title: Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.
abstract: Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine-6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds.
authors.affiliation: Department of Pediatrics, Medical University Graz, Graz, Austria. barbara.plecko@meduni-graz.at
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Karl
authors.initials: K
authors.lastname: Paul
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stoeckler-Ipsiroglu
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Hans
authors.initials: H
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Luecke
authors.forename: Matteo
authors.initials: M
authors.lastname: di Capua
authors.forename: Christoph
authors.initials: C
authors.lastname: Korenke
authors.forename: Christiane
authors.initials: C
authors.lastname: Hikel
authors.forename: Elke
authors.initials: E
authors.lastname: Reutershahn
authors.forename: Michael
authors.initials: M
authors.lastname: Freilinger
authors.forename: Fritz
authors.initials: F
authors.lastname: Baumeister
authors.forename: Friedrich
authors.initials: F
authors.lastname: Bosch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Erwa
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009154:Mutation; D011732:Pyridoxal Phosphate / Q000172:deficiency; D011736:Pyridoxine / Q000627:therapeutic use*; D017386:Sequence Homology, Amino Acid; D026681:Vitamin B 6 Deficiency / Q000235:genetics
chemical_list: D011732:Pyridoxal Phosphate; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D011736:Pyridoxine