Abstract
Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.
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Change history
13 November 2020
A Correction to this paper has been published: https://doi.org/10.1038/s10038-020-00867-w
References
Yasuda T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med J. 1991;17:1–13.
Inoue S. One pedigree of hereditary tremor with epileptiform seizures. Seishin Shinkeigaku Zasshi. 1951;53:33–7.
Kudo J, Kudo T, Yamauchi T. Seven families of heredofamilial tremor with epilepsy. Clin Neurol. 1984;24:1–8.
Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H. Cortical tremor: a variant of cortical reflex myoclonus. Neurology. 1990;40:1561–5.
Inazuki G, Naito H, Ohama E, Kawase Y, Honma Y, Tokiguchi S, et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy—the nosological place of familial essential myoclonus and epilepsy (FEME). Seishin Shinkeigaku Zasshi. 1990;92:1–21.
Uyama E, Tokunaga M, Murakami T, Kuwano A, Kondo I, Uchino M. Familial adult myoclonus epilepsy: a new phenotype of autosomal dominant myoclonic epilepsy. Ann Neurol. 1996;40:505.
Okino S. Familial benign myoclonus epilepsy of adult onset: a previously unrecognized myoclonic disorder. J Neurol Sci. 1997;145:113–8.
Okuma Y, Shimo Y, Shimura H, Hatori K, Hattori T, Tanaka S, et al. Familial cortical tremor with epilepsy: an under-recognized familial tremor. Clin Neurol Neurosurg. 1998;100:75–8.
Guerrini R, Bonanni P, Patrignani A, Brown P, Parmeggiani L, Grosse P, et al. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: a newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2. Brain. 2001;124:2459–75.
Mikami M, Yasuda T, Terao A, Nakamura M, Ueno S, Tanabe H, et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am J Hum Genet. 1999;65:745–51.
Mori S, Nakamura M, Yasuda T, Ueno SI, Kaneko S, Sano A. Remapping and mutation analysis of benign adult familial myoclonic epilepsy in a Japanese pedigree. J Hum Genet. 2011;56:742–7.
Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018;50:581–90.
Yeetong P, Pongpanich M, Srichomthong C, Assawapitaksakul A, Shotelersuk V, Tantirukdham N, et al. TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4. Brain. 2019;142:3360–6.
Florian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, et al. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with familial adult myoclonic epilepsy type 3. Nat Commun. 2019;10:1–14.
Corbett MA, Kroes T, Veneziano L, Bennett MF, Florian R, Schneider AL, et al. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun. 2019;10:1–10.
Kobayashi K, Hitomi T, Matsumoto R, Watanabe M, Takahashi R, Ikeda A. Nationwide survey in Japan endorsed diagnostic criteria of benign adult familial myoclonus epilepsy. Seizure. 2018;61:14–22.
Cen Z, Jiang Z, Chen Y, Zheng X, Xie F, Yang X, et al. Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type I. Brain.2018;141:2280–8.
Lei XX, Liu Q, Lu Q, Huang Y, Zhou XQ, Sun HY, et al. TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy. Eur J Neurol. 2019;26:513–18.
Zeng S, Zhang M, Wang X, Hu Z, Li J, Ki N, et al. Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy. J Med Genet. 2019;56:265–70.
Acknowledgements
The authors thank the BAFME patients, suspected BAFME patients, and the healthy control subjects for their participation. The authors also thank Ms. Kyoko Meguro for her technical assistance.
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Terasaki, A., Nakamura, M., Urata, Y. et al. DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A. J Hum Genet 66, 419–429 (2021). https://doi.org/10.1038/s10038-020-00855-0
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DOI: https://doi.org/10.1038/s10038-020-00855-0
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