SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome

Anna Schossig, Agnès Bloch-Zupan, Adrian Lussi, Nicole I Wolf, Salmo Raskin, Monika Cohen, Fabienne Giuliano, Julie Jurgens, Birgit Krabichler, David A Koolen, Nara Lygia de Macena Sobreira, Elisabeth Maurer, Michèle Muller-Bolla, Johann Penzien, Johannes Zschocke, Ines Kapferer-Seebacher

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)54-62
Number of pages9
JournalJournal of Medical Genetics
Volume54
Issue number1
DOIs
Publication statusPublished - Jan 2017

Cite this

Schossig, A., Bloch-Zupan, A., Lussi, A., Wolf, N. I., Raskin, S., Cohen, M., ... Kapferer-Seebacher, I. (2017). SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome. Journal of Medical Genetics, 54(1), 54-62. https://doi.org/10.1136/jmedgenet-2016-103988
Schossig, Anna ; Bloch-Zupan, Agnès ; Lussi, Adrian ; Wolf, Nicole I ; Raskin, Salmo ; Cohen, Monika ; Giuliano, Fabienne ; Jurgens, Julie ; Krabichler, Birgit ; Koolen, David A ; de Macena Sobreira, Nara Lygia ; Maurer, Elisabeth ; Muller-Bolla, Michèle ; Penzien, Johann ; Zschocke, Johannes ; Kapferer-Seebacher, Ines. / SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 1. pp. 54-62.
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title = "SLC13A5 is the second gene associated with Kohlsch{\"u}tter-T{\"o}nz syndrome",
abstract = "BACKGROUND: Kohlsch{\"u}tter-T{\"o}nz 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.",
keywords = "Alleles, Amelogenesis Imperfecta, Brain Diseases, Cohort Studies, Dementia, Epilepsy, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Humans, Male, Membrane Proteins, Mutation, Nuclear Proteins, Pedigree, Symporters, Tooth, Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "Anna Schossig and Agn{\`e}s Bloch-Zupan and Adrian Lussi and Wolf, {Nicole I} and Salmo Raskin and Monika Cohen and Fabienne Giuliano and Julie Jurgens and Birgit Krabichler and Koolen, {David A} and {de Macena Sobreira}, {Nara Lygia} and Elisabeth Maurer and Mich{\`e}le Muller-Bolla and Johann Penzien and Johannes Zschocke and Ines Kapferer-Seebacher",
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Schossig, A, Bloch-Zupan, A, Lussi, A, Wolf, NI, Raskin, S, Cohen, M, Giuliano, F, Jurgens, J, Krabichler, B, Koolen, DA, de Macena Sobreira, NL, Maurer, E, Muller-Bolla, M, Penzien, J, Zschocke, J & Kapferer-Seebacher, I 2017, 'SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome' Journal of Medical Genetics, vol. 54, no. 1, pp. 54-62. https://doi.org/10.1136/jmedgenet-2016-103988

SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome. / Schossig, Anna; Bloch-Zupan, Agnès; Lussi, Adrian; Wolf, Nicole I; Raskin, Salmo; Cohen, Monika; Giuliano, Fabienne; Jurgens, Julie; Krabichler, Birgit; Koolen, David A; de Macena Sobreira, Nara Lygia; Maurer, Elisabeth; Muller-Bolla, Michèle; Penzien, Johann; Zschocke, Johannes; Kapferer-Seebacher, Ines.

In: Journal of Medical Genetics, Vol. 54, No. 1, 01.2017, p. 54-62.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome

AU - Schossig, Anna

AU - Bloch-Zupan, Agnès

AU - Lussi, Adrian

AU - Wolf, Nicole I

AU - Raskin, Salmo

AU - Cohen, Monika

AU - Giuliano, Fabienne

AU - Jurgens, Julie

AU - Krabichler, Birgit

AU - Koolen, David A

AU - de Macena Sobreira, Nara Lygia

AU - Maurer, Elisabeth

AU - Muller-Bolla, Michèle

AU - Penzien, Johann

AU - Zschocke, Johannes

AU - Kapferer-Seebacher, Ines

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/1

Y1 - 2017/1

N2 - 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.

AB - 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.

KW - Alleles

KW - Amelogenesis Imperfecta

KW - Brain Diseases

KW - Cohort Studies

KW - Dementia

KW - Epilepsy

KW - Exome

KW - Female

KW - Genetic Linkage

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Membrane Proteins

KW - Mutation

KW - Nuclear Proteins

KW - Pedigree

KW - Symporters

KW - Tooth

KW - Clinical Trial

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1136/jmedgenet-2016-103988

DO - 10.1136/jmedgenet-2016-103988

M3 - Article

VL - 54

SP - 54

EP - 62

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 1

ER -