Neurometabolic Disorders

DavidSweetser,MD,PhDChiefofMedicalGeneticsandMetabolism

MassGeneralHospitalfor Children

Sept. 5, 2017

Disclosures

• None

Acknowledgement – Neela Sahai, MD

LearningObjectives

• Cluesyouaredealingwithametabolicdisorder

• Hallmarksofthemajorclassesofmetabolicdisorders

• Diagnosticandtreatmentstrategies

Importance

• Rare,butinaggregatesignificantburdenofpediatricmorbidity

• Timelyinstitutionofspecifictreatmentsmaypreventpermanentneurologicalimpairment

• Familialimplications

InbornErrorsofMetabolism

ØSinglegenedefectsØDefectsinanenzymeortransportproteinØAbnormalitiesinthesynthesisorcatabolismofproteins,carbohydrates,fats,orcomplexmolecules.

ØIndividuallyrarebutcollectivelynumerous

NeurologicalManifestations

ØDevelopmentaldelayØVisual/auditorylossØAtaxia,Encephalopathies,myelopathies,neuropathies,seizures,braindysgenesis…..

ØAdultonset– psychiatric,aggression,mood/behavioraldisorders

ØNeuroimagingoftenhelpful

Common in IEM, may be only manifestation

ImagingFindingsinIEM

* - macrocephaly, ** enhancementAmerican Journal of Roentgenology. 2014;203: W315-W327

ChallengesinDiagnosis

• Commonnon-specificsymptoms– Poorfeeding– hypotonia– Sepsis– Vomitinganddehydration– Developmentaldelay,behavioralproblems– Seizures

• ClinicalHeterogeneity– Symptoms,onset,progression

CluestoDiagnosis

• Prioraffected/abnormal/lostchild• Parentalconsanguinity• Developmentalregressionorplateau• Body/urineodor,micro/macrocephaly,Sz• Dysmorphology,“coarsefeatures”• Hepatomegaly,skeletalanomalies• Episodicdecompensations

ClinicalPresentations

ØAcutesymptomsinneonatalperiodØIntermittent/RecurrentsymptomsØLater-onsetacutesymptomsØChronicandprogressivenonspecificsymptoms

ØSpecificandpermanentsymptoms

NeonatalPresentation

• Fulltermnormalnewbornthatdeteriorateswithoutapparentclinicalcause– Seizures– Feedingdifficulties– Hypotonia– Lethargy– Vomiting/dehydration– Respiratorydistress

JuvenileOnset

• Episodicdecompensations– Withcatabolism,intakespecificfood(protein)– Withfever,exercise

• Symptoms– Poorfeeding,vomiting,lethargy,Sz,MS∆– Metabolic– acidosis,hypoglycemia,hyperammonemia

– Ataxia– Death

Chronicprogressive

• Lossofmotor,cognitive,speechabilities• Systemicfindings

– Skeletal,HSM,ophthalmologic(retina,lens)• Coarsefeatures• Newonsetseizures,spasticity,hyperreflexia,ataxis

ClinicalAssociations• Psychosis/catatonia– Ureacycledisorders,Neimann PickTypeC,

acuteintermittentporphyria,hereditarycoporphyria,homocystinuria,TaySachs,Wilsons

• Peripheralneuropathy– Fabrydisease,porphyria,Vit (B12,E,B1)def,POLG1,mitochondrialDOs

• Neutropenia – organicacidurias,GSDIb

• Macrocephaly– Glutaric aciduriaTypeI(+ICH),D-2-hydroxyglutaricaciduria,Canavandisease,Alexander,Megalencephalic leukodystrophy

• Progressiveexternalophthalmoplegia- ANT1,Twinkle, POLG1,myotonicdystrophy,SCA,MNGIE

METABOLIC PATHWAYS

Pathophysiology

ØToxicaccumulationofmetabolites

ØImpairedenergyproduction/utilization

ØDecreasedsynthesisorcatabolismofcomplexmolecules

ToxicMetabolites

• Aminoacid(MSUD,PKU)• Organicacidurias(MMA,PA,IVA)• Carbohydrate(galactosemia,fructoseintolerance)

