Pyridoxine-dependent Epilepsy (PDE) [G40.8]
Dr. rer. nat. Karin Mayer
Pyridoxine-dependent Epilepsy (PDE) is a condition that begins early in life and is inherited in an autosomal recessive pattern. PDE is unresponsive to all standard anticonvulsants except pyridoxine (vitamin B6). It is thought to have an incidence of between 1:20,000 and 1:500,000. Epileptic seizures usually begin in the first 24 to 48 hours of life (neonatal) but can occur up to 3 years old (late onset disease). Various types of seizures occur (myoclonic, atonic, partial or generalized, and infant spasms). Ventricular enlargement, cerebral atrophy, intracerebral bleeding and / or myelinization disturbances are visible using cerebral imaging. Clinical diagnosis can be confirmed in patients experiencing an acute seizure by the administration of 100 mg, and up to a maximum of 500 mg, pyridoxine intravenously resulting in immediate cessation of the seizure. Additional biomarkers which reinforce the diagnosis are a raised concentration of α-aminoadipic semialdehyde (α-AASA) in urine and plasma as well as raised pipecolic acid in plasma and cerebrospinal fluid.
The molecular cause of PDE is homozygous or combined heterozygous mutations in the ALDH7A1 gene that encodes α-aminoadipic semialdehyde dehydrogenase (antiquitin). Antiquitin is involved in the catabolism of lysine in the central nervous system; it is localized in radial glial cells, astrocytes and ependymal cells. A change in Antiquitin activity leads to an increased concentration of δ1-piperideine-6-carboxylate (P6C), the cyclic Schiff base of α-aminoadipic semialdehyde (α-AASA). P6C in turn, inactivates pyridoxal 5-phosphate (PLP) resulting in abnormal neurotransmitter metabolism. Pyridoxal phosphate, the active metabolite of pyridoxine, is a cofactor for glutamic acid decarboxylase in the formation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), thus its deficiency results in an excess of excitatory neurotransmitters. Antiquitin deficiency leads, among other things, to neural migration disturbances. More than 95% of all ALDH7A1 mutations are point mutations leading to an amino acid substitution or a premature translational stop of protein biosynthesis. Genomic deletions have only been described in isolated cases. The mutation p.Glu399Gln represents 33% of all mutant alleles. There is no clear genotype-phenotype correlation. However, missense mutations with residual enzyme activity seem to have more favorable development prognoses.