Update in Metabolic Epilepsies

Recent years have brought major progress in the field of epileptic encephalopathies that are caused by inborn errors of metabolism (IEM). Though rare, their early recognition is crucial to enable specific treatment and avoid irreversible brain damage. Diagnostic work-up is based on age of onset, seizure semiology, EEG characteristics, concomitant clinical or radiologic findings and the identification of specific biomarkers in body fluids.

A newborn with myoclonic seizures that are resistant to common anticonvulsants should undergo a standardized cofactor trial with pyridoxine, 30 mg/kg/day in two to three single dosages over 3 consecutive days. If ineffective, add-on of folinic acid, 3–5 mg/kg/day or a switch to pyridoxal 5′-phosphate (unlicensed chemical compound), 30–60 mg/kg/day in 4–6 single dosages has to be considered. Vitamine B6 dependent epilepsies can occur due to 5 inborn errors of metabolism, which can be separated by distinct biomarkers. These include Antiquitin deficiency, Pyridox(am)ine 5′-phosphate oxidase deficiency, hyperprolinemia type 2, severe forms of congenital hypophosphatasia and Mabry syndrome. In Antiquitin deficiency add-on treatment with a lysine restricted diet and arginine supplementation might improve cognitive outcome. Recent research has unraveled a novel group of patients with pyridoxine responsive PNPO deficiency and a considerable pyridoxine response in patients with KCNQ2 mutations. Folinic acid responsive seizures are allelic to Antiquitin deficiency, but can also occur in toddlers suffering from folate transporter deficiency type 1 (FOLR1). These patients have acquired microcephaly, ataxia and hypomyelination on MRI. In GLUT1 deficiency we have seen an expanding spectrum of early onset absence seizures, myoclonic astatic epilepsy and late onset GM seizures with paroxysmal exercise induced dyskinesia. GLUT1 and FOLR1 deficiency both need CSF for determination of the respective biomarkers, which is low glucose and low MTHF in the latter. Creatine deficiency syndromes manifest with myoclonic or absence seizures, mental retardation and speech problems, can be recognized by low creatine peaks on MRS or biomarkers in plasma an urine and improve upon oral supplementation of creatine. Novel therapies as the supplementation of a cofactor precursor are under investigation for Molybdenum cofactor deficiency type A and intracerebral enzyme replacement therapy for NCL 2.