• Cholesterol(SmithLemli Opitz,NiemannPickTypeC)

• Copper(Menkes,Wilsons)• Neurotransmitters(tetrahydrobiopterindef)

ToxicMetabolites- Features

• Usuallynotdysmorphic• Intervalswithoutsymptoms• Acute,episodic,orchronicdecompensation• Triggers– ingestions,illness,fasting

• DX– labtesting• Rx– preventcatabolism,diet,clearance

NewbornScreening- PKU

PKU

• SevereID• Postnatalmicrocephaly• BehavioralDO,ASDs• Seizures• Rashes• Decreasedpigmentation• Odor– “mousy”,“musty”

(phenyllactate,phenylpyruvate)

phenylalanine

tyrosine

Phenylalaninehydroxylase

BH4

High signal intensity in white matter regions around anterior and posterior horns of both lateral ventriclesand brain atrophy in phenylketonuria

Iran J Child Neurol. 2015 Winter; 9(1): 1–16.

PKU

http://www.ncbi.nlm.nih.gov/books/NBK55827/

Specific Therapy Guidelines

Confirmation testing

Glucose Fatty Acids

Urea

Urea Cycle

Ammonia TCA Cycle

PyruvateAcetyl CoA

RespiratoryChain

ATP

Amino Acids

Organic Acids

OrganicAcidDisorders

ØMetabolicabnormalitiesØ Systemicinvolvement(includingneurological)

“CLASSICAL/TYPICAL”

“CEREBRAL”

ØMetabolicderangementabsentØ Exclusivelyneurological

•Propionic Acidemia•Methylmalonic Acidemia (+Cbl A,B,C def)

•Isovaleric Acidemia•Multiple Carboxylase Deficiency•Multiple Co-A Dehydrogenase Deficiency (Glutaric Acidemia,Type 2)•Maple Syrup Urine Disease

•Glutaric Acidemia-I

•N-acetylaspartic Deficiency

•Succinic Semialdehyde Dehydrogenase Deficiency

•L-2 hydroxyglutaric Aciduria

CatabolismofBranchedChainAminoAcidsLeucine Isoleucine Valine

2-oxoisovaleric acid2-oxocaproic acid 2-oxo-3-methyl-valeric acid

2-methylbutyryl-CoA Isobutryl-CoAIsovaleryl-CoA

3 methylcrotonyl-CoA2-methyl-acetoacetyl-CoA

3-hydroxy 3-methyl-glutaryl-CoA

3-hydroxy isobutyric acid

Acetoacetate Acetyl-CoA

3-methylmalonic semialdehyde

Propionyl-CoA

Methylmalonyl-CoA Succinyl-CoA

MSUD

IVA

PAMMA

AcutePresentation

ØPoorfeedingØVomitingØLethargy/ChangeinneurologicalstatusØRespiratorydistressØAbnormalmuscletoneØSeizures

AgeofOnset&SeverityVariable

GeneralLaboratoryFindings

ØMetabolicacidosiswithincreasedaniongapØKetosisØHyperammonemiaØHypoglycemiaØNeutropeniaØThrombocytopeniaØElevatedamylase/lipase

ØUrineorganicacidanalysisbyGC/MSØPlasmaaminoacidanalysis

• Elevatedglycine• BranchedchainaminoacidsincreasedinMSUD• Otherwise,typicallynormal

ØPlasmaacylcarnitineprofileØUrinaryacylglycine profile

DiagnosticTesting

Non-AcutePresentationØDevelopmentaldelays+/- SeizuresØFailuretothriveØChronicvomitingØHypotoniaØRecurrentinfectionsØRecurrentpancreatitisØCardiomyopathy (especiallyPA)ØRenalDiseaseØOdors(SweatyFeetinIVA,MADD;BurntSugarinMSUD)

NeurologicalComplications

ØMetabolic“stroke”(acuteorprogressiveextrapyramidal symptoms):MMA,PA,IVA

ØOpticatrophyandretinitis:MMA,PAEvidencesuggestsopticatrophyandstroke(andcardiomyopathy)duetosecondarydefectsinrespiratorychain.

