Metabolic&Genetic Causes of Infantile Epileptogenic

7/26/2019 Metabolic&Genetic Causes of Infantile Epileptogenic

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Metabolic and Genetic Causes of

Infantile EpileptogenicEncephalopathies

Douglas R. Nordli, Jr., MD

Epilepsy Center, Childrens Memorial Hospital

Chicago, Illinois, USA


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Metabolic Diseases

More than 11,000 characterized inherited

disorders in man

200 associated seizures and epilepsy

50 present in infancy


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Metabolic Disorders- Important to

Recognize

Prompt Treatment

Prognosis

Genetic Implications for FamilyReduce Unnecessary Testing

Peace of Mind

Increase Our Understanding of Physiology


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How to Organize the Material?

Seizure type

Myoclonic seizures, tonic seizures, spasms

General Category of Disease Peroxisomal, lysosomal, mitochondrial, etc.

Pathophysiological Mechanisms


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Pathophysiology: Energy Failure


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Staring and Unresponsive


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GLUT-1 DS, De Vivos Disease

Focal seizures in Infancy

Generalized seizures later

Gen 2.5-3 Hz spike-wave discharges Ann Neurol 2003: PET study

Thalamic involvement is hallmark

(Generalized spikes waves also seen inhyperammonemia/hypoglycemia)


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Another Energy Failure Syndrome

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

100uV

1sec


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Another Patient with Energy Failure

Disorder


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MELAS

With Stroke-like episodes

EEG shows focal features, including focal

slowing, attenuation, and spikes


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Excitatory/Inhibitory Transmission

Note discontinuity; multifocal IEDs

After Treatment


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Excessive Excitation

Increased Glutamate/GABA

GlutamateGABA

Requires B6EEGs are discontinuous, multifocal IEDs


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3 month-old


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Early Myoclonic Epilepsy

Described by Aicardi

Non-ketotic hyperglycinemia


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Accumulation of Toxic SubstancesAfter protein mealBaseline

Note attenuation of background,

peculiar monorhythmic thetaMultifocal spikes


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OTC

Ornithine transcarbamylase deficiency

Worsened by protein load

Accumulation of Ammonia

EEG shows a low-voltage pattern, withdiffuse slowing and multifocal epileptiformdischarges.

Two patients studied by Verma et al. in1984 demonstrated episodes of sustainedmonorhythmic theta activity.


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Destructive Lesions


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Infant with Progressive

Microcephaly

Background

AttenuationPeriodic

Brush-like

pattern


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Destructive Lesions

Erode complexity

Some have peculiar EEG features

Alpers- brush-like pattern NCL- vanishing EEG


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Pathophysiology

Process Example EEG

Malformations PDH/PC,

Zellweger

Chaotic: B/S,

Hypsarhythmia

GABA/Glut Pyridoxine Dep Chaotic: B/S

Destructive

Lesions

NCL Reduced

voltage(vanishing)

Toxins Urea Cycle Slowing, MultipleIEDs, some

unique patterns

Insufficient Fuel GLUT-1 DS Gen S/W


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Metabolic

Defect

Energy Failure

Disturbance of

excitation/inhibition

Accumulation of toxic

substances

Calcium damage to

mitochondria and

Blood Brain Barrier

Defect causing further

seizures


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Van Vliet et al 2007


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Kleen and Holmes, 2008


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Seizure types associated with

metabolic diseases in infancy

Myoclonic seizures

Infantile spasms

Mixed seizures- combination of focal andgeneralized elements

Some tonic seizures


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Problems using seizure type to

identify metabolic disease

Limited repertoire in infants

Seizures are etiologically non-specific


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Screening Using EEG Patterns


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Burst-Suppression Pattern


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Inborn Errors of Metabolism:

