral edema z Deep cerebellar WM, dorsal pons, cerebral peduncles, internal capsule, deep cerebral WM z Restricted diffusion, drop in ADC by 20-30% MRS – Mild elevation lactate, abnormal methyl proton peak at .9ppm on long echo (TE-270 ms) Imaging milder forms of MSUD: Lack of myelination superimposed on damage to areas listed in classical MSUD MapleMaple syrupsyrup urineurine diseasedisease T2 DWI ADC map Hx: 1 week old male vomiting & lethargy MRI: Restricted diffusion in the cerebellar WM, cerebral peduncles & dorsal pons MapleMaple syrupsyrup urineurine diseasedisease

MRS: Lactate peak and branched chain amino acid peak Cho NAA NAA

Cr Branched chain amino Lactate acids

Image from Barkovich JE. Pediatric neuroimaging, 4th ed. ApproachApproach toto DEEPDEEP whitewhite mattermatter disordersdisorders IsIs therethere isis brainstembrainstem (corticospinal(corticospinal tract)tract) involvement?:involvement?: 1.1. IfIf NONO,, consider:consider: MetachromaticMetachromatic leukodystrophyleukodystrophy PhenylketonuriaPhenylketonuria MucopolysaccharidosesMucopolysaccharidoses LoweLowe diseasedisease MerosinMerosin deficientdeficient muscularmuscular dystrophydystrophy RadiationRadiation oror chemotherapychemotherapy damagedamage MetachromaticMetachromatic leukodystrophyleukodystrophy

AutosomalAutosomal recessiverecessive LysosomalLysosomal disorderdisorder ArylsulfataseArylsulfatase (AS)(AS) deficiencydeficiency SulfatidesSulfatides accumulateaccumulate inin brain,brain, kidneys,kidneys, liver,liver, GB,GB, peripheralperipheral nervesnerves Dx:Dx: lowlow ASAS inin urineurine && peripheralperipheral bloodblood 33 types:types: infant,infant, juvenile,juvenile, adultadult zz InfantileInfantile formform isis mostmost commoncommon MetachromaticMetachromatic leukodystrophyleukodystrophy

InfantileInfantile form:form: 1212-- 1818 monthsmonths EarlyEarly motormotor signssigns ofof peripheralperipheral neuropathyneuropathy LaterLater decreasedecrease intelligence,intelligence, speech,speech, coordinationcoordination DeathDeath 66 monthmonth -- 44 yearsyears afterafter DXDX MetachromaticMetachromatic leukodystrophyleukodystrophy

Imaging:Imaging: DeepDeep WM,WM, symmetric,symmetric, confluentconfluent BrightBright onon T2;T2; nono enhancementenhancement SparesSpares subcorticalsubcortical WMWM earlyearly TigroidTigroid oror leopardleopard skinskin appearanceappearance duedue toto perivascularperivascular spacespace distensiondistension OtherOther sitessites ofof involvement:involvement: zz CorpusCorpus callosum,callosum, internalinternal capsule,capsule, corticospinalcorticospinal tracts,tracts, cerebellarcerebellar WMWM MetachromaticMetachromatic leukodystrophyleukodystrophy

Hx:Hx: 22--yearyear--oldold malemale withwith vomitingvomiting CT:CT: NonspecificNonspecific lowlow densitydensity ofof deepdeep WMWM MetachromaticMetachromatic leukodystrophyleukodystrophy

MRI:MRI: DeepDeep WM,WM, sparingsparing subcorticalsubcortical WMWM && nono leadingleading edgeedge ofof enhancementenhancement

T2 FLAIR T1+Gd MetachromaticMetachromatic leukodystrophyleukodystrophy

AdvancedAdvanced diseasedisease withwith ‘‘tigroidtigroid’’ appearanceappearance MucopolysaccharidosisMucopolysaccharidosis

GroupGroup ofof rarerare lysosomallysosomal enzymeenzyme deficiencydeficiency disordersdisorders AllAll involveinvolve metabolismmetabolism ofof glycosaminoglycansglycosaminoglycans Imaging:Imaging: DelayedDelayed myelination,myelination, atrophy,atrophy, hydrocephalus,hydrocephalus, cystscysts inin periventricularperiventricular WM,WM, corpuscorpus callosum,callosum, basalbasal gangliaganglia Presentation,Presentation, prognosisprognosis dependdepend onon specificspecific disorderdisorder HurlerHurler diseasedisease isis mostmost commoncommon MucopolysaccharidosisMucopolysaccharidosis

HxHx:: 1515--monthmonth--oldold malemale withwith HurlerHurler syndromesyndrome MRIMRI:: T2T2 deepdeep WMWM brightbright signalsignal,, distendeddistended perivascularperivascular spacesspaces givegive MucopolysaccharidosisMucopolysaccharidosis

CystsCysts -- perivascularperivascular spacesspaces && corpuscorpus callosumcallosum MucopolysaccharidosesMucopolysaccharidoses InferiorInferior beakbeak ofof spinespine