Delayed Brain Maturation

Myelination delay, Immature gyral pattern, Incomplete opercularization, Hypoplastic corpus callosum cerebellar vermis

Basal Ganglia Lesions

PallidumPutamenCaudate

Irreversible volume loss (predominantly supratentorial atrophy).

Progressive White MatterChanges

Neuroimaging

Brainstem and Cerebellar Changes

Imaging:AcutePresentation

MRI of MMA patient aged 20 daysBilateral lesions of the pallidum with swelling and restricted diffusion as the most prominent finding

J Inherit Metab Dis (2008) 31:368–378

MRI at age 12 months: D. Severely delayed myelinationE. The pallidum appears slightly T2 hyperintense, but this is not definitely abnormal at a maturation stage of 6 months F. Sagittal images demonstrate a thinned corpus callosum dorsally and a wide foramen of Magendi , the latter apparently due to slight volume reduction of the inferior vermis.

Neuro-Imaging

I Harting et al. Looking beyond the basal ganglia: The spectrum of MRI changes in methylmalonic acidaemia. J Inherit Metab Dis (2008) 31:368–378

Imaging:PropionicAcidemia

Abnormal Signal in Bilateral Basal Ganglia and Brain Atrophy in an MRI from a 4-year-old boy with propionic-acidemia

Iran J Child Neurol. 2015 Winter; 9(1): 1–16.

ØPresymptomatic treatment• DietaryTreatment:Reduceintakeofoffendingaminoacids

viarestrictionofnaturalproteinwhilemaintainingasufficientintakeofessentialnutrientsandenergysubstrates)

• Aminoacidsupplements• Carnitine• CofactorsØEarlyaggressivetreatmentofintercurrentillness

ØManagementofmetaboliccrisisØTreatmentofmanifestations

Treatment

“Cerebral”OrganicAcidDisorders

ØMetabolicabnormalitiesgenerallyabsentØ Elevationofdiagnosticmetabolites(organicacids)maybeslight.

Ø Progressiveneurologicalsymptoms•Epilepsy•Macrocephaly •Metabolicstroke•Extrapyramidal symptoms•Ataxia•Myoclonus

Ø Progressivefindingsonneuro-imaging•Disturbancesofmyelination•Cerebellar atrophy•Frontotemporal atrophy•Hypodensities/infarctsofbasalganglia•Symmetricalpathologyapparentlyindependentofvascularsupply.

Glutaric Aciduria-TypeIØMacrocephaly atbirth(~50%)Ø Softneurologicalfindings:HypotoniaØAcuteencephalopathic crisisat3–18months

• Often butnotalwaysprecipitatedbyintercurrent illness• Rapid(24-48hrs)lossofneuronsincaudateandputamen• Subsequentdystonia,choreoathetosis,significantmotordisabilities

• Cognitiveabilitiesareoftenpreservedtilllateincourse

Ø Episodesmayberecurrent,butdisabilitymostoftenduetoasingleepisodeofacutestriatal necrosis

Ø ClinicalSpectrum:Developmentaldelaysfrombirthtoasymptomaticcase

A,B.FrontotemporalatrophyC.HighsignalintensitiesincaudateandputamenD.EdemawithacuteepisodeE.Eventualatrophycaudate,putamenF.Subduralhygromas,hemorrhages

Am J Med Genet C Semin Med Genet. 2006 May 15; 142C(2): 86–94.

