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Abstract

Objective

Folinic acid–responsive seizures and pyridoxine-dependent epilepsy are two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to α-aminoadipic semialdehyde (α-AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. We report two patients whose CSF showed the marker of folinic acid–responsive seizures, but who responded clinically to pyridoxine. We performed genetic and biochemical testing of samples from these patients, and seven others, to determine the relation between these two disorders.

Methods

CSF samples were analyzed for the presence of α-AASA and pipecolic acid. DNA sequencing of the ALDH7A1 gene was performed.

Results

Both patients reported here had increased CSF α-AASA, CSF pipecolic acid, and known or likely pathogenic mutations in the ALDH7A1 gene, consistent with α-AASA dehydrogenase deficiency. Analysis of CSF samples from seven other anonymous individuals diagnosed with folinic acid–responsive seizures showed similar results.

Interpretation

These results demonstrate that folinic acid–responsive seizures are due to α-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene. Thus, folinic acid–responsive seizures are identical to the major form of pyridoxine-dependent epilepsy. We recommend consideration of treatment with both pyridoxine and folinic acid for patients with α-AASA dehydrogenase deficiency, and consideration of a lysine restricted diet. The evaluation of patients with neonatal epileptic encephalopathy, as well as those with later-onset seizures, should include a measurement of α-AASA in urine to identify this likely underdiagnosed and treatable disorder. Ann Neurol 2008