Pyridoxine dependent epilepsy

Posted by & filed under Part 08: AMINO ACIDS.

Pyridoxine dependent epilepsy (PDE) was first described by Hunt in 1954. In 1969, Dr Scriver suggested that PDE was caused by reduced binding of pyridoxal phosphate to glutamate decarboxylase leading to buildup of excitotoxic glutamate and deficiency of inhibitory GABA in the brain.

In 2005, a group identified the gene ALDH7A1 encoding antiquitin (P6C-alpha-AASA dehydrogenase) as the culprit in PDE. This astute discovery was made following the report of pipecolic acid accumulation in PDE and by hypothesizing that P6C inactivates pyridoxal phosphate in a similar fashion as P5C in hyperprolinemia type II.

Nat Med. 2006 Mar;12(3):307-9. Epub 2006 Feb 19.
Mutations in antiquitin in individuals with pyridoxine-dependent seizures.
Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA,
Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT.

For great reviews, see:

J Inherit Metab Dis. 2006 Apr;29(2-3):317-26.
B(6)-responsive disorders: A model of vitamin dependency.
Clayton PT.

OMMBID chapter 86.1.

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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

One Response to “Pyridoxine dependent epilepsy”

  1. pcampeau

    Chapter 86.1 abstract:

    Pyridoxine-Dependent Epilepsy Due to -Aminoadipic Semialdehyde Dehydrogenase (Antiquitin) Deficiency

    Author: Peter T. Clayton

    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.

    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.

    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 -aminoadipic semialdehyde (-AASA)–which, in aqueous solution, is in equilibrium with its cyclic Schiff base, L-1-piperideine-6-carboxylic acid (P6C). The mutant alleles from children with PDE, when overexpressed in Chinese hamster ovary cells, have an activity of -AASA:NAD oxidoreductase (EC that is <2% that of wild-type antiquitin

    Children with antiquitin (-AASA dehydrogenase) deficiency accumulate L-pipecolic acid, P6C, and -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.

    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.

    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 -aminobutyric acid (GABA).

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