MRIFindings:GA-I

GlutaricAciduria-TypeI

Acetyl CoA

Lysine Tyrptophan

Crotonyl CoA

Glutaryl CoA

FAD

FAD- 2H

ØDiagnosis:• UOA- Glutaric&3-hydroxyglutaricacids• Plasmaacylcarnitines- Glutarylcarnitine (C5DC)*• EnzymeandGCDHgeneanalysis

Ø Pathogenesis:• StriataltoxicityofGA• Metabolitesactasglutamateanalogsatthe

NMDAreceptorsandGlutamatereceptors• InhibitionofGABAsynthesis• Mitochondrialtoxicity

Glutaryl CoAdehydrogenase

*Note – low excretors missed on NBS

ØPresymptomatic treatmenttopreventencephalopathic crisis&neurologicalsymptoms

• DietaryTreatment:ReduceLysineintakeviarestrictionofnaturalproteinwhilemaintainingasufficientintakeofessentialnutrientsandenergysubstrates)

• Lysinefreeaminoacidsupplements• Carnitine• Riboflavin:InriboflavinresponsivecasesØEarlyaggressivetreatmentofintercurrentillness(especiallybeforeage6years)

GA- ITreatment

Ø Baclofen &diazepamasfirstlinetreatmentfordystonia.

Ø Intrathecal baclofen forseveredystonia/spasticity.Ø Trihexyphenidyl assecond-linetreatmentfordystonia.

Ø Botulinum toxinasadditionaltherapyforseverefocaldystonia.

Ø AvoidAntiepileptics,L-dopaandamantadine forthetherapyofmovementdisordersinGA-I.

Ø Long-termbenefitofdystonic patientsfrompallidotomy isuncertain

ØAvoidValproate

GA- I:TreatmentofNeurologicalComplications

CanavanDisease

ØMacrocephaly,Hypotonia,DevelopmentalDelays:Apparentby3-monthsofage.

Ø Severemotordelays.ØWithagehypotoniagiveswaytospasticity.ØOpticatrophymaybepresent.NohearinglossØ Seizures,SleepdisturbancesØ Variablelifeexpectancy;usuallyintoteens.Ø ClinicalSpectrum:Mildformexists

CanavanDisease:MRS

markedly increased level of N-acetylaspartic acid (NAA)

Iran J Child Neurol. 2015 Winter; 9(1): 1–16.

ØDiagnosis:• Urine-IncreasedN-acetylaspartate• EnzymeandASPAgeneanalysis

Ø Pathogenesis:• Deficiencyofacetateresultinginimpairedoligodendrocyte maturationand

myelination• OxidativestressinducedbyNAA• ExcitationofNMDAreceptorsandGlutamatereceptors• ExcessNAAimpairsosmoticbalance

Canavan Disease

N-acetylaspartate

Acetate Aspartic Acid

Aspartoacylase

Canavan Disease:TreatmentØPrimarilysupportive,trialsexistØ Glyceryltriacetate (4.5g/kg/d)1:• 2infants;Ages8months&1yr;treatedfor4.5&6monthsrespectively.• Nosignificantsideeffects/toxicityobserved• Nomotorimprovement. (earliertreatment??)Ø LithiumCitrate(45mg/kg/day)2:• 6infants;Meanage9.5monthstreatedfor6weeks.• Nosignificantsideeffects/toxicityobserved.• ModestdropinNAA• Alertnessimprovedbutnomotorimprovement(onGMFT).(stabilized?)• Imaging:DTIimages(n=2)acrossCCsuggestedmicro-structural

improvement.ModestdropinT1relaxationtimesonselectedbrainareas(CCandFWM)

Ø LipoicAcid(antioxidant)

1. Segal R et al. A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab. 2011 Jul;103(3):203-6.2.Assadi M et al. Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease.Eur J Paediatr Neurol. 2010 Jul;14(4):354-9.

