TBC1D24 genotype-phenotype correlation

Simona Balestrini, Mathieu Milh, Claudia Castiglioni, Kevin Lüthy, Mattea J. Finelli, Patrik Verstreken, Aaron Cardon, Barbara Gnidovec Stražišar, J. Lloyd Holder, Gaetan Lesca, Maria M. Mancardi, Anne L. Poulat, Gabriela M. Repetto, Siddharth Banka, Leonilda Bilo, Laura E. Birkeland, Friedrich Bosch, Knut Brockmann, J. Helen Cross, Diane DoummarTemis M. Félix, Fabienne Giuliano, Mutsuki Hori, Irina Hüning, Hulia Kayserili, Usha Kini, Melissa M. Lees, Girish Meenakshi, Leena Mewasingh, Alistair T. Pagnamenta, Silvio Peluso, Antje Mey, Gregory M. Rice, Jill A. Rosenfeld, Jenny C. Taylor, Matthew M. Troester, Christine M. Stanley, Dorothee Ville, Magdalena Walkiewicz, Antonio Falace, Anna Fassio, Johannes R. Lemke, Saskia Biskup, Jessica Tardif, Norbert F. Ajeawung, Aslihan Tolun, Mark Corbett, Jozef Gecz, Zaid Afawi, Katherine B. Howell, Karen L. Oliver, Samuel F. Berkovic, Ingrid E. Scheffer, Fabrizio A. De Falco, Peter L. Oliver, Pasquale Striano, Federico Zara, Phillipe M. Campeau, S. M. Sisodiya

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalNeurology
Volume87
Issue number1
DOIs
Publication statusPublished - Jul 5 2016

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Genetic Association Studies
Mutation
Myoclonic Epilepsy
Epilepsy
Brain Diseases
Neuroimaging
Electroencephalography
Computer Simulation
Genes
Physical Examination
Seizures
Phenotype
Research

ASJC Scopus subject areas

  • Medicine(all)
  • Clinical Neurology

Cite this

Balestrini, S., Milh, M., Castiglioni, C., Lüthy, K., Finelli, M. J., Verstreken, P., ... Sisodiya, S. M. (2016). TBC1D24 genotype-phenotype correlation. Neurology, 87(1), 77-85. https://doi.org/10.1212/WNL.0000000000002807

TBC1D24 genotype-phenotype correlation. / Balestrini, Simona; Milh, Mathieu; Castiglioni, Claudia; Lüthy, Kevin; Finelli, Mattea J.; Verstreken, Patrik; Cardon, Aaron; Stražišar, Barbara Gnidovec; Holder, J. Lloyd; Lesca, Gaetan; Mancardi, Maria M.; Poulat, Anne L.; Repetto, Gabriela M.; Banka, Siddharth; Bilo, Leonilda; Birkeland, Laura E.; Bosch, Friedrich; Brockmann, Knut; Cross, J. Helen; Doummar, Diane; Félix, Temis M.; Giuliano, Fabienne; Hori, Mutsuki; Hüning, Irina; Kayserili, Hulia; Kini, Usha; Lees, Melissa M.; Meenakshi, Girish; Mewasingh, Leena; Pagnamenta, Alistair T.; Peluso, Silvio; Mey, Antje; Rice, Gregory M.; Rosenfeld, Jill A.; Taylor, Jenny C.; Troester, Matthew M.; Stanley, Christine M.; Ville, Dorothee; Walkiewicz, Magdalena; Falace, Antonio; Fassio, Anna; Lemke, Johannes R.; Biskup, Saskia; Tardif, Jessica; Ajeawung, Norbert F.; Tolun, Aslihan; Corbett, Mark; Gecz, Jozef; Afawi, Zaid; Howell, Katherine B.; Oliver, Karen L.; Berkovic, Samuel F.; Scheffer, Ingrid E.; De Falco, Fabrizio A.; Oliver, Peter L.; Striano, Pasquale; Zara, Federico; Campeau, Phillipe M.; Sisodiya, S. M.

