Neurometabolic Disorders David Sweetser, MD, PhD Chief of Medical Genetics and Metabolism MassGeneral Hospital for Children Sept. 5, 2017
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
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