Burst-Suppression Pattern Neonatal citrullinemia

Non-ketotic hyperglycinemia

Propionic acidemia

Leighs syndrome D-glycine acidemia

Molybdenum cofactor deficiency

Menkes disease

Holocarboxylase synthetase deficiency

Neonatal adrenoleukodystrophy

H psarh thmia


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Hypsarhythmia


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Hypsarhythmia

Zellweger Syndrome

Neonatal adrenoleukodystrophy

Neuroaxonal dystrophy Non-ketotic hyperglycinemia

Phenylketonuria

Carbohydrate deficient glycoproteinsyndrome type III


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Relatively-Specific IEDs

Peculiar, fast repetitive, needle-like central spikes


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Organizing by Epilepsy Syndrome

Advantages:

Typical method of practice

Incorporates more clinical information

Some are caused by metabolic defects

Disadvantage:

Still not cause specific


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Possibly caused by Metabolic

Diseases

Benign Myoclonic Epilepsy

Severe Myoclonic Epilepsy (Dravet)

Early Myoclonic Encephalopathy (Aicardi)

Benign Non-epileptic Infantile Spasms (Lombroso)

Localization-related epilepsies with spasms

West

Early Infantile Epileptogenic Encephalopathy (Ohtahara)

Benign Infantile Partial Seizures (Watanabe)

Localization-related epilepsies Neonatal Seizures

Multifocal epilepsies with focal seizures

Multifocal epilepsy with generalized seizures

Severe- Migrating Partial Seizures (Coppola et al.)

Pleomorphic

Epilepsies


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Age of Presentation Correlates with

Epilepsy Syndrome/EEG Features

Age EEG Epilepsy

Neonatal Burst-

Suppression

EME, EIEE

Early Infantile Hypsarhythmia West

Late Infantile Multifocal Spikes/

More specific

LIEE

Childhood Gen S/W, EPC,Others (more specific)

PME, LGS


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Not Likely to be Metabolic

Disorders

Benign Myoclonic Epilepsy

Severe Myoclonic Epilepsy (Dravet)

Early Myoclonic Encephalopathy (Aicardi)

Benign Non-epileptic Infantile Spasms (Lombroso)

Localization-related epilepsies with spasms

West

Early Infantile Epileptogenic Encephalopathy (Ohtahara)

Benign Infantile Partial Seizures (Watanabe)

Localization-related epilepsies

Neonatal Seizures

Multifocal epilepsies with focal seizures

Multifocal epilepsy with generalized seizures

Severe- Migrating Partial Seizures (Coppola et al.)


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Syndrome Epidemiol Phenotype EEG

%Epilepsy Onset


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Approach to Metabolic Disorders

Presenting with Seizures

By Age

Then By Epilepsy Syndrome

Age EEG Features Screening Tests Disorders


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Neonatal Burst-Suppression or

Multifocal Spikes

B6 Administration B6 Responsive Disorders

CSF Amino Acids Nonketotic Hypeglycinemia

Urinary Sulfite Dipstick/Serum

Uric Acid

Molybdenum Cofactor Deficiency/Sulfite Oxidase

Deficiency

Very Long Chain Fatty Acids

(VLCFA)

Peroxisomal Disorders

Lactate/Pyruvate Pyruvate Dehydrogenase Deficiency, Pyruvate

Carboxylase Deficiency, Leigh syndrome

Serum Ammonia Early-Onset Multiple Carboxylase Deficiency

Urea Cycle Defects-neonatal citrullinemia

Low Amplitude Slowing Urea Cycle Defects- carbamoyl phosphate synthetase,

ornithine transcarbamoylase, argininosuccinate

synthetase

Comblike rhythm Serum Amino Acids/UrineOrganic Acids Maple Syrup Urine Disease

Dysmature features during

sleepIsovaleric acidemia

Background slowing Proprionic Acidemia

Multifocal spikes, backgroundslowing and depression

Methylmalonic Acidemia


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Early Infancy Burst-Suppression/ Multifocal

spikes/slowed background

Serum Amino Acids Methylenetetrahydrofolate Reductase Deficiency

Hypsarhythmia Serum copper/ceruloplasmin Menkes Disease

NONE PEHO Syndrome

Serum AminoAcids/Urine

Organic Acids

Phenylketonuria and hyperphenylalaninemia,

tyrosinemia type III, Hyperornithinemia-

hyperammonemia-homocitrullinuria syndrome

Variety of organic acidurias including 3-mehtylglutaconic aciduria, 3-hyroxy-3-mehtylglutaric

aciduria, e-ydroxybutyric aciduria, 4-Hydroxybutyric

aciduria

Lysosomal Hydrolases Tay-Sachs (hexosaminidase A)

