Wafaa AL ShehhiPediatric Neurology resident R5December 2014

Epilepsy in Inborn Error of Metabolism

Epilepsy in IEM •E

pilepsy due to inborn error of energy metabolism:1.M

itochondrial disorders.2.D

isorders of creatin metabolism.3.G

LUT1 deficiency.4.H

ypoglycaemia.

Epilepsy in IEM •D

isturbed neuronal function due to accumulation of storage products.•T

oxic effects:1.U

rea cycle defects.2.D

isorders of Amino Acid metabolism.3.D

isorders of organic acid metabolism.4.D

isorders of purine and pyrimidine metabolism.

Epilepsy in IEM •D

isturbed neurotransmitter systems:1.N

on-ketotic hyperglycinaemia.2.D

efects of GABA metabolism.•A

ssociated brain malformation.•V

itamin responsive epilepsies:1.P

yridoxine-dependent epilepsy and pyridox(am)ine phosphate oxygenase deficiency.

2. Folinic acid responsive seizures.

3. Biotinidase deficiency and holocarboxylase synthase deficiency.

4. thiamin-biotin responsive basal ganglia disease.

Epilepsy in IEM •O

ther disorders:1.M

olybdenum cofactor deficiency and sulphite oxidase deficiency.2.M

enkes disease.3.D

eficiency of serine biosynthesis.4

. Congenital disorders of glycosylation (CDG).

5. Inborn error of brain excitability.

Epilepsy due to inborn error of energy metabolism

Mitochondrial disorders •E

pilepsy is found in 26-60% of all mitochondrial disorders. (Darin et al.2001,Wolf and Smeitink 2002)

•Epilepsy occurs in about half of all patients with leigh syndrome.(Rahman et al. 1996)

•It is common in disease with early onset and severe psychomotor retardation.

Mitochondrial disorders •D

ecreased ATP production, the main biochemical consequence of impaired respiratory chain function, probably leads to unstable membrane potentials, making neurons prone to epileptic activity because about 40% of neuronal ATP production is needed for Na, K-ATPase and maintenace of the membrane potential (Kunz 2002).

Mitochondrial disorders •M

ERRF- caused by mutations in the mitochondrial tRNA for lysine.•T

hey presents in the seconde decade or later with progressive myoclonic epilepsy with typical EEG findings of giant, somatosensory potentials and photosensitivity.

Mitochondrial disorders •M

ELAS caused by mutations in the mitochondrial tRNA for leucine•M

ELAS frequently leads to seizures, espicially during acute stroke like episodes.

•In infancy and childhood onset mitochondrial encephalopathies, myoclonic seizures are frequent, sometimes with very discreet clinical manifestation (eyelid flutter) and there is profound mental retardation. (lizuka et al.2002, lizuka et al.2003).

Mitochondrial disorders •8

% of all children with infantile spasms suffer from a mitochondrial disease (Sadleir et al.2004).

•Status Epilepticus is also seen which is either convulsive or non-convulsive.

•Epilepsia partialis continua Alpers’ disease and some cases which are caused by mutations in mitochondrial DNA polymerase gamma, causing mitochondrial depletion (Naviaux and Nguyen 2004, Ferrari et al.2005).

Disorders of creatine metabolism•3

different defects:•I

mpaired creatine transport into the brain in the X-linked creatine transporter defect (Salomons et al. 2001).

•Impaired creatine synthesis in GAMT (guanidinoacetate methyltrasferase) and AGAT (arginineglycine amidinotransferase) deficiencies (Stockler et al.1996, Item et al .2001).

Disorders of creatine metabolism•O

nly GAMT deficiency is regularly associated with with epilepsy, which is often refractory to conventional treatment.

•Creatine supplementation alone frequently leads to improvement.

•In some patients, reducing the toxic compound guanidinoacetate by dietary reduction of arginine and supplementary ornithine has been found to achieve epilepsy control (Schulze et al.2001)

Disorders of creatine metabolism•S

eizure types are many and various.•I

nfants can present with west syndrome, atypical absences, astatic and generalized tonic-clonic seizures being common later on.

•Imaging findings can be normal even in untreated adults (Schulze et al.2003); but in some cases, basal ganglia signal abnormalities can be found.

