Pyridoxine-dependent epilepsy (PDE) 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 start in the first 24 to 48 hours of life (neonatal) but the onset can be up to 3 years of age (late onset). Different seizure types, including myoclonic, atonic, partial or generalized,or 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 as a result of acute intravenous administration of 100 mg to a maximum of 500 mg pyridoxine and after discontinuation of antiepileptic medication. Additional biomarkers supporting the diagnosis include elevated concentrations of delta-aminoadipic semialdehyde (delta-AASA) in urine and plasma and elevated concentrations of pipecolic acid in plasma and cerebrospinal fluid.
PDE is caused by homozygous or combined heterozygous pathogenic variants in the ALDH7A1 gene encoding alpha-aminoadipic semialdehyde dehydrogenase (antiquitin). Antiquitin is involved in lysine catabolism in the central nervous system 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-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 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 enzyme activity seem to have a more favorable developmental prognosis.
References
Coughlin et al. 2019, J Inherit Metab Dis 42:353 / Al Teneiji et al. 2017, Metab Brain Dis 32:443 / van Karnebeek et al. 2016, Pediatr Neurol 59:6 / Stockler et al. 2011, Mol Genet Metab 104:48 / Mills et al. 2010, Brain 133:2148 / Scharer et al. 2010, J Inherit Metab Dis 33:571 / Pérez et al. 2007, Hum Mutat 28:19 / Mills et al. 2006, Nat Med 12:307 / Baxter et al. 2001, Dev Med Child Neurol 43:416