title: Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum.
abstract: Pyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6' carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported.
  
  
  
  We present a phenotypic spectrum of antiquitin deficiency based on a literature review (2006 to 2015) of reports (n = 49) describing the clinical presentation of confirmed patients (n > 200) and a further six patient vignettes. Possible presentations include perinatal asphyxia; neonatal withdrawal syndrome; sepsis; enterocolitis; hypoglycemia; neuroimaging abnormalities (corpus callosum and cerebellar abnormalities, hemorrhage, white matter lesions); biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities); and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions.
  
  
  
  The phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is refractory seizures during the first year of life. Given its amenability to treatment with lysine-lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of pyridoxine-dependent epilepsy is essential. All infants presenting with unexplained seizures should be screened for antiquitin deficiency by determination of α-aminoadipic semialdehyde/pyrroline 6' carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada. Electronic address: cvankarnebeek@cw.bc.ca.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Tiebout
authors.affiliation: Department of Neurology, St Elisabeth Twee Steden Hospital, Tilburg, The Netherlands.
authors.forename: Jikkemien
authors.initials: J
authors.lastname: Niermeijer
authors.affiliation: Department of Pediatric Neurology, Emma Children's Hospital, University of Amsterdam, AMC, Amsterdam, The Netherlands.
authors.forename: Bwee Tien
authors.initials: BT
authors.lastname: Poll-The
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada.
authors.forename: Aisha
authors.initials: A
authors.lastname: Ghani
authors.affiliation: Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
authors.affiliation: Department of Pediatrics, Children's Hospital auf der Bult, Hannover, Germany; Department of Neuropediatrics, Children's Hospital auf der Bult, Hannover, Germany.
authors.forename: Jost Wigand
authors.initials: JW
authors.lastname: Richter
authors.affiliation: Department of Pediatrics, Children's Hospital auf der Bult, Hannover, Germany; Department of Neuropediatrics, Children's Hospital auf der Bult, Hannover, Germany.
authors.forename: Hans Juergen
authors.initials: HJ
authors.lastname: Christen
authors.affiliation: Department of Medical Genetics, University of California San Francisco, San Francisco, California.
authors.forename: Renata
authors.initials: R
authors.lastname: Gallagher
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Hartmann
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada. Electronic address: sstockler@cw.bc.ca.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
mesh_terms: D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D010641:Phenotype
keywords: B6 vitamer; lysine catabolism; metabolic epilepsy; neonatal encephalopathy; seizures; treatment