title: Pyridoxine responsiveness in novel mutations of the PNPO gene.
abstract: OBJECTIVE
  To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations.
  
  
  METHODS
  We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria.
  
  
  RESULTS
  We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5'-phosphate (PLP).
  
  
  CONCLUSIONS
  This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5'-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.
authors.affiliation: From the Department of Pediatrics (B.P., L.A.), Division of Child Neurology, University Hospital Zurich, Switzerland; the Department of Pediatrics (B.P.), Division of Neurology and Inborn Errors of Metabolism, Medical University Graz, Austria; radiz-"Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich" (B.P., L.A.); CRC Clinical Research Center (B.P.), University Childrens' Hospital Zurich, Switzerland; the Laboratory of Metabolic Diseases (K.P., E.P., D.H.), Department of Pediatrics, University Hospital Graz, Austria; UCL Institute of Child Health (P.M., P.C.), Clinical and Molecular Genetics Unit, London, UK; Childrens Hospital St. Gallen (O.M., O.H.), Switzerland; the Department of Pediatrics (G.H.), Klinikum Esslingen; the Department of Pediatrics (S.K.), St. Marien Hospital, Landshut, Germany; the Division of Child Neurology (M.C.) and Division of Biochemical Diseases (S.S.), Department of Pediatrics, University of British Columbia, Vancouver, Canada; the Department of Pediatrics, Division of Child Neurology (N.W.), VU University Medical Center and Neuroscience Campus Amsterdam; and the Department of Clinical Chemistry (E.S.), Vrije Universiteit Amsterdam, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Karl
authors.initials: K
authors.lastname: Paul
authors.forename: Philippa
authors.initials: P
authors.lastname: Mills
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
authors.forename: Oliver
authors.initials: O
authors.lastname: Maier
authors.forename: Oswald
authors.initials: O
authors.lastname: Hasselmann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schmiedel
authors.forename: Simone
authors.initials: S
authors.lastname: Kanz
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Nicole
authors.initials: N
authors.lastname: Wolf
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler
authors.forename: Lucia
authors.initials: L
authors.lastname: Abela
authors.forename: Doris
authors.initials: D
authors.lastname: Hofer
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000483:Alleles; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D016466:CHO Cells; D002872:Chromosome Deletion; D003412:Cricetulus; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D057915:Drug Substitution; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006580:Genetic Carrier Screening; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D011732:Pyridoxal Phosphate / Q000627:therapeutic use; D011734:Pyridoxaminephosphate Oxidase / Q000172:deficiency* / Q000235:genetics; D011736:Pyridoxine / Q000627:therapeutic use*; D012640:Seizures / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D013036:Spasms, Infantile / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D013226:Status Epilepticus / Q000139:chemically induced
chemical_list: D011732:Pyridoxal Phosphate; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D011734:Pyridoxaminephosphate Oxidase; D011736:Pyridoxine