Abstracts

Rationale: Pyridoxine is converted to its biologically active form, pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine oxidase (PNPO), and serves as a cofactor in nearly 200 central nervous system reactions. PNPO deficiency leads to P5P dependent epilepsy, typically a neonatal or infantile onset epileptic encephalopathy treatable with P5P or in some cases pyridoxine. Systemic manifestations of PNPO deficiency have been underappreciated.Methods: A case series (N = 5) of patients seen at our center with PNPO deficiency was conducted. Laboratory data, including complete blood count, chemistries, liver function tests, cerebrospinal fluid and genetic studies, and clinical characteristics were collected.Results: All were born prematurely, 3 of 5 had anemia, 3 of 5 had failure to thrive, 2 of 5 had elevated alkaline phosphatase, and 3 of 5 had mild elevations in aspartate aminotransferase. A reversible retinopathy and movement disorder was observed in one patient, who was the most severely affected. All patients had neonatal onset epilepsy and were on a continuum of developmental delay to encephalopathy. EEG features included absence or slowing of the posterior dominant rhythm (3 patients), absent sleep graphoelements (2), and multifocal and generalized spike discharges. Four of 5 had documented mutations in the PNPO gene, including 3 patients with c.674G>T;R225L and 1 patient with c.686 G>A;R229Q.Conclusions: PNPO deficiency causes P5P dependent epilepsy and associated encephalopathy but also a range of systemic manifestations. The degree of encephalopathy appears to correlate with the degree of systemic illness. The retinopathy may be considered analogous to gyrate atrophy associated with mutations in B6-dependent ornithine aminotransferase (OAT) deficiency. OAT requires P5P as a cofactor; therefore, its absence may provide a mechanism for improvement of the retinopathy following P5P administration. The retinopathy and these systemic symptoms add to the broadening clinical spectrum of P5P dependent epilepsy.