TBC1D24 genotype–phenotype correlation: Epilepsies and other neurologic features

Balestrini, Simona; Milh, Mathieu; Castiglioni, Claudia; L?thy, Kevin; Verstreken, Patrik; Cardon, Aaron; Stra?i?ar, Barbara Gnidovec; Holder, J. Lloyd; Lesca, Gaetan; Mancardi, Maria M.; Finelli, Mattea J.; Poulat, Anne L.; Repetto, Gabriela M.; Banka, Siddharth; Bilo, Leonilda; Birkeland, Laura E.; Bosch, Friedrich; Brockmann, Knut; Cross, J. Helen; Doummar, Diane; F?lix, Temis M.; Giuliano, Fabienne; Hori, Mutsuki; H?ning, 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....

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.

Citation

Balestrini, S., Milh, M., Castiglioni, C., Lüthy, K., Verstreken, P., Cardon, A., Stražišar, B. G., Holder, J. L., Lesca, G., Mancardi, M. M., Finelli, M. J., Poulat, A. L., Repetto, G. M., Banka, S., Bilo, L., Birkeland, L. E., Bosch, F., Brockmann, K., Cross, J. H., Doummar, D., …Sisodiya, S. (2016). TBC1D24 genotype–phenotype correlation: Epilepsies and other neurologic features. Neurology, 87(1), 77-85. https://doi.org/10.1212/wnl.0000000000002807

• Journal Article Type: Article
• Acceptance Date: Mar 28, 2016
• Online Publication Date: Jun 8, 2016
• Publication Date: Jul 5, 2016
• Deposit Date: Jul 25, 2021
• Publicly Available Date: Jul 27, 2021
• Journal: Neurology
• Print ISSN: 0028-3878
• Electronic ISSN: 1526-632X
• Publisher: American Academy of Neurology
• Peer Reviewed: Peer Reviewed
• Volume: 87
• Issue: 1
• Pages: 77-85
• DOI: https://doi.org/10.1212/wnl.0000000000002807
• Keywords: Clinical Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/5832356
• Publisher URL: https://n.neurology.org/content/87/1/77