Krabbes Disease (galactosylceramidase)

Multifocal spikes a-N-acetylgalactosaminidase (Schindlers Disease)

Declining amplitude, very fast

central spikes

Biotin Treatment/Biotinidase

Screen

Biotinidase Deficiency

Background slowing, rhythmic

temporal theta in type II (juvenile

form)

Urinary oligosaccharides GM1 Gangliosidosis (Beta-Galactosidase)

Slowing/Posterior Spikes, Later 3

Hz spike-wave discharges

CSF glucose GLUT-1 Deficiency Syndrome

f H h h i S l h i f C b h d d fi i l i d CDG


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Late Infancy Hypsarhythmia Serum electropheresis for

CDG

Carbohydrate-deficient glycoprotein syndrome, CDG

Type III

High Voltage, multifocal

spikes

Lysosomal Hydrolases Metachromatic Leukodystrophy

low-amplitude fast activity (12

to 15 Hz) alternating with

generalized slowing

Urine mucopolysaccharides Sanfilippos syndrome

Vanishing EEG in 1

Pseudoperiodic d/c in 2

Skin Biopsy with EM Infantile NCL; Late infantile NCL

continuous anterior high-

voltage 1 to 3/s spike-wave

like activity

NONE Alpers

LINCL Veneselli et al,

2001

Childhood and

Adolescence

Background slowing, focal

spikes

Urine OA, Serum AA homocystinuria


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Adolescence spikes

Rhythmic trains of spike or

sharp waves at 6 to 10/s

Gaucher cells in Bone Marrow Gaucher Type III

*Epilepsia Partialis Continua

(EPC)

Blood glucose Diabetes Mellitus with nonketotic hyperosmolar coma

* Focal slowing and spikes, 14-and 6-Hz positive bursts Lactate MELAS

*EPC and Posterior

attenuation/slowing

VLCFA Adrenoleukodsytrophy

Positive vertex spikes Urine oligosaccharides Sialidosis type I

4-6 Hz spike-wave discharges Sialidosis type II

Generalized 3-5 Hz SW, frontal

predominance

DNA testing (no screen tests) Baltic Myoclonus

Generalized atypical spike-

wave discharges

Lactate/Pyruvate MERRF

Generalized spike-wave and

photoparoxysmal response

Triplet Repeats (no screening

test available)

Dentatorubral-pallidoluysian atrophy

Generalized S/W, occipital

spikes, with PPR

Skin Biopsy Lafora Disease

Multifocal spikes NCL type III

High-amplitude fast activity

(16 to 24 Hz), unaltered by eyeopening

Nerve Biopsy Neuroaxonal dystrophy

Table 3. Genes identified in idiopathic epilepsy syndromes

L G P d R f


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Locus Gene Product References

Syndromes beginning in the first year of life

Benign familial

neonatal seizures

20q13.3 KCNQ2 KV7.2 (K+channel)

(Biervert et al., 1998;

Singh et al., 1998)

8q24 KCNQ3 KV7.3 (K+channel)

(Charlier et al.,

1998)

Benign familial

neonatal-infantile

seizures

2q23-q24.3 SCN2ANaV1.2 (Na

+

channel)

(Heron et al., 2002;

Berkovic et al., 2004;

Striano et al., 2006;

Herlenius et al.,

2007)

Ohtahara syndrome

9q34.1 STXBP1Syntaxin binding

protein 1(Saitsu et al., 2008)

Xp22.13 ARXAristaless-relatedhomeobox protein

(Kato et al., 2007;Fullston et al., 2009)

