Clinical characteristics: Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B₆ vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%.

About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures.

Diagnosis/testing: The diagnosis of PNPO deficiency is established in a proband with suggestive findings (i.e., infantile onset of a wide range of seizure types resistant to common anti-seizure medications and a positive standardized vitamin B₆ trial) and (most commonly) biallelic pathogenic variants in PNPO identified by molecular genetic testing or deficient PNPO enzyme activity.

Management: Targeted therapy: Pharmacologic treatment: PLP, the active form of vitamin B₆, is typically given orally, divided into 4-6 single daily doses. The lowest effective PLP dose should be used to avoid possible liver toxicity. PN is typically given orally, divided into 3-4 single daily doses. PN side effects can include sensory (or motor) neuropathy, usually reversible with dose reduction.

Supportive care: Supportive care often includes specialists from multiple disciplines such as neurology, developmental pediatrics, speech-language therapy, physical therapy, occupational therapy, and mental health.

Surveillance: Routine monitoring of seizure control and possible adverse effects of PLP therapy; neurologic examination for emergence of new findings and/or response to medications used in symptomatic treatment; and assessment of development/educational needs.

Agents/circumstances to avoid: Avoid anti-seizure medications (such as carbamazepine, valproate, phenytoin, and phenobarbital) that can reduce plasma PLP concentration. Attention to PLP dose requirements when hydrazines or isoniazid are given to treat other conditions.

Evaluation of relatives at risk: When prenatal testing has not been performed on a pregnancy at risk, prompt evaluation of a newborn sib is essential to determine if treatment with either PN or PLP is necessary.

Pregnancy management: Although empiric data on the utility of maternal PN supplementation during pregnancy for a fetus known to have or be at risk for PNPO deficiency are limited, consider giving 50-100 mg/day of PN to the mother during the last 20 weeks of pregnancy. PN (not PLP) supplementation is recommended for two reasons: the mother has the capacity to metabolize PN into PLP, and the risk of PLP hepatotoxicity in pregnancy is unknown.

Genetic counseling: PNPO deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PNPO pathogenic variant, each sib of an affected individual, irrespective of sex, has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once both PNPO pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for PNPO deficiency are possible.