Pyridoxine‐dependent epilepsy: Current perspectives and questions for future research

Abstract

Pyridoxine-dependent epilepsy (PDE) was historically defined by a dramatic clinical response to a trial of pyridoxine and the re-emergence of seizures after withdrawal of pyridoxine. Research conducted over the last seven decades has revealed that the phenotype of PDE results from multiple genetic disorders, and the most common disorder, PDE-ALDH7A1, is caused by a deficiency of an enzyme involved in lysine metabolism. PDE-ALDH7A1 is characterized by more than epilepsy, as many patients have abnormalities of brain development, and most patients have intellectual and developmental disability. Treatment aimed at the underlying metabolic defect, in addition to pyridoxine supplementation, has improved clinical outcomes. Recently discovered biomarkers and genetic testing allow for the diagnosis of PDE-ALDH7A1 without the need of a pyridoxine trial and hold the promise for newborn screening. Despite these many advances, PDE-ALDH7A1 remains a clinical and biochemical conundrum. The increasing use of model systems and an international collaboration of clinician-scientists are among the reasons to be optimistic that these questions will be answered in the near future and that the clinical outcomes and quality of life will continue to improve for patients with PDE-ALDH7A1.

Pearls & Oy-sters: Delayed Response to Pyridoxine in Pyridoxine-Dependent Epilepsy

“…Given that PNPO deficiency is on the differential diagnosis of refractory neonatal epileptic encephalopathy, 3,4,6,9 the addition of enteral PLP should be considered when there is an incomplete response to pyridoxine, as discussed in published protocols. 5 Caused by biallelic pathogenic variants in the PNPO gene, PNPO deficiency also ultimately leads to a decrease in PLP, causing downstream effects on PLP-dependent enzymes.…”

“…4,5 PLP is an active B6 vitamer that acts as a cofactor for multiple essential enzymes; downstream dysregulation of these enzymatic pathways through PLP deficiency causes neonatal epileptic encephalopathy which is salvaged by pyridoxine supplementation. 3–5,10…”

“…Although atypical cases are described, 4,8,10 PDE- ALDH7A1 classically presents in the neonatal period with prolonged and drug-refractory seizures, status epilepticus, and encephalopathy. 6,7,9 Various seizure types are described, including clonic, tonic, myoclonic, autonomic, sequential, and electrographic only.…”

Developmental milestones as ACNS turns one year old

“…2 Curtis Coughlin and Sidney Gospe contributed an outstanding summary of pyridoxine dependency. 3 These authors were instrumental in unraveling the clinical features, genetics, and molecular mechanisms of pyridoxine dependency, so not surprisingly, their review is a tour de force. Nordli and Galan provide a detailed case-based review of magnetoencephalography, a valuable tool for identifying an epileptogenic zone and for pinpointing language, motor, and visual functions in relation to a brain lesion.…”

“…The first article after the opening editorial was Harvey Sarnat's eloquent review of axonal pathfinding and guidance in the development of the nervous system, a basic science topic with obvious clinical relevance 2 . Curtis Coughlin and Sidney Gospe contributed an outstanding summary of pyridoxine dependency 3 . These authors were instrumental in unraveling the clinical features, genetics, and molecular mechanisms of pyridoxine dependency, so not surprisingly, their review is a tour de force .…”