Pyridoxine-dependent epilepsy

PDE-ALDH7A1 is a vitamin B6-responsive epileptic encephalopathy of the central nervous system. Seizures respond poorly to standard anti-seizure medication but are controlled by daily pharmacologic pyridoxine, and the phenotypic spectrum ranges from classic neonatal-onset to atypical late-onset disease. Newborns with the classic presentation develop seizures shortly after birth, often preceded by encephalopathy with irritability, fluctuating tone and poor feeding; affected neonates are frequently misdiagnosed initially as hypoxic-ischaemic encephalopathy. Mothers may recall unusual intrauterine movements from the late second trimester, likely representing fetal seizures. Atypical late-onset presentations occur after age 2 months and as late as adolescence; some individuals show initial response to anti-seizure medication that subsequently fails, while others exhibit delayed pyridoxine responsiveness. Intellectual disability is common, and earlier seizure onset and longer diagnostic delay are associated with poorer cognitive outcome, although individuals with normal intellectual function have been reported.

The estimated incidence is 1 per 64,352 live births (as of 2019). This figure derives from based on 185 reported individuals.

Pyridoxine-dependent epilepsy is caused by germline biallelic pathogenic variants in ALDH7A1 (5q23.2), the sole disease-associated gene. The gene encodes α-aminoadipic semialdehyde dehydrogenase (antiquitin), which functions in the saccharopine pathway of L-lysine catabolism. Reduced antiquitin activity leads to accumulation of Δ1-piperideine-6-carboxylate, which condenses with and inactivates pyridoxal 5′-phosphate (the active form of vitamin B6); the resulting PLP deficiency disrupts neurotransmitter metabolism and produces seizures responsive to pharmacologic pyridoxine supplementation. The mechanism of disease causation is loss of function.

Pyridoxine-dependent epilepsy is inherited in an autosomal recessive manner. The parents of an affected individual are typically obligate carriers of one pathogenic ALDH7A1 variant. Each pregnancy of two carriers carries a 25% recurrence risk for an affected child, a 50% risk of an asymptomatic carrier and a 25% chance of inheriting neither pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is established by molecular genetic testing identifying biallelic pathogenic variants in ALDH7A1. Supportive biochemical findings include elevated α-aminoadipic semialdehyde (α-AASA) and pipecolic acid in plasma, urine and CSF, with novel metabolites 6-oxo-pipecolate and 2-OPP detectable by next-generation metabolic screening. Brain MRI may show thinning of the corpus callosum and other structural abnormalities. Clinical response to pyridoxine is supportive but not diagnostic.

Main differential diagnoses include:

• PNPO deficiency: neonatal-onset seizures responsive to pyridoxal 5′-phosphate rather than pyridoxine; PNPO
• PLPBP (PLPHP) deficiency: seizures with onset within the first week of life, responsive to PN or PLP; PLPBP
• Pyridoxine-responsive seizures: intractable seizures may have only partial improvement in seizure control with the addition of pyridoxine; ALDH4A1, ALPL, CACNA1A, KCNQ2, MOCS2, PGAP3, PIGA, PIGL, PIGO, PIGS, PIGV
• Molybdenum cofactor deficiency: neonatal seizures with secondary α-AASA elevation and elevated S-sulfocysteine; GPHN, MOCS1, MOCS2, MOCS3

• Establishing the diagnosis: A molecular genetic diagnosis confirms the underlying cause, distinguishes the condition from clinical and biochemical mimics and ends the diagnostic odyssey for affected individuals and their families.
• Surveillance and clinical management: Identification of a pathogenic variant is a prerequisite for individualised surveillance and targeted medical care, including monitoring of seizure control, developmental progress and treatment-related complications, decided by the treating physicians in consultation with the affected individual.
• Family member testing: Once the familial pathogenic variants are known, predictive and carrier testing of at-risk relatives and reproductive counselling become technically possible.

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