Treatable inherited metabolic epilepsies

Article Figures & Data

Table 1

- Common inherited treatable metabolic epilepsies.

IEM	Genetic causes	Treatments
Pyridoxine dependent epilepsy	ALDH7A1	Pyridoxine +/- folinic acid
	PROSC	Arginine, Lysine restricted diet
Pyridox(am)ine 50 -Phosphate oxidase (PNPO)	PNPO	PLP +/- Pyridoxine
Deficiency
Biotinidase deficiency	BTD	Biotin
Glucose transporter 1 deficiency syndrome	SLC2A1	Ketogenic diet
Biotin-thiamine-responsive basal ganglia disease	SLC19A3	Biotin, Thiamine
Serine biosynthesis defects	PHGDH, PSAT1, PSPH	Serine + Glycine
Molybdenum cofactor deficiency type - A	MOCS1	cyclic pyranopterin monophosphate
Cobalamin C deficiency	MMACHC	cobalamin, betaine
Cerebral folate deficiency	FOLR1	Folinic acid
Creatine deficiency syndromes	GAMT	Creatine, arginine-restricted diet, ornithine
	GATM	creatine monohydrate
	SLC6A8	creatine monohydrate
Pyruvate dehydrogenase deficiency	PDHA1 PDHB, DLAT, PDHX, PDP1	Ketogenic diet
DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome	KCNJ11	sulfonylurea
Hyperinsulinism-Hyperammonemia syndrome	GLUD1	Diazoxide + protein restriction
Tetrahydrobiopterin deficiency (BH4)
PTPS deficiency	PTS	BH4, L-dopa, 5-HTP
DHPR deficiency	QDPR	Low phenylalanine diet, Folinic acid, L-dopa,
GTPCH deficiency	GCH1	5-HTP
PCD	PCBD1
SPR deficiency	SPR	L-Dopa, 5-HTP

Table 2

- Main clinical, EEG, and MRI findings suggesting inherited metabolic epilepsies.

Features
Onset	Early: neonatal, infancy or early childhood
Seizure types	Myoclonic, tonic, infantile spasms Seizures worsening with fasting (GLUT1) or with high protein meals (urea cycle defects) Progressive myoclonic epilepsy phenotype Seizures refractory to anti-epileptic drugs Seizures worsening with anti-epileptic drugs
Neurological features	Developmental delay /regression Movement disorders Fluctuating course of illness
Systemic symptoms	Dysmorphic features Organomegaly Ophthalmological abnormalities (cataracts, retinitis pigmentosa,cherry red spot, optic nerve atrophy)
Family history	Parental consanguinity Metabolic or unexplained neurological disorder Death of unknown etiology
EEG	Burst-suppression, multifocal spike discharges, hypsarrhythmia Comb-like rhythm (maple syrup urine disease)
MRI/MRS	Normal / non specific abnormalities Corpus callosum dysgenesis (pyruvate dehydrogenase deficiency) Abnormal MRS in cerebral creatine deficiency or GABA transaminase deficiency

Table 3

- Suggested biochemical and genetic testing in early refractory seizures.

Source	Diagnostic test
Blood	Blood glucose, electrolytes, creatine, ammonia, lactic acid, uric acid, copper, ceruloplasmin, homocysteine, biotinidase assay, VLCFA, transferrin isoelectric focusing, serum amino acids
Urine	alpha-aminoadipic semialdehyde acid, pipecolic acid, thiosulfate, xanthine, hypoxanthine, organic acids, guanidinoacetate, creatine, creatinine.
CSF	Glucose, lactate, pyruvate, neurotransmitters
Genetic testing	Array CGH, next generation sequencing (epilepsy panel, Whole exome sequencing)
VLCFA - very long chain fatty acid