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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Collaborators KTZS Consortium: Clara Joseph, (UFR Odontologie, Département d'Odontologie Pédiatrique, Université de Nice Sophia-Antipolis, UCA, France; CHU de Nice, Pôle Odontologie, UF soins pour enfants), Serge Perelman (Hôpitaux pédiatriques de Nice CHU-Lenval, Nice), Elke von Hülsen (kbo-Kinderzentrum München gGmbH, Munich, Germany), Cleber de Souza (Pontifícia Universidade Católica do Paraná (PUCPR) Curitiba, Brazil), Alfried Kohlschütter (University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany), Otmar Tönz (Kindersptial, Kantonsspital Lucerne, Lucerne, Switzerland), Judith S Verhoeven (Translational MRI, University of Leuven (KU Leuven), Leuven, Belgium).
Contributors AS: conception and design of the study, acquisition and analysis of clinical and genetic data, and draft and revision of the manuscript. AB-Z: acquisition of data, analysis and interpretation, and revision of the manuscript. AL: dental histology. NIW: patient recruitment, acquisition of data and revision of the manuscript. SR, MC and FG: patient recruitment and acquisition of clinical data, and revision of the manuscript. BK: genetic linkage analysis and revision of manuscript. DAK: patient recruitment and acquisition of clinical dental data, and revision of the manuscript. JJ, NLdMS and EM: genetic data analysis and revision of manuscript. MM-B: patient recruitment and acquisition of clinical dental data, and revision of the manuscript. JP: patient recruitment and acquisition of clinical dental data, and revision of the manuscript. JZ: conception and design of the study, acquisition and analysis of clinical and genetic data, draft and revision of the manuscript, and guarantor of the study. IK-S: conception and design of the study, interpretation of dental data, and draft and revision of the manuscript.
Funding This work was supported by grants from the Propter Homines Foundation, Liechtenstein, the French Ministry of Health (National Program for Clinical Research, PHRC 2008 No 4266, amelogenesis imperfecta), the EU-funded project (ERDF) A27 ‘Oro-dental manifestations of rare diseases’, supported by the RMT-TMO Offensive Sciences initiative, INTERREG IV Upper Rhine program and by the INTERREG V RARENET program, the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame programme Investissements d'Avenir labelled ANR-10-IDEX-0002-02. This research was funded by the University of Strasbourg Institute for Advanced Study (USIAS) as part of a USIAS Fellowship granted to Agnès Bloch-Zupan, as well as grants from the US NIH, NHGRI and NEI (T32GM07814, 2T32EY007143-21 and 1U54HG006542).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Committee of the Medical University Innsbruck; French National Commission for Informatics and Liberty; Bioethics Commission of French Ministry of Higher Education and Research.
Provenance and peer review Not commissioned; externally peer reviewed.