Case Study – Late Onset Seizures in Pyridoxamine 5′-Phospate oxidase (PNPO) deficiency

Sarah Weatherspoon, William A. Langley, Kelly Ward, Kristie Patterson, Peter L. Nagy, Keith Hyland

PNPO deficiency is an autosomal recessive disorder that leads to pyridoxal 5’-phosphate deficiency and typically results in neonatal or early onset seizures. The latest age reported for presentation is 5 months in an infant with infantile spasms (Mills et al 2014). Here we reemphasize that PNPO deficiency can respond to pyridoxine and demonstrate that the disorder can present with seizures that first occur after nine months of life. Methods: CSF pyridoxal 5’-phosphate measurement and NGS analysis of the PNPO gene were performed using standard methodologies (Medical Neurogenetics Laboratories) Results: A male child with mild speech delay initially presented with febrile seizures at 10 months of age, followed by nonfebrile convulsive seizures and myoclonic atonic seizures. The patient was admitted for EEG monitoring at 15 months, during which time he developed non convulsive status epilepticus that resolved with phenobarbital. However, he remained severely encephalopathic. Pyridoxine and folinic acid were started empirically while awaiting test results. The encephalopathy resolved after 4 days. Analysis of CSF showed slightly decreased pyridoxal 5’-phosphate (14 nmol/l: ref. range 15-51); neurotransmitter metabolites, alpha aminoadipic semialdehyde and amino acids were unremarkable. NGS analysis revealed two heterozygous pathogenic variants in the PNPO gene (Asp33Val and Arg141Cys). Both variants have been previously associated with pyridoxine responsive PNPO deficiency and in vitro expression studies have demonstrated the activity of each to be approximately 50% of the wild type PNPO activity.