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SLC13A5 is the second gene associated with Kohlschütter–Tönz syndrome
  1. Anna Schossig1,
  2. Agnès Bloch-Zupan2,3,4,
  3. Adrian Lussi5,
  4. Nicole I Wolf6,
  5. Salmo Raskin7,8,
  6. Monika Cohen9,
  7. Fabienne Giuliano10,
  8. Julie Jurgens11,
  9. Birgit Krabichler1,
  10. David A Koolen12,
  11. Nara Lygia de Macena Sobreira11,
  12. Elisabeth Maurer1,
  13. Michèle Muller-Bolla13,14,
  14. Johann Penzien15,
  15. Johannes Zschocke1,
  16. Ines Kapferer-Seebacher16
    1. 1Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
    2. 2Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France
    3. 3Pôle de Médecine et Chirurgie Bucco-dentaires, Centre de Référence des Manifestations Odontologiques des Maladies Rares, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France
    4. 4Institut de Génétique et de Biologie Moléculaire and Cellulaire-Centre Européen de Recherche en Biologie et en Médecine, Université de Strasbourg, IGBMC-CERBM CNRS UMR7104, INSERM U964, Illkirch, France
    5. 5Department of Preventive, Restorative and Pediatric Dentistry, School of Dental Medicine, University of Bern, Bern, Switzerland
    6. 6Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
    7. 7Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil
    8. 8Genetika-Centro de Aconselhamento e Laboratório de Genética, Curitiba, Brazil
    9. 9kbo-Kinderzentrum München gGmbH, Munich, Germany
    10. 10Centre de Référence Anomalies du Développement et Syndromes Malformatifs PACA, Service de Génétique Médicale, CHU Nice, Nice, France
    11. 11McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    12. 12Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
    13. 13UFR Odontologie, Département d'Odontologie Pédiatrique, Université de Nice Sophia-Antipolis, UCA, Nice, France
    14. 14CHU de Nice, Pôle Odontologie, UF soins pour enfants; Laboratory URB2i—EA 4462, Paris Descartes, France
    15. 15Department of Neuropaediatrics, Klinikum Augsburg, Augsburg, Germany
    16. 16Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck, Austria
    1. Correspondence to Dr Ines Kapferer-Seebacher, Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Anichstraße 35, Innsbruck A-6020, Austria; ines.kapferer{at}


    Background Kohlschütter–Tönz syndrome (KTZS) is a rare autosomal-recessive disease characterised by epileptic encephalopathy, intellectual disability and amelogenesis imperfecta (AI). It is frequently caused by biallelic mutations in ROGDI. Here, we report on individuals with ROGDI-negative KTZS carrying biallelic SLC13A5 mutations.

    Methods In the present cohort study, nine individuals from four families with the clinical diagnosis of KTZS and absence of ROGDI mutations as well as one patient with unexplained epileptic encephalopathy were investigated by clinical and dental evaluation, parametric linkage analysis (one family), and exome and/or Sanger sequencing. Dental histological investigations were performed on teeth from individuals with SLC13A5-associated and ROGDI-associated KTZS.

    Results Biallelic mutations in SLC13A5 were identified in 10 affected individuals. Epileptic encephalopathy usually presents in the neonatal and (less frequently) early infantile period. Yellowish to orange discolouration of both deciduous and permanent teeth, as well as wide interdental spaces and abnormal crown forms are major clinical signs of individuals with biallelic SLC13A5 mutations. Histological dental investigations confirmed the clinical diagnosis of hypoplastic AI. In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI.

    Conclusions We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI. Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene. Hypersensitivity of teeth as well as high caries risk requires individual dental prophylaxis and attentive dental management.

    • Epilepsy and seizures
    • Molecular genetics
    • Kohlschütter-Tönz syndrome
    • Amelogenesis imperfecta

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