SuccinicSemialdehyde DehydrogenaseDeficiency

Ø PsychomotorretardationØHypotoniaØ AtaxiaØ Seizures(~50%)ØHyperkinetic,aggressiveandself-injuriousbehaviorØ HallucinationsØ SleepdisturbancesØ Basalgangliasigns(choreoathetosis,dystonia &myoclonus)infew

Glutamate

GABA

Succinic Semialdehyde

Succinate

TCA Cycle

Succinic semialdehyde dehydrogenase

gamma-hydroxybutyrate

Glutamic acid decarboxylase

GABA transaminaseSSAreductase

GHB dehydrogenase

Succinic Semialdehyde DehydrogenaseDeficiency

DiagnosticLaboratoryInvestigations

UrinaryOrganicAcids:Elevated4-hydroxybutyrate*Enzyme(Leucocytes)andALDH5A1 geneanalysis

PathogenesisDownregulationofGABAReceptors

*Volatile – may be missed on UOA (CSF)

MRI Findings Succinic SemialdehydeDehydrogenase Deficiency.

P. L. Pearl et al. Neurology 2003;60:1413-1417

©2003 by Lippincott Williams & Wilkins

T2hyperintensitiesGlobuspallidi (43%)Cerebellardentatenucleus(17%)Subcorticalwhitematter(7%)Brainstem(7%)

Alsocerebralor/andcerebellaratrophy,anddelayedmyelination.

ØManagement of manifestations• Antiepileptics: o Carbamazepine & Lamotrigineo Vigabatrin (irreversible inhibitor of GABA-transaminase)-

Inconsistent results.o Avoid Valproate• Neurobehavioral: Methylphenidate, thioridazine,

risperidal, fluoxetine, and benzodiazepines.

SuccinicSemialdehyde DehydrogenaseDeficiency:Treatment

ØUnder Investigation • Taurine, rapamycin, SGS-742 GABA-B R antagonist

Seizures

•Non ketotic hyperglycinemia •Sulfite Oxidase Deficiency

UREACYCLEDISORDERS

NONKETOTICHYPERGLYCINEMIA

SULFITEOXIDASEDEFICIENCYHOMOCYSTINURIA

PHENYLKETONURIA

AminoAcidDisordersNeonatal Period

•Urea Cycle Defects•Non ketotic hyperglycinemia •Sulfite Oxidase Deficiency

Acute Ataxia

•Urea Cycle Defects (ASA, OTC)

Thromboembolic Events

• Homocystinuria

•Serine Deficiency

Only few examples shown here

UreaCycleDisordersGlutamineAlanineGlycineAspartateGlutamate

Ammonia

Carbamoylphosphate

Nitrogen Pool

Citrulline

Citrulline

Ornithine

Ornithine

Argininosuccinate Arginine

Fumarate

Urea

Nacetylglutamate

Aspartate

Carbamoylphosphate synthetase

N acetylglutamate synthetase

Ornithine transcarboxylase

Argininosuccinic synthetase

Argininosuccinic lyase

Arginase

Mitochondria

Cytosol

NAGS

CPS

OTC

ASS

ASL

UreaCycleDisordersGlutamineAlanineGlycineAspartateGlutamate

Ammonia

Carbamoylphosphate

Nitrogen Pool

Citrulline

Citrulline

Ornithine

Ornithine

Argininosuccinicate Arginine

Fumarate

Urea

Nacetylglutamate

Aspartate

Carbamoylphosphate synthetase

N acetylglutamate synthetase

Ornithine transcarboxylase

Argininosuccinic synthetase

Argininosuccinic lyase

Arginase

Mitochondria

Cytosol

NAGS

CPS

OTC

ASS

ASL

Hippurate

+PhenylbutyratePhenylacetylglutamine

Orotic Acid

AcutePresentation

ØHyperammonemic EncephalopathyØ RareinArginase DeficiencyØHyperventilationisanearlyfindingØ Inmilderformstriggeredbystress/illnessØOutcomesdependonseverityanddurationofhyperammonemia

ØDamageresembleshypoxic-ischemiceventsorstroke.Lacunar infarctsandwhitematterdisruptionarecommonfindings

UreaCycleDefects

ØNAGS:SimilartoCPS

ØCPS:Consideredmostsevere;Noorotic acid.Ø OTC:Xlinked.15%O + hyperammonemia

ØASS(CITI)ØASL(ASA):Trichorrhexis nodosa.Hepaticenlargementandfibrosis.

