Pyridoxine-dependent epilepsy (EPD) is an early-onset, autosomal recessive inherited epilepsy that does not respond to any known anticonvulsants apart from pyridoxine (vitamin B6). The estimated prevalence is 1:20,000 to 1:500,000. In most cases, epileptic seizures initially occur in the first 24 to 48 hours (neonatal) or by 3 years of age (late onset). Different seizure types including myoclonic, atonic, partial or generalized, infantile spasms, may occur. Cerebral imaging reveals ventricular dilation, cortical atrophy, intracerebral hemorrhage, and/or myelination abnormalities. A clinical diagnosis can be confirmed if seizures are immediately interrupted following acute intravenous pyridoxine administration of 100 mg to a maximum of 500 mg and after discontinuation of antiepileptic medication. Additional biomarkers supporting the diagnosis include elevated concentrations of delta-aminoadipine semialdehyde (delta-AASA) in urine and plasma and elevated concentrations of pipecolic acid in plasma and CSF.
The molecular cause of EPD are homozygous or combined heterozygous pathogenic variants in the ALDH7A1 gene encoding alpha-aminoadipine semialdehyde dehydrogenase (antiquitin). Antiquitin is involved in lysine catabolism in the CNS and localized in radial glial cells, astrocytes, and ependymal cells. Altered activity of antiquitin leads to increased levels of delta-1-piperidine-6-carboxylate (P6C), the Schiff base of delta-aminoadipine semialdehyde (delta-AASA). P6C in turn inactivates pyridoxal-5-phosphate (PLP) and causes abnormal neurotransmitter metabolism. Pyridoxal-5-phosphate, the active substrate of pyridoxine, is a cofactor of glutamate decarboxylase during synthesis of the inhibitory neurotransmitter gamma-aminobutyrate (GABA) and its deficiency results in an excess of excitatory neurotransmitters. Antiquitin deficiency leads, among others, to neuronal migration disorders. More than 95% of all pathogenic ALDH7A1 variants are point mutations leading to amino acid substitutions or premature translational arrest of protein biosynthesis. Genomic deletions have only been described in isolated cases. The variant p.Glu399Gln accounts for 33% of all variant alleles. There is no clear genotype-phenotype correlation. However, missense variants with residual activity of the enzyme seem to have more favorable developmental prognosis.
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