This document discusses various inborn errors of metabolism that can cause epilepsy. It covers disorders of mitochondrial function, creatine metabolism, GLUT1 deficiency, hypoglycemia, storage disorders, disorders of the urea cycle and amino acid metabolism, organic acid disorders, purine/pyrimidine metabolism, disturbances to neurotransmitter systems, brain malformations, and some vitamin-responsive epilepsies like pyridoxine-dependent epilepsy and pyridox(am)ine phosphate oxygenase deficiency. Specific genetic disorders are discussed in each category along with their associated seizure types, diagnostic testing, treatment approaches, and prognosis.

1. Wafaa AL Shehhi
Pediatric Neurology resident R5
December 2014
Epilepsy in Inborn Error
of Metabolism

2. Epilepsy in IEM
pilepsy due to inborn error of energy metabolism:
itochondrial disorders.
isorders of creatin metabolism.
LUT1 deficiency.
ypoglycaemia.

3. Epilepsy in IEM
isturbed neuronal function due to accumulation of storage products.
oxic effects:
rea cycle defects.
isorders of Amino Acid metabolism.
isorders of organic acid metabolism.
isorders of purine and pyrimidine metabolism.

4. Epilepsy in IEM
isturbed neurotransmitter systems:
on-ketotic hyperglycinaemia.
efects of GABA metabolism.
ssociated brain malformation.
itamin responsive epilepsies:
yridoxine-dependent epilepsy and pyridox(am)ine phosphate
oxygenase deficiency.
. Folinic acid responsive seizures.

5. Epilepsy in IEM
ther disorders:
olybdenum cofactor deficiency and sulphite oxidase deficiency.
enkes disease.
eficiency of serine biosynthesis.
. Congenital disorders of glycosylation (CDG).
. Inborn error of brain excitability.

6. Epilepsy due to inborn
error of energy
metabolism

7. Mitochondrial disorders
pilepsy is found in 26-60% of all mitochondrial disorders. (Darin et
al.2001,Wolf and Smeitink 2002)
pilepsy occurs in about half of all patients with leigh syndrome.(Rahman
et al. 1996)
t is common in disease with early onset and severe psychomotor
retardation.

8. Mitochondrial disorders
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).

9. Mitochondrial disorders
ERRF- caused by mutations in the mitochondrial tRNA for lysine.
hey presents in the seconde decade or later with progressive myoclonic
epilepsy with typical EEG findings of giant, somatosensory potentials
and photosensitivity.

10. Mitochondrial disorders
ELAS  caused by mutations in the mitochondrial tRNA for leucine
ELAS frequently leads to seizures, espicially during acute stroke like
episodes.
n 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).

11. Mitochondrial disorders
% of all children with infantile spasms suffer from a mitochondrial
disease (Sadleir et al.2004).
tatus Epilepticus is also seen which is either convulsive or non-
convulsive.
pilepsia 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).

12. Disorders of creatine metabolism
different defects:
mpaired creatine transport into the brain in the X-linked creatine
transporter defect (Salomons et al. 2001).
mpaired creatine synthesis in GAMT (guanidinoacetate
methyltrasferase) and AGAT (arginineglycine amidinotransferase)
deficiencies (Stockler et al.1996, Item et al .2001).

13. Disorders of creatine metabolism
nly GAMT deficiency is regularly associated with with epilepsy, which is
often refractory to conventional treatment.
reatine supplementation alone frequently leads to improvement.
n 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)

14. Disorders of creatine metabolism
eizure types are many and various.
nfants can present with west syndrome, atypical absences, astatic and
generalized tonic-clonic seizures being common later on.
maging findings can be normal even in untreated adults (Schulze et
al.2003); but in some cases, basal ganglia signal abnormalities can be
found.

15. Disorders of creatine metabolism
iagnosis: increased excretion of guanidino coumpounds in urine.
ll three defects can be assumed when the prominent creatine and
creatine phosphate peak is absent in MRS of brain.

16. GLUT1 Deficiency
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).
D.
herapy resistent epilepsy beginning in the first year of life, acquired
microcephaly and mental retardation.