ØARG:Acutepresentationuncommon.Pogressivespasticitymostcommonpresentation.Alsotremor,ataxia,andchoreoathetosis

Diagnosis

ØAmmoniaØElectroloytes &BloodGasesØPlasmaAminoAcidsØUrinaryOrotic AcidØMolecularTesting

TreatmentØTreatmentofAcuteHyperammonemia• IVNitrogenScavengerDrugs• Hemodialysis• SupplementationwithArginine,Citrulline&Carbamyl

glutamate(dependingondisorder)

ØLongTermManagement:• Dietaryrestrictionofprotein• Useofspecializedformulas• Oralnitrogen-scavengingdrugs.• SupplementationwithArginine,Citrulline&Carbamyl

glutamate• AvoidanceofValproic acid,Prolongedfastingorstarvation,

Intravenoussteroids,Largebolusesofproteinoraminoacids.

§ Progressivelethargy§ Hypotonia§Myoclonic Jerks§ Apnea

SEVERE

MILD

§ Hypotonia§ Delays§ Seizures

NEONATAL

INFANTILE

80%

20%

50%

§Limiteddevelopment(DQ<20).§Intractableseizures§Progressivespasticity§Swallowingdysfunction

§ DQ(20-60).§Seizures§Limitedspasticity§Hyperactive§Choreic movements

Non-Ketotic Hyperglycinemia(GlycineEncephalopathy)

§Brain malformations (Thinning/agenesis of the corpus callosum)§ Delayed myelination § Atrophy § High-signal lesions in white matter consistent with vacuolating myelin. § Abnormal glycine peak by proton MRS

Kanekar and Byler. Metab Brain Dis (2013) 28:717–720

Axial diffusion-weighted MR images in 4 day-old neonate presenting with encephalopathy and respiratory failure.(a) and (b) restricted diffusion in posterior limbs of the internal capsules (arrows). (c)Axial T2weighted image at the same level shows no signal abnormality. (d, e) Axial diffusion weighted MR images of pons show restricted diffusion in the dorsal midbrain and pons

Non-Ketotic Hyperglycinemia(GlycineEncephalopathy)

Glycine

CO2

Ammonia

P H

L

T

THF

CH2-THF

FAD

FADH2

CH2-NH3

H

Fe-SNFU1

Non-Ketotic Hyperglycinemia(GlycineEncephalopathy)

Pathogenesis:NMDAReceptorOverstimulation

GlycineCleavageComplex

Glycine

CO2

Ammonia

P H

L

T

THF

5,10 methyleneTHF

NAD

NADH + H+

CH2-NH3

H

GlycineCleavageComplex

Gene: GLDC

Gene : AMT

Gene : GCHS

Glycine

SLC6A9Fe-SNFU1

Ø ElevatedGlycineinPlasma,Urine,CSFØ ElevatedCSF/GlycineRatioØ ElevationofCSFonlywithSLC6A9

Marker NeonatalForm AtypicalForm NormalsCSFglycineconcentration >80µmol/L >30µmol/L <20µmol/L

Plasmaglycineconcentration Varies Varies 125-450CSF/plasmaglycineratio >0.08 0.04-0.2 <0.02

ØMolecularGeneticTesting(GLDC,AMT,GCSH,NFU1,SLC6A9)ØActivityofGlycineCleavageSystem(80mglivertissue)Ø 13C-glycine Breath Test

Non-Ketotic Hyperglycinemia(GlycineEncephalopathy)Diagnosis

ØBenzoate(Sodium)250-750mg/kg/dayØN-methyl-D-aspartate receptorantagonists(Ketamine,Felbamate &Dextromethorphan)