Early onset spasms Xp22 STK9/CDKL5cyclin-dependent

kinase-like 5

(Kalscheuer et al.,

2003)

X-linked infantile

spasmsXp22.13 ARX

Aristaless-related

homeobox protein

(Stromme et al.,

2002; Gecz et al.,

2006)Syndromes with prominent febrile seizures

Dravet syndrome

(severe myoclonic

epilepsy of infancy)

2q24 SCN1ANaV1.1 (Na

+

channel)

(Claes et al., 2001;

Nabbout et al., 2003;

Wallace et al., 2003;

Harkin et al., 2007)

Genetic

(generalized)epilepsy with febrile

seizures plus

(GEFS+)

2q24 SCN1ANaV1.1 (Na

+

channel)

(Escayg et al.,

2000b; Sugawara

et al., 2001; Wallace

et al., 2001b)

19q13.1 SCN1B1subunit (Na

+

channel)

(Wallace et al.,

1998, 2002;

Audenaert et al.,

2003; Scheffer et al.,

2007)

5q34 GABRG2 2subunit (GABAA

receptor)

(Baulac et al., 2001;

Harkin et al., 2002)

Childhood absenceepilepsy with febrile

seizures

5q34 GABRG2 2subunit (GABAA

receptor)

(Wallace et al.,2001a; Kananura

et al., 2002)

Epilepsy and mental

retardation limited to

females

Xq22 PCDH19 protocadherin(Dibbens et al.,

2008)

Ottman et

al, 2010

Epilepsia


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General Screening Tests

CBC with differential

SMAC-20

Serum AAUrine OA

Serum lactate/pyruvate

Very Long Chain Fatty AcidsSerum ammonia


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Neonatal Seizures

Urea cycle defects

Organic Acidurias

Biotin Metabolism (multiple carboxylase,

holocarboxylase synthetase) Peroxisomal (Zellweger)

Other: Molybdenum cofactor/sulfite

oxidase, fructose, pyridoxine

S


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Additional Neonatal Screening

Tests

B6 Administration, P5P, folinic acid

CSF amino acids


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Additional Infant Screening Tests

Lysosomal Hydrolases

Urine oligosaccharides/mucopolysaccharides

Biotin treatment

CSF glucose

Serum copper/ceruloplasmin

Lysosomal hydrolases

Serum electropheresis for CDG Selective: Enzyme testing for NCL

Additi l Childh d S i


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Additional Childhood Screening

Tests

Urine oligosaccharides

Selective:

Bone marrow for Gaucher

Nerve biopsy for neuroaxonal dystrophy

Skin biopsy for NCL, Lafora

Muscle biopsy for MELAS, MERRF

DNA testing for MELAS, MERRF, DRPLA,

Baltic Myoclonus

S l t d EEG P tt d


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Selected EEG Patterns and

their disorders

EEG pattern Disorder

Comb-like rhythm Maple Syrup Urine

Propionic Acidemia

Fast central spikes Tay-Sachs DiseaseRhythmic vertex positive

spikes

Sialidosis type I

Vanishing EEG Infantile NCL (type I)

High-amplitude 16-24

hertz activity

Infantile neuroaxonal

dystrophy

Diminished spikes duringsleep,Giant SSEPs

PME

Marked photosensitivity PME and NCL,

particularly type II


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Conditions with Treatment Implications

Biotin deficiency Defects in Serine Metabolism

Pyridoxine dependency/ P5P

Glucose transporter defect (De Vivo)

Creatine deficiency

Folate

Biogenic Amines

Certain Aminoacidurias Some Organic Acidurias

Alpers and other mitochondrial cytopathies


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Conclusions

Rational approach is possible

Several Clues Seizure types: myoclonic, spasms, tonic, mixed

Epilepsies: NS, EME, West, Pleomorphic

Clinical: unexplained encephalopathy

Organization by epilepsy syndrome/age

EEG can be very useful

Selective Diagnostic Testing Dont forget treatable conditions

Metabolic&Genetic Causes of Infantile Epileptogenic

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