Disorders of creatine metabolism•D

iagnosis: increased excretion of guanidino coumpounds in urine.•A

ll three defects can be assumed when the prominent creatine and creatine phosphate peak is absent in MRS of brain.

GLUT1 Deficiency•I

mpaired transport of glucose across the blood brain barrier is due to dominant mutations in the gene for the glucose transporter 1 (GLUT1,Seidner et al.1998).

•AD.

•Therapy resistent epilepsy beginning in the first year of life, acquired microcephaly and mental retardation.

GLUT1 Deficiency•A

taxia and movement disorders such as dystonia.•S

ymptoms may worse during the fasted state.•E

EG: increase in generalised or focal epileptiform discharges that improve after eating( Von Moers et al.2002).

•Neuroimaging: Normal.

GLUT1 Deficiency•D

iagnosis: reduced CSF-blood glucose ratio < 0.46 and mutation analysis of the gene.

•Treatment: ketogenic diet.

•Chloral hydrate and diazepam, should not be used in this disease, as may further impair GLUT1.(Klepper et al.1999).

Hypoglycemia •P

rolonged seizures due to hypoglycemia may lead to hippocampal sclerosis and subsequently to temporal lobe epilepsy; in newborns, lesions in the occipital lobe are prominent.

•Hypoglycemia may be due to an underlying metabolic disease, e.g. defects of gluconeogenesis.

Hypoglycemia•F

or every chid presenting with hypoglycemia , blood glucose, B-hydroxybutyrate, free fatty acids, lactate, amino acids, acyl-carnitine esters, ammonia, insulin, growth hormone and cortisol and urine ketones and organic acids are mandatory investigations at the time of hypoglycemia.

Disturbed neuronal function due to accumulation of storage products

•Tay sachs disease: epilepsy a prominent feature of it, with myoclonus, atypical absences and motor seizures.

•Sialidosis type 1 leads to progressive myoclonus epilepsy, a distinguishing feature being a retinal cherry red spot. (Zupanc and Legros 2004).

Disturbed neuronal function due to accumulation of storage products

•In different neuronal ceroid lipofuscinoses, epilepsy is a major feature (Cooper 2003).

•In NCL1, seizures start at the end of the first year of life, with myoclonus, atonic and tonic-clonic seizures.

•EEG: early and severe depression.

•Brain MRI: cortical, cerebellar and white matter atrophy and secondary white matter signal abnormalities.

•ERG: severely attenuated and VEPs are absent early in the disease course. (Mitchison et al. 1998).

Disturbed neuronal function due to accumulation of storage products

•Late infantile form(NCL2) is usually after the second year of life.

•Seizures might be generalized tonic- clonic, atonic and astatic and myoclonic; children may present with the clinical picture of myoclonic-astatic epilepsy.

•EEG: spikes with slow, photic stimulation. Giant potentials with visual- evoked and somatosensory evoked responses are found.

•Diagnosis: by enzymatic studies of the activity of palmitoylprotein thioesterase (NCL1) and tripeptidylpeptidase1 (NCL2).

•Mutation analysis of gene.

Toxic effects

Urea cycle defects•S

eizures are frequent during the early stages of hyperammonaemia, especially in newborns, before profound coma has developed.

•With good metabolic control of the underlying disease, epilepsy is rare in the course of these disorders.

Disorders of amino acid metabolism •P

KU:•I

n untreated PKU, epilepsy occurred in about a quarter to half of all patients, west syndrome with hypsarrhythmia and infantile spasms being the most common epileptic syndrome in infancy.(Yanling et al.1999).

•MSUD:

•Seizures may accompany decompensation of MSUD in neonatal period.

•EEG: comb-like rhythm resembling a mu rhythm in the central areas( Thap 1992).

Disorders of organic acid metabolism•M

ethylmalonic aciduria and Propionic aciduria:•T

hree main clinical presentations:

1.A severe neonatal onset form with acute metabolic decompensation and neurological distress.

2.An acute, intermittent, late-onset form with recurrent episodes of metabolic decomppensation.

3.A chronic, progressive form presenting as hypotonia, failure to thrive.

•MMAmethylmalonyl CoA mutase deficiency.

•PApropionyl CoA carboxylase deficiency.