ØManagementofmanifestationsØAvoidValproate

Non-Ketotic Hyperglycinemia:Treatment

Molybdenumcofactordeficiency

MbmolybdopterinSulfateoxidase xanthineoxidase

Xanthine,hypoxanthine

Uricacid

CysteineSulfites

Sulfurdioxide

Sulfate+2e-

Sulfateoxidasedeficiency Xanthineoxidasedeficiency

Genes– MOCS1,MOSC2,GPHN

Intractableseizures,infantilespasmsDysmorphicfeatures

ProgressiveencephalopathyLensdislocationEczematousrashHyperekplexia

Xanthinuria,lowuricacidArthropathy,myopathy

nephropathy,renalfailure

Molybdenumcofactordeficiency

Managementandtreatment

• Antiepileptic's• Dietslowinsulfurcontainingaminoacidsalongwithsulfate

supplementationhavepositivebiochemicalresponsesbutnolastingneurologicalimprovement.

MoCo typeAdef – RX(cPMP),aprecursortoMoCo.stoppedSz,neurotoxicity– noreversal

GenetictherapywithaMOCS1 - futureRx?

Impairedenergyproduction/utilization

• Mitochondrialrespiratorychain• Krebscycledisorders– PDHD,pyruvatecarboxylase

• Fattyacidoxidationdefects• Defectsingluconeogenesisorglycogenosis

MitochondrialDisorders• MELAS– mitochondrialencehpalopathy,lacticacidosis,and

stroke-likeepisodes)• MERRF– myoclonicepilepsyandraggedredfibers• LHON- Leber hereditaryopticneuropathy• KSS– Kearns-Sayresyndrome• CPEO– chronicprogressiveexternalophthalmoplegia• POLG1– relateddisorders• MNGIE– mitochondrialneurogastrointestinal

encephalomyopathy• PrimarycoenzymeQ10deficiency

Features• Multiplesystemsaffected

– Muscle,brain,heart,endocrine– CNSencephalopathy,Sz,dementia,stroke-likeepisodes,ataxia,spasticity,deafness,ptosis,opticatrophy,retinopathy

• Hypoglycemia,metacidosis,hypotonia,FTT• Inheritance– maternal(mito),AD,AR(nuclear)

• DX- labs,biopsies,genetictesting• RX– avoidcatabolism,vitamins,supplements

POLG1– relateddisorders• NuclearencodedDNApolymerasesubunitgene• Spectrumofphenotypes• Similarwithinafamily• Multisystemic – NOTdiabetesorcardiomyopathy

– Psychiatric,Sz,extrapyramidalsymptoms,cerebellar

– Migraines,stroke-likeepisodes,SNHL,– retinopathy,ptosis,ophthalmoplegia,Cataracts,corticalvisualloss

– peripheralneuropathy,DM,ovarian/testicularfailure,liverfailure,GIdysmotility,CM

RX• AVOIDValproic acidàliverfailure• Supportivecare

– Levodopaforextrapyramidalsymptoms

• Alpers-Huttenlocher syndrome• Childhoodmyocerebrohepatic syndrome• Myoclonicepilepsymyopathysensoryataxia• Ataxianeuropathyspectrum• AR/ADprogressiveexternalophthalmoplegia

MNGIE(mitochondrialneurogastrointestinal encephalomyopathy)

• Thymidinephosphorylasedeficiency– Phosphorylatesthymidine,deoxyuridine– Pyrimidinesalvage– criticalformtDNA– mtDNA deletions,mutations,depletionovertime

• Symptoms(meanonset18yo,asearlyas5mo)– SevereGIdysmotility(pseudoobstruction)– Cachexia– Ptosis/ophthalmoplegia,SNHL– Peripheralsensorimotorneuropathy(paresthesias,pain,footdrop)– Asymptomaticleukoencephalopathy

• DX– Enzymeassay(Columbia),genesequencing

MNGIE(mitochondrialneurogastrointestinal encephalomyopathy)

• DX– Enzymeassay(Columbia),genesequencing

• RX– Supportive

• GI– nutritionalsupport,attentiontoswallowingdifficultiesandairwayprotection,Rxbacterialovergrowth

• Neuropathy- amitriptyline,nortriptyline,andgabapentin• PT,OT• Protectliver– TPN,carewithmedsmetabolizedbyliver• Avoidmito toxicmeds– valproate,phenytoin,Tc,metformin,trazadone