In: Neurology, Vol. 87, No. 1, 05.07.2016, p. 77-85.

Research output: Contribution to journalArticle

Balestrini, S, Milh, M, Castiglioni, C, Lüthy, K, Finelli, MJ, Verstreken, P, Cardon, A, Stražišar, BG, Holder, JL, Lesca, G, Mancardi, MM, Poulat, AL, Repetto, GM, Banka, S, Bilo, L, Birkeland, LE, Bosch, F, Brockmann, K, Cross, JH, Doummar, D, Félix, TM, Giuliano, F, Hori, M, Hüning, I, Kayserili, H, Kini, U, Lees, MM, Meenakshi, G, Mewasingh, L, Pagnamenta, AT, Peluso, S, Mey, A, Rice, GM, Rosenfeld, JA, Taylor, JC, Troester, MM, Stanley, CM, Ville, D, Walkiewicz, M, Falace, A, Fassio, A, Lemke, JR, Biskup, S, Tardif, J, Ajeawung, NF, Tolun, A, Corbett, M, Gecz, J, Afawi, Z, Howell, KB, Oliver, KL, Berkovic, SF, Scheffer, IE, De Falco, FA, Oliver, PL, Striano, P, Zara, F, Campeau, PM & Sisodiya, SM 2016, 'TBC1D24 genotype-phenotype correlation', Neurology, vol. 87, no. 1, pp. 77-85. https://doi.org/10.1212/WNL.0000000000002807
Balestrini S, Milh M, Castiglioni C, Lüthy K, Finelli MJ, Verstreken P et al. TBC1D24 genotype-phenotype correlation. Neurology. 2016 Jul 5;87(1):77-85. https://doi.org/10.1212/WNL.0000000000002807
Balestrini, Simona ; Milh, Mathieu ; Castiglioni, Claudia ; Lüthy, Kevin ; Finelli, Mattea J. ; Verstreken, Patrik ; Cardon, Aaron ; Stražišar, Barbara Gnidovec ; Holder, J. Lloyd ; Lesca, Gaetan ; Mancardi, Maria M. ; Poulat, Anne L. ; Repetto, Gabriela M. ; Banka, Siddharth ; Bilo, Leonilda ; Birkeland, Laura E. ; Bosch, Friedrich ; Brockmann, Knut ; Cross, J. Helen ; Doummar, Diane ; Félix, Temis M. ; Giuliano, Fabienne ; Hori, Mutsuki ; Hüning, Irina ; Kayserili, Hulia ; Kini, Usha ; Lees, Melissa M. ; Meenakshi, Girish ; Mewasingh, Leena ; Pagnamenta, Alistair T. ; Peluso, Silvio ; Mey, Antje ; Rice, Gregory M. ; Rosenfeld, Jill A. ; Taylor, Jenny C. ; Troester, Matthew M. ; Stanley, Christine M. ; Ville, Dorothee ; Walkiewicz, Magdalena ; Falace, Antonio ; Fassio, Anna ; Lemke, Johannes R. ; Biskup, Saskia ; Tardif, Jessica ; Ajeawung, Norbert F. ; Tolun, Aslihan ; Corbett, Mark ; Gecz, Jozef ; Afawi, Zaid ; Howell, Katherine B. ; Oliver, Karen L. ; Berkovic, Samuel F. ; Scheffer, Ingrid E. ; De Falco, Fabrizio A. ; Oliver, Peter L. ; Striano, Pasquale ; Zara, Federico ; Campeau, Phillipe M. ; Sisodiya, S. M. / TBC1D24 genotype-phenotype correlation. In: Neurology. 2016 ; Vol. 87, No. 1. pp. 77-85.
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abstract = "Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38{\%}) had myoclonic epilepsies. The other patients carried diagnoses of focal (25{\%}), multifocal (2{\%}), generalized (4{\%}), and unclassified epilepsy (6{\%}), and early-onset epileptic encephalopathy (25{\%}). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.",
author = "Simona Balestrini and Mathieu Milh and Claudia Castiglioni and Kevin L{\"u}thy and Finelli, {Mattea J.} and Patrik Verstreken and Aaron Cardon and Stražišar, {Barbara Gnidovec} and Holder, {J. Lloyd} and Gaetan Lesca and Mancardi, {Maria M.} and Poulat, {Anne L.} and Repetto, {Gabriela M.} and Siddharth Banka and Leonilda Bilo and Birkeland, {Laura E.} and Friedrich Bosch and Knut Brockmann and Cross, {J. Helen} and Diane Doummar and F{\'e}lix, {Temis M.} and Fabienne Giuliano and Mutsuki Hori and Irina H{\"u}ning and Hulia Kayserili and Usha Kini and Lees, {Melissa M.} and Girish Meenakshi and Leena Mewasingh and Pagnamenta, {Alistair T.} and Silvio Peluso and Antje Mey and Rice, {Gregory M.} and Rosenfeld, {Jill A.} and Taylor, {Jenny C.} and Troester, {Matthew M.} and Stanley, {Christine M.} and Dorothee Ville and Magdalena Walkiewicz and Antonio Falace and Anna Fassio and Lemke, {Johannes R.} and Saskia Biskup and Jessica Tardif and Ajeawung, {Norbert F.} and Aslihan Tolun and Mark Corbett and Jozef Gecz and Zaid Afawi and Howell, {Katherine B.} and Oliver, {Karen L.} and Berkovic, {Samuel F.} and Scheffer, {Ingrid E.} and {De Falco}, {Fabrizio A.} and Oliver, {Peter L.} and Pasquale Striano and Federico Zara and Campeau, {Phillipe M.} and Sisodiya, {S. M.}",
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TY - JOUR