17. GLUT1 Deficiency
taxia and movement disorders such as dystonia.
ymptoms may worse during the fasted state.
EG: increase in generalised or focal epileptiform discharges that improve
after eating( Von Moers et al.2002).
euroimaging: Normal.

18. GLUT1 Deficiency
iagnosis: reduced CSF-blood glucose ratio < 0.46 and mutation analysis
of the gene.
reatment: ketogenic diet.
hloral hydrate and diazepam, should not be used in this disease, as may
further impair GLUT1.(Klepper et al.1999).

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

20. Hypoglycemia
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.

21. Disturbed neuronal function due to
accumulation of storage products
ay sachs disease: epilepsy a prominent feature of it, with myoclonus,
atypical absences and motor seizures.
ialidosis type 1 leads to progressive myoclonus epilepsy, a distinguishing
feature being a retinal cherry red spot. (Zupanc and Legros 2004).

22. Disturbed neuronal function due to accumulation
of storage products
n different neuronal ceroid lipofuscinoses, epilepsy is a major feature
(Cooper 2003).
n NCL1, seizures start at the end of the first year of life, with myoclonus,
atonic and tonic-clonic seizures.
EG: early and severe depression.
rain MRI: cortical, cerebellar and white matter atrophy and secondary
white matter signal abnormalities.
RG: severely attenuated and VEPs are absent early in the disease course.
(Mitchison et al. 1998).

24. Disturbed neuronal function due to accumulation
of storage products
ate infantile form(NCL2) is usually after the second year of life.
eizures might be generalized tonic- clonic, atonic and astatic and
myoclonic; children may present with the clinical picture of myoclonic-
astatic epilepsy.
EG: spikes with slow, photic stimulation. Giant potentials with visual-
evoked and somatosensory evoked responses are found.
iagnosis: by enzymatic studies of the activity of palmitoylprotein
thioesterase (NCL1) and tripeptidylpeptidase1 (NCL2).
utation analysis of gene.

26. Toxic effects

27. Urea cycle defects
eizures are frequent during the early stages of hyperammonaemia,
especially in newborns, before profound coma has developed.
ith good metabolic control of the underlying disease, epilepsy is rare in
the course of these disorders.

28. Disorders of amino acid metabolism
KU:
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).
SUD:
eizures may accompany decompensation of MSUD in neonatal period.
EG: comb-like rhythm resembling a mu rhythm in the central
areas( Thap 1992).

29. Disorders of organic acid metabolism
ethylmalonic aciduria and Propionic aciduria:
hree main clinical presentations:
severe neonatal onset form with acute metabolic decompensation and
neurological distress.
n acute, intermittent, late-onset form with recurrent episodes of
metabolic decomppensation.
chronic, progressive form presenting as hypotonia, failure to thrive.
MAmethylmalonyl CoA mutase deficiency.

30. Disorders of organic acid metabolism
lutaric aciduria type 1:
deficiency of glutaryl-CoA dehydrogenase.
R.
CDH gene mutationlocated on 19p13.2.
acrocephaly,complex extrapyramidal syndrome, choreic movements,
hypotonia, subdural haemorrhages and seizures.

31. Disorders of purine and pyrimidine metabolism
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).
lso patients show severe psychomotor retardation and autistic features.
modified Bratton-Marshall test is used for screening of urine.
o specific treatment available.
rognosis: poor.
eizures occur in half of patients affected with dihydropyrimidine
dehydrogenase deficiency.( Van Kuilenburg et al. 1999).

32. Disturbed neurotransmitter systems
KH
disorder in glycin degradation.
n 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.
EG: 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).
iagnosis: 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.

33. Disturbed neurotransmitter systems
efects of GABA metabolism:
eficiency of GABA transaminase is an extremely rare disease.
eizures may be present from birth.
ABA levels are elevated in CSF and plasma.
o treatment for this disorder.
uccinic semialdehyde dehydrogenase deficiency causes mild to moderate
global mental retardation.
pproximately half of the patients develop epilepsy and there may be other
neurological symptoms as ataxia.(Pearl et al.2003).

