Clinical characteristics: Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B₆). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common, particularly in classic PDE-ALDH7A1.

In classic PDE-ALDH7A1, untreated seizures begin within the first weeks to months of life. Dramatic presentations of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Electrographic seizures can occur without clinical correlates.

In atypical PDE-ALDH7A1, findings in untreated individuals can include late-onset seizures beginning between late infancy and age three years, seizures that initially respond to anti-seizure medication and then become intractable, seizures during early life that do not respond to pyridoxine but are subsequently controlled with pyridoxine several months later, and prolonged seizure-free intervals (≤5 months) that occur after discontinuation of pyridoxine.

Diagnosis/testing: The diagnosis of PDE-ALDH7A1 is suspected in a proband with seizures responsive to pyridoxine administration and increased concentration of alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma. The diagnosis is established in a proband with suggestive clinical findings and biallelic pathogenic (or likely pathogenic) variants in ALDH7A1 identified by molecular genetic testing.

Management: Targeted therapies: Targeted therapy requires lifelong pharmacologic supplements of pyridoxine; the rarity of the disorder has precluded controlled studies to evaluate the optimal dose. The International PDE Consortium published clinical practice guidelines recommending pyridoxine doses by age (newborns: 100 mg/day; infants: 30 mg/kg/day with a maximum of 300 mg/day; children, adolescents, and adults: 30 mg/kg/day with a maximum of 500 mg/day) and dietary modifications targeted at reducing lysine intake. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days.

Supportive care: Supportive care for developmental delay and/or intellectual disability follows standard practice.

Prevention of secondary complications: Overuse of pyridoxine can cause a reversible sensory neuropathy.

Surveillance: Recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations include regular assessments by the treating neurologist for control of epilepsy via targeted therapy with pyridoxine, need for concomitant use of anti-seizure medications, and signs of sensory neuropathy, as well as regular assessments of developmental progress and educational needs.

Evaluation of relatives at risk: Prenatal molecular genetic testing of fetuses at risk may be performed to inform maternal pyridoxine supplementation during pregnancy and facilitate initiation of treatment at birth. If prenatal testing has not been performed on a pregnancy at risk, the neonate should receive therapeutic doses of pyridoxine until molecular genetic testing for the family-specific ALDH7A1 variants has been completed.

Pregnancy management: Maternal supplemental pyridoxine at a dose of 50-100 mg/day throughout the last half of pregnancy and after birth may be considered if the fetus is known to be affected or, if diagnostic prenatal testing is not pursued, in an at-risk fetus and neonate until the diagnosis has been ruled out.

Genetic counseling: PDE-ALDH7A1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALDH7A1 pathogenic variant, each sib of an affected individual 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 the ALDH7A1 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for PDE-ALDH7A1 are possible.