Disorders of organic acid metabolism•G

lutaric aciduria type 1:•A

deficiency of glutaryl-CoA dehydrogenase.•A

R.•G

CDH gene mutationlocated on 19p13.2.•M

acrocephaly,complex extrapyramidal syndrome, choreic movements, hypotonia, subdural haemorrhages and seizures.

Disorders of purine and pyrimidine metabolism •A

denylosuccinate lyase deficiency…… affects de novo purine synthesis, epilepsy is frequent and starts either after the first year of life or early in the neonatal period.( Van den Berghe et al.1997,Castro et al. 2002).

•Also patients show severe psychomotor retardation and autistic features.

•A modified Bratton-Marshall test is used for screening of urine.

•No specific treatment available.

•Prognosis: poor.

•Seizures occur in half of patients affected with dihydropyrimidine dehydrogenase deficiency.( Van Kuilenburg et al. 1999).

Disturbed neurotransmitter systems•N

KH

•A disorder in glycin degradation.

•In neonatal period, patient presents with lethargy, hypotonia, hiccups, ophthalmoplegia and disturbance of other vegetative functions of the brain stem. As the coma deepens, apnea and frequent, segmental, myoclonic jerks develop.

•EEG: no normal background activity, burst suppression pattern, changing to high voltage slow activity, and then to hysarrhythmia by around three months if the infant survives(Applegarth and Toone 2004).

•Diagnosis: increased glycin concentration in all body fluids and by demonstration of an elevated CSF to plasma glycin ratio (>0.08), can be confirmed by a decreased activity of the hepatic glycin cleavage system and mutation analysis.

•Brain MRI: normal or agenesis or hypoplasia of the corpus callosum.

Disturbed neurotransmitter systems•D

efects of GABA metabolism:D

eficiency of GABA transaminase is an extremely rare disease.•S

eizures may be present from birth.•G

ABA levels are elevated in CSF and plasma.•N

o treatment for this disorder.

Succinic semialdehyde dehydrogenase deficiency causes mild to moderate global mental retardation.

•Approximately half of the patients develop epilepsy and there may be other neurological symptoms as ataxia.(Pearl et al.2003).

•The biochemical hallmark is the accumulation of 4-hydroxybutyric acid in body fluids.

•Vigabatrin show response in some patients but can worsen symptoms in others.( Gropman 2003).

Associated brain malformations•Z

ellweger syndrome has the characteristic malformations of cortical development.

•Polymicrogyria of the frontal and opercular region is frequent and pachygyria may also found.

•Germinolytic cysts in the caudo-thalamic notch are typical. (Barkovich and Peck 1997).

•Epilepsy in zellweger syndrome typically consists of partial motor seizures.

Associated brain malformations•D

isorders of O- glycosylation (walker-warburg syndrome, muscle-eye-brain disease,fukuyama muscle dystrophy) lead to brain malformation including cobblestone lissencephaly, patients often suffer from intractable seizures (Grewal and Hewitt 2003).

•EEG show abnormal beta- activity.

Vitamin responsive epilepsies

Pyridoxine dependent epilepsy•A

R.•P

DE related to deficiency of α-aminoadipic semialdehyde dehydrogenase (antiquitin) an enzyme involved in the degradation of lysine.

•Mutations in the ALDH7A1 gene on 5q31.(Plecko et al 2007)

•P

renatal History: mothers may report increase fetal movements that likely represent intrauterine fetal seizures .

Pyridoxine dependent epilepsyC

lassic •S

eizure onset hours to days after birth. •S

eizure refractory to AED treatment.•R

apid resolution of seizure with B6 IV or oral.•R

emains seizure-free after withdrawal of AED.•R

ecurrence of seizures with withdrawal of B6.

Pyridoxine dependent epilepsyA

typical •L

ate onset up to 3 years age.•I

nitial response to AED treatment.•A

bsence of initial response to B6 therapy, up to 7 day.•S

eizure free without B6 therapy as long as 5 years.•N

eed for larger pyridoxine doses in some patients.

Diagnosis •C

linically, with dramatic cessation of seizure event after administration of pyridoxine with EEG improve.

•Plasma and CSF pipecolic acid > Elevated.

•Plasma , CSF and urine α-aminoadipic semialdehyde (AASA) > Elevated.

