title: Confirmation of mutations inPROSCas a novel cause of vitamin B6-dependent epilepsy.
abstract: Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPLorALDH4A1). In neonatal seizures, defects inALDH7A1 and PNPOexplain a major fraction of cases. Very recently biallelic mutations inPROSCwere shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6plasma profiles on pyridoxine did not enable the differentiation of patients withPROSCmutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients withPROSCmutations was indistinguishable fromALDH7A1andPNPOdeficiency. We therefore confirmPROSCas a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6profile under pyridoxine treatment.
authors.affiliation: Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.|radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich", University of Zurich, Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.affiliation: Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweier
authors.affiliation: radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich", University of Zurich, Zurich, Switzerland.|Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Anaïs
authors.identifier: 0000-0001-6762-0819
authors.initials: A
authors.lastname: Begemann
authors.affiliation: Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schmitt
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, G. Gaslini Institute, Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Sozialpädiatrisches Zentrum, Dritter Orden, München-Nymphenburg, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Baethmann
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, G. Gaslini Institute, Genova, Italy.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Vari
authors.affiliation: Child Neuropsychiatry, C. Poma Hospital, Mantova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Beccaria
authors.affiliation: IRCCS, University of Genova, G. Gaslini Institute, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Crowther
authors.affiliation: Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Joset
authors.affiliation: Institute of Biochemistry, University of Erlangen-Nuernberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich", University of Zurich, Zurich, Switzerland.|Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Sorina Mihaela
authors.initials: SM
authors.lastname: Papuc
authors.affiliation: radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich", University of Zurich, Zurich, Switzerland.|Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011736:Pyridoxine / Q000627:therapeutic use; D025101:Vitamin B 6 / Q000097:blood / Q000378:metabolism*
chemical_list: C485670:PLPBP protein, human; D011506:Proteins; D025101:Vitamin B 6; D011736:Pyridoxine
keywords: 
  PROSCexome sequencing.; inborn errors of metabolism; neonatal seizures; pyridoxine; vitamin B6
  