Decreasedsynthesisorcatabolismofcomplexmolecules

• Lysosomal&peroxisomal disorders• Congenitaldisordersofglycosylation• Defectsincholesterolsynthesis

– SmithLemli Opitz,C-4steroldethylase

• intracellulartrafficking– NiemannPickC

Features• Oftendysmorphic• Multi-systemic,progressive

– CentralandperipheralNSinvolvement,coarsefeatures,HSM

• Notriggers

• DX– labs,genetictesting• RX– limited,someenzymereplacements,BMT

Alexandra Garza Flores, MD

CKPlasma amino acidsUrine organic acidsCHO def transferrin

NeonatalSeizures

Etiologieshypoxic-ischemia

MeningitisHemorrhage/stroke

TraumaMalformationHypoxemia

HypocalcemiaMetabolic

Intoxication• MSUD,MMA,PA,IVA,ureacycle• Initialsymptomfreeperiod

• Sz,Poorfeeding,lethargy,respiratorydistress• HighAGmetabolicacidosis,ketosis,↑NH3

PrimaryEnergyMetabolicDefectsPyruvatemetabolism,mitochondrial

• Sz,hypotonia,poorfeed,lacticacidosis• Liverdisease,cardiomyopathy,cataracts,hearingloss,

renaltubulardefects

Peroxisomal defectsSz,hypotonia,dysmorphicfeatures,cholestasis,renalcysts,ocularabnormalities,hearingloss

C.Ficicioglu,D.Bearden/PediatricNeurology45(2011)283e291

CongenitaldisordersofGlycosylationSz,FTT,DevDelay,hepatopathy,proteinlosingenteropathy,hypoglycemia,hypotonia,immunological,skin,skeletalabnl

IsolatedNeonatalSeizures• pyridoxine-dependentseizures• folinic acid-responsiveseizures• nonketotic hyperglycinemia• sulfiteoxidasedeficiency,• molybdenumcofactordeficiency• glucosetransportertype1deficiency• 4-aminobutyrateaminotransferase(g-aminobutyricacid• transferase)deficiency• congenitalneuronalceroid-lipofuscinosis• dihydropyrimidine dehydrogenasedeficiency,creatinedeficiency• syndromes,anddefectsofserinebiogenesis

NOTDETECTEDONNEWBORNSCREEN

C.Ficicioglu,D.Bearden/PediatricNeurology45(2011)283e291

IsolatedNeonatalSeizures

C. Ficicioglu, D. Bearden / Pediatric Neurology 45 (2011) 283e291

TreatableCausesofIsolatedNeonatalSeizures

NeonatalSeizureWork-up

CBC/diff,Urinalysis,bloodglucoseElectrolytes,VBG,Ca,P,Mg,LFT,NH3BloodCSFcultures,newbornscreen,EEG

CSFanalysis– glucose(+serum)AA,L/P,CSFneurotransmitters

Urineorganicacids,plasmaaminoacidsPlasmaacylcarnitine,lactate/pyruvate,VLCFAMRI/MRS

Homocysteine,uricacidUrinepurine/pyrimidine,thiosulfateUrine/serumguandidinoacetate/creatineUrinecreatine/creatinineCarbohydratedef transferrin,N-/O-glycans?Genetictesting– infantileepilepsypanel

Forrefractory/undiagnosedSeizures

Initialevaluation

CSFSTUDIES

FINALREMARKS

ØHighIndexofSuspicionØ Initialmetabolicinvestigations

– Chemistries,CK,LFT’s– Ammonia– Urinalysis,urinaryreducingsubstances&ketones– Lactate,Pyruvate– PlasmaAminoAcids– PlasmaAcylcarnitine– UrinaryOrganicAcids– CSF

Ø MRI/MRS

References

• PKarimzadeh.ApproachtoNeurometabolic DiseasesfromaPediatricNeurologicalPointofView.IranJChildNeurol.2015Winter;9(1):1–16.

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