•Genetic test : Mutations in ALDH7A1 gene.

EEG•V

ariable.•B

urst –suppression pattern.•H

ypsarrhythmia.•N

ormalization with pyridoxine therapy within minutes.

Neuroimaging •N

on specific. •T

hin postrior corpus callosum •C

ortical dysplasia.•C

erbellar hypoplasia. •W

hite matter changes.

* MR spectroscopy may show decreased N acetylaspartate to creatine ratio in the cerebral cortex indicating neuronal loss.

Treatment •L

oading dose : 50 to 100 mg of IV pyridoxine which can result in dramatic seizure control and EEG improvement within minutes.

•These should be attempted in ICU setting, as intravenous pyridoxine is reported to cause respiratory depression , apnea, profound hypotonia and hypotention , most likely in patient who has already been loaded with AEDs.

Treatment •

Maintenance dose : of 15–10 mg/kg/day life long.•A

ED as indicated .•L

ysine restricted diet .•C

onsider folinic acid 2-5 mg /kg/day

Prognosis •P

rognosis : despite medical therapy neurodevelopmental delay especially with late onset seizure particularly in expressive language delay.

•Early diagnosis and effective treatment will improve the outcome.

Prognosis •R

isk of recurrence : as PDE is autosomal recessive risk is 25% with each pregnancy .

Therefore , mother should take 9-110 mg of pyridoxine during last half of gestation but genotype play an important role in neurological outcome .

Pyridox(am)ine phosphate oxygenase deficiency •

AR.•P

yridoxical phosphate is the active form of pyridoxine•P

LP related to PNPO gene, which encodes pyridoxine 5 -phosphate oxidase located on chromosome 17.

Pyridox(am)ine phosphate oxygenase deficiency •A

ntenatal history of fetal distress and utero fatal seizures is very common.

•History of prematurity commonly reported .

•Hypoglycemia and lactic acidosis with intractable seizure that mimic organic acidemia after birth commonly seen .

Pyridox(am)ine phosphate oxygenase deficiency •S

eizures are refractory to treatment with AEDs or pyridoxine.•T

he seizure semiology variable includes clonic or myoclonic jerks and complex.

Diagnosis •H

ypoglycemia and lactic acidosis common after birth .•B

lood and CSF amino acids: Elevated glycine and threonine.•U

rine vanillic acid present .

Diagnosis •C

SF neurotransmitters :I

ncreased L-DOPA and 3-methoxytyrosine; D

ecreased homovanillic acid and 5- hydroxyindoleacetic acid.•P

NPO gene mutation located in chromosome 17.

Treatment •P

yridoxal 5 -phosphate (Oral) dose is 30–50mg/kg/day in 3-4 divided doses.

* PLP with low dose of ACTH has been used as treatment of infantile spasm with West syndrome in Jaban.

Prognosis •U

ntreated cases have high mortality.•S

urvivors are left with poor neurocognitive outcome, despite control of seizure.

Folinic acid responsive seizures

•FARS also known as cerebral folate deficiency syndromes.

• They are usually mediated by either:

- genetic or

- autoimmune mechanisms

• That cause low concentration of CSF 5-methyl tetrahydrofolate (MTHF).

•Studies found that FARS due to alfa AASA dehydrogenase deficiency and mutations in ALDH7A1 gene.(Gallagher et al. 2009).

Folinic acid responsive seizures•E

tiology : Folate Antibody mediated.•B

iochemical markers: CSF 5-methyltetrahydrofolate , serum folate antibodies .

•Sensorineural hearing loss after approximately 6 years of age.

Folinic acid responsive seizures•I

n un treated cases visual disturbances manifest after 3 years of age and sensorineural hearing loss after approximately 6 years of age.

•35% autistic spectrum disorders.

•Work up :

CSF MTHF level is typically low.

Autoantibodies to folate are often present in serum.

Folinic acid responsive seizures•T

reatment : Folinic acid (oral) Folinic acid (oral) 3- 5 mg/kg twice daily .

•Outcome: Favorable outcome if treated before 6 years of age.

Biotinidase deficiency and holocarboxylase deficiency

•The classic role of biotin is to function as the coenzyme of four important carboxylases involved in gluconeogenesis, fatty acid synthesis and catabolism of several amino acids.