34. Associated brain malformations
ellweger syndrome has the characteristic malformations of cortical
development.
olymicrogyria of the frontal and opercular region is frequent and
pachygyria may also found.
erminolytic cysts in the caudo-thalamic notch are typical. (Barkovich and
Peck 1997).
pilepsy in zellweger syndrome typically consists of partial motor
seizures.

35. Associated brain malformations
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).
EG show abnormal beta- activity.

36. Vitamin responsive
epilepsies

37. Pyridoxine dependent epilepsy
R.
DE related to deficiency of α-aminoadipic semialdehyde
dehydrogenase (antiquitin) an enzyme involved in the degradation
of lysine.
utations in the ALDH7A1 gene on 5q31.(Plecko et al 2007)
renatal History: mothers may report increase fetal movements
that likely represent intrauterine fetal seizures .

39. Pyridoxine dependent epilepsy
lassic
eizure onset hours to days after birth.
eizure refractory to AED treatment.
apid resolution of seizure with B6 IV or oral.
emains seizure-free after withdrawal of AED.
ecurrence of seizures with withdrawal of B6.

40. Pyridoxine dependent epilepsy
typical
ate onset up to 3 years age.
nitial response to AED treatment.
bsence of initial response to B6 therapy, up to 7 day.
eizure free without B6 therapy as long as 5 years.
eed for larger pyridoxine doses in some patients.

41. Diagnosis
linically, with dramatic cessation of seizure event after
administration of pyridoxine with EEG improve.
lasma and CSF pipecolic acid > Elevated.
lasma , CSF and urine α-aminoadipic semialdehyde (AASA) >
Elevated.
enetic test : Mutations in ALDH7A1 gene.

42. EEG
ariable.
urst –suppression pattern.
ypsarrhythmia.
ormalization with pyridoxine therapy within minutes.

43. Neuroimaging
on specific.
hin postrior corpus callosum
ortical dysplasia.
erbellar hypoplasia.
hite matter changes.
MR spectroscopy may show decreased N acetylaspartate to
creatine ratio in the cerebral cortex indicating neuronal loss.

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

45. Treatment
Maintenance dose : of 15–10 mg/kg/day life long.
ED as indicated .
ysine restricted diet .
onsider folinic acid 2-5 mg /kg/day

46. Prognosis
rognosis : despite medical therapy neurodevelopmental delay
especially with late onset seizure particularly in expressive
language delay.
arly diagnosis and effective treatment will improve the outcome.

47. Prognosis
isk of recurrence : as PDE is autosomal recessive risk is 25% with
each pregnancy .
herefore , mother should take 9-110 mg of pyridoxine during last
half of gestation but genotype play an important role in
neurological outcome .

48. Pyridox(am)ine phosphate oxygenase deficiency
AR.
yridoxical phosphate is the active form of pyridoxine
LP related to PNPO gene, which encodes pyridoxine 5 -phosphate
oxidase located on chromosome 17.

49. Pyridox(am)ine phosphate oxygenase deficiency
ntenatal history of fetal distress and utero fatal seizures is very
common.
istory of prematurity commonly reported .
ypoglycemia and lactic acidosis with intractable seizure that mimic
organic acidemia after birth commonly seen .

51. Pyridox(am)ine phosphate oxygenase deficiency
eizures are refractory to treatment with AEDs or pyridoxine.
he seizure semiology variable includes clonic or myoclonic jerks
and complex.

52. Diagnosis
ypoglycemia and lactic acidosis common after birth .
lood and CSF amino acids: Elevated glycine and threonine.
rine vanillic acid present .

53. Diagnosis
SF neurotransmitters :
ncreased L-DOPA and 3-methoxytyrosine;
ecreased homovanillic acid and 5- hydroxyindoleacetic acid.
NPO gene mutation located in chromosome 17.

54. Treatment
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.

55. Prognosis
ntreated cases have high mortality.
urvivors are left with poor neurocognitive outcome, despite control
of seizure.

56. Folinic acid responsive seizures
ARS 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).
tudies found that FARS due to alfa AASA dehydrogenase

58. Folinic acid responsive seizures
tiology : Folate Antibody mediated.
iochemical markers: CSF 5-methyltetrahydrofolate , serum folate
antibodies .
ensorineural hearing loss after approximately 6 years of age.

