pyridoxinedependent

Pyridoxinedependent refers to a group of conditions in which seizures or epileptic encephalopathy are responsive to pyridoxine (vitamin B6) and are caused by defects in vitamin B6 metabolism or utilization. The best characterized form is pyridoxine-dependent epilepsy (PDE), an autosomal recessive disorder most commonly due to biallelic mutations in the ALDH7A1 gene (antiquitin). ALDH7A1 deficiency leads to accumulation of reactive metabolites that inactivate pyridoxal phosphate, the active form of vitamin B6, resulting in seizures that typically begin in the neonatal period or early infancy and may be refractory to standard antiseizure medications but rapidly remit with high-dose pyridoxine treatment.

Pathophysiology and diagnosis: PDE arises from impaired detoxification of certain amino-acid-derived compounds, with accumulation of pipecolic acid and alpha-amino adipic semialdehyde (AASA). These metabolites can sequester pyridoxal phosphate, causing functional B6 deficiency in the brain. Diagnosis is supported by a dramatic clinical response to an acute intravenous pyridoxine test (often 100 mg), followed by genetic testing for ALDH7A1 mutations. Biochemical markers, such as elevated pipecolic acid and AASA in blood or urine, can aid confirmation.

Management and prognosis: Acute management involves rapid administration of intravenous pyridoxine to determine response, followed by long-term high-dose oral pyridoxine supplementation, with dosing tailored to weight and clinical response. Lifelong pyridoxine therapy is typically required. A related condition, PNPO deficiency, also causes B6-responsive seizures but generally requires pyridoxal phosphate rather than pyridoxine. Early recognition and treatment improve seizure control and developmental outcomes, though prognosis varies with timing of diagnosis and associated neurological factors.