title: Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy.
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 alpha-aminoadipic semialdehyde (alpha-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 alpha-AASA and pipecolic acid. DNA sequencing of the ALDH7A1 gene was performed.
  
  
  RESULTS
  Both patients reported here had increased CSF alpha-AASA, CSF pipecolic acid, and known or likely pathogenic mutations in the ALDH7A1 gene, consistent with alpha-AASA dehydrogenase deficiency. Analysis of CSF samples from seven other anonymous individuals diagnosed with folinic acid-responsive seizures showed similar results.
  
  
  CONCLUSIONS
  These results demonstrate that folinic acid-responsive seizures are due to alpha-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 alpha-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 alpha-AASA in urine to identify this likely underdiagnosed and treatable disorder.
authors.affiliation: Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado at Denver, CO, USA. gallagher.renata@tchden.org
authors.forename: Renata C
authors.initials: RC
authors.lastname: Gallagher
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
authors.forename: Gunter
authors.initials: G
authors.lastname: Scharer
authors.forename: Keith
authors.initials: K
authors.lastname: Hyland
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Waters
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.forename: Efraim H
authors.initials: EH
authors.lastname: Rosenberg
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid*; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000627:therapeutic use*; D016014:Linear Models; D008239:Lysine / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010875:Pipecolic Acids / Q000134:cerebrospinal fluid; D011736:Pyridoxine / Q000627:therapeutic use*; D012640:Seizures / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics; D053719:Tandem Mass Spectrometry / Q000379:methods; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D015306:Biogenic Monoamines; D010875:Pipecolic Acids; D014803:Vitamin B Complex; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; C031345:pipecolic acid; D008239:Lysine; D011736:Pyridoxine; D002955:Leucovorin