59. Folinic acid responsive seizures
n un treated cases visual disturbances manifest after 3 years of
age and sensorineural hearing loss after approximately 6 years of
age.
5% autistic spectrum disorders.
ork up :
CSF MTHF level is typically low.
Autoantibodies to folate are often present in serum.

60. Folinic acid responsive seizures
reatment : Folinic acid (oral) Folinic acid (oral) 3- 5 mg/kg twice
daily .
utcome: Favorable outcome if treated before 6 years of age.

61. Biotinidase deficiency and holocarboxylase
deficiency
he 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.
iotinidase 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.

62. Biotinidase deficiency
iotinidase deficiency is autosomal recessive neurocutaneous
metabolic disorder causing multiple carboxylase deficiency.
Etiology : Biotinidase gene mutation localized at chromosome
3p25.
eurological manifestation: hypotonia, lethargy, seizures.
allmark: skin rash and alopecia.
reatment: 5-20 mg/day.

63. Holocarboxylase deficiency
nset: few houres after birth to 8 years of age.
cute presentation with symptoms very similar to those with severe
organic acidurias lethargy,hypotonia,vomiting,sz and
hypothermia.
evere metabolic acidosis ,ketosis and hyperammonemia.
air loss and skin lesions.
iagnosis:
HLCS gene mutation.

64. Biotin- thiamin basal ganglia responsive disease
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.

65. Biotin- thiamin basal ganglia responsive disease
ecause biotin is not a substrate for hTHTR2, the precise
mechanism by which biotin is effective in improving this condition
remains unknown.
BGD typical clinical picture consisted of recurrent subacute
encephalopathy leading to coma, seizures, and extra pyramidal
manifestations.
arkinsonian signs (cogwheel rigidity)and pyramidal tract signs
(quadriparesis, hyperreflexia)

66. Diagnosis
iochemical markers:
- Decreased serum biotinidase
lactic acidosis; and hyperammonemia;
levated 3-hydroxyisovalerate, 3-methylcrotonylglycine and methyl
citrate;
levated CSF lactate and pyruvate.
rain MRI: bilateral lesions of the caudate nucleus and putamen.

67. Diagnosis/ Treatment
enetic study: Biotin responsive basal ganglia > SLC19A3
gene
iotin (oral) dose 5-10 mg/kg /day.

68. Miscellaneous
disorders

69. Molybdenum cofactor deficiency and sulphite
oxidase deficiency

70. Molybdenum cofactor deficiency and sulphite
oxidase deficiency
R.
ncephalopathy, intractable seizures and lens dislocation.
erebral MRI: cystic degeneration of white matter and severe atrophy.
iagnosis :
simple dipstick test for sulphite in fresh urine.
ow plasma uric acid.

71. Menke’s disease
- chromosomal, recessive disorder.
ften presenting with infantile spasms resistant to treatment.
he characteristic hair abnormalities point to the diagnosis.
iagnosis: low serum copper and ceruloplasmin.

72. Deficiency of serine biosynthesis
enzyme defects: 3-phosphoglycerate dehydrogenase deficiency and
3- phosphoserine phosphatase deficiency.
icrocephaly, seizures- 1st
year of life, often as west syndrome.
iagnosis: decrease CSF serine.
rain MRI: atrophy due to lack of white matter and hypomyelination.
espond to oral supplementation of serine(De Koning and Klomp
2004).

73. Congenital disorders of glycosylation (CDG)
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)
t is an important symptom in CDG Ic (Grunewald et al.2000).
iganosis: isoelectric focussing of transferrin.
x: AED depend on seizure type.

74. Take home message
atient with intractable seizures almost always think about metabolic
causes.
tart with treatable diseases.

79. References
pilepsy in IEM, Nicole I.Wolf, epileptic Disord Vol.7, No.2,June 2005.
ew treatment paradigms in neonatal metabolic epilepsies, P.L.Pearl,
SSIEM symposium 2008, J Inherited Metab Dis 2009.
nborn metabolic diseases, 5th
edition, Saudubray.