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Neurogenetics
Short report
Confirmation of mutations in PROSC as a novel cause of vitamin B 6 -dependent epilepsy
  1. Barbara Plecko1,2,
  2. Markus Zweier3,
  3. Anaïs Begemann2,3,
  4. Deborah Mathis4,
  5. Bernhard Schmitt1,
  6. Pasquale Striano5,
  7. Martina Baethmann6,
  8. Maria Stella Vari5,
  9. Francesca Beccaria7,
  10. Federico Zara8,
  11. Lisa M Crowther1,
  12. Pascal Joset3,
  13. Heinrich Sticht9,
  14. Sorina Mihaela Papuc2,3,
  15. Anita Rauch2,3
  1. 1 Division of Child Neurology, University Children’s Hospital Zurich, Zurich, Switzerland
  2. 2 radiz – “Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich”, University of Zurich, Zurich, Switzerland
  3. 3 Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
  4. 4 Clinical Chemistry, University Children’s Hospital Zurich, Zurich, Switzerland
  5. 5 Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, G. Gaslini Institute, Genova, Italy
  6. 6 Sozialpädiatrisches Zentrum, Dritter Orden, München-Nymphenburg, Munich, Germany
  7. 7 Child Neuropsychiatry, C. Poma Hospital, Mantova, Italy
  8. 8 IRCCS, University of Genova, G. Gaslini Institute, Genova, Italy
  9. 9 Institute of Biochemistry, University of Erlangen-Nuernberg, Erlangen, Germany
  1. Correspondence to Professor Barbara Plecko, Division of Child Neurology, University Children’s Hospital, Steinwiesstrasse 75, 8032 Zurich; Barbara.Plecko{at}kispi.uzh.ch

Abstract

Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPL or ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPO explain a major fraction of cases. Very recently biallelic mutations in PROSC were 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 B6 plasma profiles on pyridoxine did not enable the differentiation of patients with PROSC mutations. 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 with PROSC mutations was indistinguishable from ALDH7A1 and PNPO deficiency. We therefore confirm PROSC as a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6 profile under pyridoxine treatment.

  • neonatal seizures
  • inborn errors of metabolism
  • vitamin B6
  • pyridoxine
  • PROSCexome sequencing.

https://doi.org/10.1136/jmedgenet-2017-104521

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    Footnotes

    • Contributors BP set up the study design, contributed biological samples of patients and drafted the manuscript.

      DM has established the method for vitamin B6 vitamer analysis, ran and interpreted all vitamin B6 assays and gave substantial input to the manuscript.

      BS has contributed biological samples of patients and critically reviewed the manuscript.

      MB provided biological samples and critically reviewed the manuscript.

      PS, MSV and FB provided clinical data and biological samples of patients and revised the manuscript.

      FZ screened some patients for PNPO and ALDH7A1 mutations and provided DNA samples.

      LC has helped in data interpretation and critically reviewed the manuscript.

      MZ and AR contributed substantially to the conception and design of the study, supervised the genetic data acquisition and interpretation and gave major input to the manuscript.

      AB performed the Sanger sequencing, contributed to interpretation of variants and gave input to the manuscript.

      SMP and PJ contributed to the acquisition and interpretation of the whole exome sequencing data.

      HS contributed the mutational modelling.

    • Competing interests None declared.

    • Ethics approval IRB of Zurich.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been updated since it published Online First. The author name Maria Stella Vari has been corrected.