T1 - TBC1D24 genotype-phenotype correlation

AU - Balestrini, Simona

AU - Milh, Mathieu

AU - Castiglioni, Claudia

AU - Lüthy, Kevin

AU - Finelli, Mattea J.

AU - Verstreken, Patrik

AU - Cardon, Aaron

AU - Stražišar, Barbara Gnidovec

AU - Holder, J. Lloyd

AU - Lesca, Gaetan

AU - Mancardi, Maria M.

AU - Poulat, Anne L.

AU - Repetto, Gabriela M.

AU - Banka, Siddharth

AU - Bilo, Leonilda

AU - Birkeland, Laura E.

AU - Bosch, Friedrich

AU - Brockmann, Knut

AU - Cross, J. Helen

AU - Doummar, Diane

AU - Félix, Temis M.

AU - Giuliano, Fabienne

AU - Hori, Mutsuki

AU - Hüning, Irina

AU - Kayserili, Hulia

AU - Kini, Usha

AU - Lees, Melissa M.

AU - Meenakshi, Girish

AU - Mewasingh, Leena

AU - Pagnamenta, Alistair T.

AU - Peluso, Silvio

AU - Mey, Antje

AU - Rice, Gregory M.

AU - Rosenfeld, Jill A.

AU - Taylor, Jenny C.

AU - Troester, Matthew M.

AU - Stanley, Christine M.

AU - Ville, Dorothee

AU - Walkiewicz, Magdalena

AU - Falace, Antonio

AU - Fassio, Anna

AU - Lemke, Johannes R.

AU - Biskup, Saskia

AU - Tardif, Jessica

AU - Ajeawung, Norbert F.

AU - Tolun, Aslihan

AU - Corbett, Mark

AU - Gecz, Jozef

AU - Afawi, Zaid

AU - Howell, Katherine B.

AU - Oliver, Karen L.

AU - Berkovic, Samuel F.

AU - Scheffer, Ingrid E.

AU - De Falco, Fabrizio A.

AU - Oliver, Peter L.

AU - Striano, Pasquale

AU - Zara, Federico

AU - Campeau, Phillipe M.

AU - Sisodiya, S. M.

PY - 2016/7/5

Y1 - 2016/7/5

N2 - Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

AB - Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

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