•Biotinidase cleaves biocytin to biotin which serves as a cofactor for five biotin-dependent carboxylase enzymes: pyruvate carboxylase, propionyl- CoA carboxylase,beta-methylcrotonyl-CoA carboxylase, and two isoenzymes of acetyl-CoA carboxylase.

Biotinidase deficiency •B

iotinidase deficiency is autosomal recessive neurocutaneous metabolic disorder causing multiple carboxylase deficiency.

• Etiology : Biotinidase gene mutation localized at chromosome 3p25.

•Neurological manifestation: hypotonia, lethargy, seizures.

•Hallmark: skin rash and alopecia.

•Treatment: 5-20 mg/day.

Holocarboxylase deficiency •O

nset: few houres after birth to 8 years of age.•A

cute presentation with symptoms very similar to those with severe organic acidurias lethargy,hypotonia,vomiting,sz and hypothermia.

•Severe metabolic acidosis ,ketosis and hyperammonemia.

•Hair loss and skin lesions.

•Diagnosis:

• HLCS gene mutation.

•Biotin concentration in plasma and urine normal.

•Carboxylase activities in lymphocytes are deficient.

Biotin- thiamin basal ganglia responsive disease •T

he disease is autosomal recessive and associated with mutations in the SLC19A3 gene

The SLC19A3 gene encodes human thiamine transporter 2 (hTHTR2),3 a second thiamine transporter.

Biotin- thiamin basal ganglia responsive disease •B

ecause biotin is not a substrate for hTHTR2, the precise mechanism by which biotin is effective in improving this condition remains unknown.

•BBGD typical clinical picture consisted of recurrent subacute encephalopathy leading to coma, seizures, and extra pyramidal manifestations.

•Parkinsonian signs (cogwheel rigidity)and pyramidal tract signs (quadriparesis, hyperreflexia)

Diagnosis •B

iochemical markers:

- Decreased serum biotinidase-

lactic acidosis; and hyperammonemia;-E

levated 3-hydroxyisovalerate, 3-methylcrotonylglycine and methyl citrate;

-Elevated CSF lactate and pyruvate.

-Brain MRI: bilateral lesions of the caudate nucleus and putamen.

Diagnosis/ Treatment •G

enetic study: Biotin responsive basal ganglia > SLC19A3 gene

•Biotin (oral) dose 5-10 mg/kg /day.

Miscellaneous disorders

Molybdenum cofactor deficiency and sulphite oxidase deficiency

Molybdenum cofactor deficiency and sulphite oxidase deficiency

•AR.

•Encephalopathy, intractable seizures and lens dislocation.

•Cerebral MRI: cystic degeneration of white matter and severe atrophy.

•Diagnosis :

•a simple dipstick test for sulphite in fresh urine.

•Low plasma uric acid.

Menke’s disease •X

- chromosomal, recessive disorder.•O

ften presenting with infantile spasms resistant to treatment.•T

he characteristic hair abnormalities point to the diagnosis.•D

iagnosis: low serum copper and ceruloplasmin.

Deficiency of serine biosynthesis•2

enzyme defects: 3-phosphoglycerate dehydrogenase deficiency and 3- phosphoserine phosphatase deficiency.

•Microcephaly, seizures- 1st year of life, often as west syndrome.

•Diagnosis: decrease CSF serine.

•Brain MRI: atrophy due to lack of white matter and hypomyelination.

•Respond to oral supplementation of serine(De Koning and Klomp 2004).

Congenital disorders of glycosylation (CDG)•E

pilepsy is one of the less prominent symptoms seen in children with CDG type Ia, sometimes only during the acute, stroke like episodes (Jaeken 2003)

•It is an important symptom in CDG Ic (Grunewald et al.2000).

•Diganosis: isoelectric focussing of transferrin.

•Rx: AED depend on seizure type.

Take home message •P

atient with intractable seizures almost always think about metabolic causes.

•Start with treatable diseases.

References •E

pilepsy in IEM, Nicole I.Wolf, epileptic Disord Vol.7, No.2,June 2005.•N

ew treatment paradigms in neonatal metabolic epilepsies, P.L.Pearl, SSIEM symposium 2008, J Inherited Metab Dis 2009.

•Inborn metabolic diseases, 5th edition, Saudubray.