SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome.
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.



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.



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.



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.
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Anna
A
Schossig
Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France.|Pôle de Médecine et Chirurgie Bucco-dentaires, Centre de Référence des Manifestations Odontologiques des Maladies Rares, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France.|Institut 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.
Agnès
A
Bloch-Zupan
Department of Preventive, Restorative and Pediatric Dentistry, School of Dental Medicine, University of Bern, Bern, Switzerland.
Adrian
A
Lussi
Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Nicole I
NI
Wolf
Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil.|Genetika-Centro de Aconselhamento e Laboratório de Genética, Curitiba, Brazil.
Salmo
S
Raskin
kbo-Kinderzentrum München gGmbH, Munich, Germany.
Monika
M
Cohen
Centre de Référence Anomalies du Développement et Syndromes Malformatifs PACA, Service de Génétique Médicale, CHU Nice, Nice, France.
Fabienne
F
Giuliano
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Julie
J
Jurgens
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Birgit
B
Krabichler
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
David A
DA
Koolen
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nara Lygia
NL
de Macena Sobreira
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Elisabeth
E
Maurer
UFR Odontologie, Département d'Odontologie Pédiatrique, Université de Nice Sophia-Antipolis, UCA, Nice, France.|CHU de Nice, Pôle Odontologie, UF soins pour enfants; Laboratory URB2i-EA 4462, Paris Descartes, France.
Michèle
M
Muller-Bolla
Department of Neuropaediatrics, Klinikum Augsburg, Augsburg, Germany.
Johann
J
Penzien
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Johannes
J
Zschocke
Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck, Austria.
Ines
I
Kapferer-Seebacher
D000483:Alleles; D000567:Amelogenesis Imperfecta / Q000235:genetics*; D001927:Brain Diseases / Q000235:genetics; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D027981:Symporters / Q000235:genetics*; D014070:Tooth
D008565:Membrane Proteins; D009687:Nuclear Proteins; C572461:ROGDI protein, human; C470492:SLC13A5 protein, human; D027981:Symporters
Amelogenesis imperfecta; Epilepsy and seizures; Kohlschütter-Tönz syndrome; Molecular genetics