Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment

Abstract

Pyridoxine dependency is an uncommon but important cause of intractable seizures presenting in infancy and early childhood. This paper discusses recent clinical, biochemical and genetic studies and how the findings should change our approach in evaluating young patients with antiepileptic drug-resistant seizures. Originally thought to be due to abnormal binding of pyridoxal phosphate to glutamic acid decarboxylase resulting in decreased gamma-aminobutyric acid, mutations in the gene encoding this enzyme have been ruled out. While linkage to 5q31 has been demonstrated, a disease-causing gene in that region has not been identified. Further haplotype analysis of six affected kindreds has demonstrated genetic heterogeneity for this rare disorder. Other studies demonstrate that some children with intractable seizures respond to pyridoxal phosphate rather than pyridoxine, including a rare form of neonatal epileptic encephalopathy shown to be due to mutations in the PNPO gene for pyridox(am)ine 5'-phosphate oxidase. While the biochemical explanation for this finding is not clear, elevated pipecolic acid levels may serve as a diagnostic marker for patients with pyridoxine-dependent seizures. The results of these studies should prompt clinicians to adopt new strategies for diagnosis and therapy for young patients with intractable seizures. Levels of both pipecolic acid and certain metabolites shown to be elevated in patients with PNPO mutations should be measured, and therapeutic trials of pyridoxal phosphate as well as pyridoxine should be considered early in the course of the management of infants and young children with intractable seizures.