CystsCysts -- perivascularperivascular spacesspaces && corpuscorpus callosumcallosum OculocerebrorenalOculocerebrorenal syndromesyndrome (Lowe(Lowe disease)disease) XX linked,linked, autosomalautosomal recessiverecessive PhosphatidylinositolPhosphatidylinositol--4,54,5--biphosphatebiphosphate--55 phosphatasephosphatase enzymeenzyme anomalyanomaly InvolvesInvolves brain,brain, lens,lens, kidneyskidneys ClinicalClinical findings:findings: z Congenital cataracts z Glaucoma z Mental retardation z Renal tubular dysfunction (Fanconi syndrome) z Metabolic bone disease OculocerebrorenalOculocerebrorenal syndromesyndrome (Lowe(Lowe disease)disease)

ImagingImaging findingsfindings cancan bebe distinctdistinct:: Bilateral,Bilateral, symmetricalsymmetrical deepdeep WMWM lowlow densitydensity onon CT,CT, withwith T1T1 andand T2T2 shorteningshortening onon MRIMRI CysticCystic areasareas withinwithin abnormalabnormal WMWM SparingSparing subcorticalsubcortical UU fibersfibers MRS:MRS: SomeSome casescases elevationelevation ofof myomyo-- inositolinositol peakpeak duedue toto gliosisgliosis oror enzymeenzyme accumulationaccumulation LoweLowe diseasedisease CT:CT: NonspecificNonspecific hypodensehypodense deepdeep WMWM MRI:MRI: DeepDeep WMWM brightbright onon T2T2 earlyearly

Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC LoweLowe diseasedisease

CongenitalCongenital cataractscataracts WMWM cystscysts onon T1T1

Orbit images courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC Image from Barkovich JE. Pediatric Neuroimaging, 4th ed. CongenitalCongenital muscularmuscular dystrophiesdystrophies

HeterogeneousHeterogeneous inheritedinherited groupgroup ofof disorderdisorder resultingresulting fromfrom mutationmutation ofof laminalamina--alphaalpha--22 genegene onon chromosomechromosome 66 Presentation:Presentation: HypotoniaHypotonia && weaknessweakness fromfrom birth,birth, possiblypossibly arthrogyroposis,arthrogyroposis, diminisheddiminished deepdeep tendontendon reflexes,reflexes, normalnormal intelligenceintelligence ModerateModerate elevationelevation ofof serumserum creatinecreatine kinasekinase CongenitalCongenital muscularmuscular dystrophiesdystrophies

MajorMajor typestypes (according(according toto vanvan derder Knapp):Knapp): FukuyamaFukuyama congenitalcongenital muscularmuscular dystrophydystrophy ƒ Associated cortical dysplasia WalkerWalker--WarburgWarburg syndromesyndrome ƒ Associated cortical dysplasia MuscleMuscle eyeeye brainbrain syndromesyndrome MerosinMerosin deficientdeficient congenitalcongenital muscularmuscular dystrophydystrophy (classic(classic form)form) MDC1CMDC1C –– brainbrain mostlymostly normalnormal MDC1DMDC1D –– brainbrain notnot normalnormal FukuyamaFukuyama congenitalcongenital muscularmuscular dystrophydystrophy JapaneseJapanese AutosomalAutosomal recessiverecessive Onset:Onset: infantileinfantile markedmarked hypotonia,hypotonia, manymany ocularocular anomaliesanomalies ImagingImaging (findings(findings areare notnot specific):specific): ƒƒ DiffuseDiffuse corticalcortical dysplasiadysplasia ƒƒ CerebellarCerebellar corticalcortical dysplasiadysplasia && subcorticalsubcortical cystscysts ƒƒ WMWM abnormalabnormal signalsignal ƒƒ PonsPons hypoplasiahypoplasia FukuyamaFukuyama congenitalcongenital muscularmuscular dystrophydystrophy 55--monthmonth--oldold JapaneseJapanese femalefemale CorticalCortical dysplasia,dysplasia, WMWM abnormalabnormal

T1 T2 T2 MerosinMerosin deficientdeficient muscularmuscular dystrophydystrophy 33 typestypes ofof congenitalcongenital muscularmuscular dystrophydystrophy (according(according toto Barkovich)Barkovich):: 1. Children with normal brains 2. Children with CNS symptoms, abnormal myelin & normal cortex 3. Children with CNS symptoms, abnormal myelin & cortical involvement Imaging:Imaging: DelayedDelayed oror hypomyelinatedhypomyelinated deepdeep cerebralcerebral WM,WM, withwith mildmild pontinepontine && cerebellarcerebellar hypoplasiahypoplasia DxDx:: musclemuscle biopsy,biopsy, MRIMRI && clinicalclinical evaluationevaluation MerosinMerosin deficientdeficient (classical)(classical) congenitalcongenital muscularmuscular dystrophydystrophy NonspecificNonspecific deepdeep WMWM brightbright onon T2T2

T2 T2 CongenitalCongenital muscularmuscular dystrophydystrophy withoutwithout merosinmerosin deficiencydeficiency CT: Nonspecific deep WM & generalized atrophy MRI: Lack of myelination without WM destruction MRS: Controversial

T2 FLAIR FLAIR

Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC ConclusionConclusion

WhiteWhite mattermatter disordersdisorders inin childrenchildren areare complex,complex, butbut anan organizedorganized approachapproach cancan allowallow formulationformulation ofof aa narrownarrow differentialdifferential diagnosisdiagnosis