title: Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy.
abstract: We report treatment outcome of eleven patients with pyridoxine-dependent epilepsy caused by pathogenic variants in ALDH7A1 (PDE-ALDH7A1). We developed a clinical severity score to compare phenotype with biochemical features, genotype and delays in the initiation of pyridoxine. Clinical severity score included 1) global developmental delay/ intellectual disability; 2) age of seizure onset prior to pyridoxine; 3) current seizures on treatment. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. Five patients had mild, four patients had moderate, and two patients had severe phenotype. Phenotype ranged from mild to severe in eight patients (no lysine-restricted diet in the infantile period) with more than 10-fold elevated urine or plasma α-AASA levels. Phenotype ranged from mild to moderate in patients with homozygous truncating variants and from moderate to severe in patients with homozygous missense variants. There was no correlation between severity of the phenotype and the degree of α-AASA elevation in urine or genotype. All patients were on pyridoxine, nine patients were on arginine and five patients were on the lysine-restricted diet. 73% of the patients became seizure free on pyridoxine. 25% of the patients had a mild phenotype on pyridoxine monotherapy. Whereas, 100% of the patients, on the lysine-restricted diet initiated within their first 7 months of life, had a mild phenotype. Early initiation of lysine-restricted diet and/or arginine therapy likely improved neurodevelopmental outcome in young patients with PDE-ALDH7A1.
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Al Teneiji
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Theodora U J
authors.initials: TU
authors.lastname: Bruun
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Dawn
authors.initials: D
authors.lastname: Cordeiro
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Jaina
authors.initials: J
authors.lastname: Patel
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Michal
authors.initials: M
authors.lastname: Inbar-Feigenberg
authors.affiliation: Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Shelly
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Metabolic Laboratory, Department of Clinical Chemistry, VU Medical Centre, Amsterdam, The Netherlands.
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada. saadet.mahmutoglu@sickkids.ca.|Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, 525 University Avenue, Suite 935, 9th Floor, Toronto, ON, M5G 1X8, Canada. saadet.mahmutoglu@sickkids.ca.
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D000293:Adolescent; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D001120:Arginine / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008239:Lysine; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011736:Pyridoxine / Q000008:administration & dosage / Q000627:therapeutic use*; D012189:Retrospective Studies; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D014815:Vitamins; D015074:2-Aminoadipic Acid; C000061:allysine; D001120:Arginine; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D008239:Lysine; D011736:Pyridoxine
keywords: ALDH7A1; Arginine; Lysine-restricted diet; Pyridoxine; Pyridoxine-dependent epilepsy