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Abstract

Abstract 

  1. Pyridoxine-dependent epilepsy (PDE) (OMIM 266100) has been recognized as a clinical entity since 1954. In the classic form of the disorder, seizures are observed within hours of birth. They are resistant to conventional anticonvulsants but cease within an hour of the administration of 50 to 100 mg of pyridoxine. Seizures remain controlled by 5 to 10 mg/kg per d of pyridoxine, restart within a few days when pyridoxine treatment is stopped, and are rapidly controlled again when treatment is restarted. This response to treatment and withdrawal of treatment has been the gold standard for the diagnosis of PDE.

  2. Even with early treatment, most children with PDE have significant learning problems (particularly affecting language skills) on follow-up. Low IQ has been improved by increasing the daily dose of pyridoxine from 5 to 15 mg/kg.

  3. The majority of children with PDE have homozygous or compound heterozygous mutations in the antiquitin (ALDH7A1) gene on chromosome 5q31. The gene product, antiquitin, is a nicotinamide adenine dinucleotide (NAD) +-dependent aldehyde dehydrogenase (ALDH) that is active on α-aminoadipic semialdehyde (α-AASA)--which, in aqueous solution, is in equilibrium with its cyclic Schiff base, L-Δ-piperideine-6-carboxylic acid (P6C). The mutant alleles from children with PDE, when overexpressed in Chinese hamster ovary cells, have an activity of α-AASA:NAD oxidoreductase (EC 1.2.1.31) that is <2% that of wild-type antiquitin

  4. Children with antiquitin (α-AASA dehydrogenase) deficiency accumulate L-pipecolic acid, P6C, and α-AASA consistent with impaired function of the L-pipecolic acid pathway of L- and D-lysine catabolism. This is thought to be the minor pathway for L-lysine catabolism in most tissues, but it is the major pathway in the brain.

  5. P6C reacts with pyridoxal-5′phosphate (PLP) at physiologic temperature and pH to form a Knoevenagel condensation product that no longer has the PLP aldehyde group essential for its function as a cofactor. This is the mechanism that leads to patients’ increased requirement for pyridoxine, a precursor of PLP.

  6. It is likely that the pathogenesis of seizures involves reduction in the concentration of PLP in the brain, with consequent disruption of one or more PLP-dependent reactions in neurotransmitter metabolism, e.g., conversion of glutamate to γ-aminobutyric acid (GABA).

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