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Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions |
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| Authors: | Mark A. Corbett Christel Depienne Liana Veneziano Karl Martin Klein Francesco Brancati Renzo Guerrini Federico Zara Shoji Tsuji Jozef Gecz |
| Affiliation: | 1. Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia;2. Institute of Human Genetics, University Hospital Essen, University Duisburg–Essen, Essen, Germany;3. Institute of Translational Pharmacology, National Research Council, Rome, Italy;4. Departments of Clinical Neurosciences, Medical Genetics, and Community Health Sciences, Hotchkiss Brain Institute and Alberta Children's Hospital, Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada;5. Institute of Translational Pharmacology, National Research Council, Rome, Italy Medical Genetics, Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy Laboratory of Human Functional Genomics, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy;6. Neuroscience and Neurogenetics Department, Meyer Children's Hospital, Florence, Italy;7. Laboratory of Neurogenetics, IRCCS Institute "G. Gaslini", Genoa, Italy;8. Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan |
| Abstract: | Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models. |
| Keywords: | DNA sequencing molecular genetics repeat expansion disorders seizure |