Pyridoxine and pyridoxal-phosphate dependent epilepsies

Antiquitin (ATQ, ALDH7A1) and Pyridox(am)ine phosphate oxidase (PNPO) deficiency are two metabolic encephalopathies which respond to high dosages of pyridoxine and pyridoxal phosphate (PLP). Their common pathophysiological denominator is deficiency of PLP, the active form of all B6 vitamers. In ATQ deficiency, the primary defect resides in lysine catabolism resulting in accumulation of a-aminoadipic semialdehyde (AASA)/pyrroline 6' carboxylate (P6C) and pipecolic acid. PLP is inactivated via a chemical binding with P6C. In PNPO deficiency, reduced synthesis of PLP from pyridoxine(phosphate) and pyridoxamine (phosphate) results in primary PLP deficiency. Clinically both conditions result in neonatal/infantile epileptic encephalopathy with pharmaco-resistant seizures. AASA (and pipecolic acid) are reliable diagnostic markers for ATQ deficiency. In the untreated state, reduced PLP (measured in CSF) is characteristic but not specific for PNPO deficiency. Molecular analysis is required to establish the diagnosis. ATQ and PNPO deficiency are treated with up to 30mg/kg of pyridoxine and/or 30-60 mg/kg of PLP orally. Some patients with PNPO deficiency respond to pyridoxine. High pyridoxine and PLP dosages result in peripheral neuropathy and liver dysfunction. While patients with normal outcomes have been reported, a majority shows neurodevelopmental impairments. Lysine-restricted diet (supplemented with lysine-free amino-acid formula) aimed at reducing AASA/P6C accumulation is an additional treatment option for ATQ deficiency to optimize seizure control and developmental outcomes.