Kakumoto Toshiyuki, Orimo Kenta, Matsukawa Takashi, Mitsui Jun, Ishihara Tomohiko, Onodera Osamu, Suzuki Yuta, Morishita Shinichi, Toda Tatsushi, Tsuji Shoji
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Eur J Hum Genet. 2025 Mar;33(3):325-333. doi: 10.1038/s41431-024-01743-3. Epub 2024 Nov 27.
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic nervous system dysfunction and cerebellar ataxia or parkinsonism. Recently, expanded GAA repeats (≥250 repeat units) in intron 1 of FGF14 have been shown to be responsible for spinocerebellar ataxia type 27B (SCA27B), a late-onset ataxia with an autosomal dominant inheritance. Patients with SCA27B may also exhibit autonomic nervous system dysfunction, potentially overlapping with the clinical presentations of MSA patients. In this study, to explore the possible involvement of expanded GAA repeats in MSA, we investigated the frequencies of expanded GAA repeats in FGF14 in 548 patients with MSA, 476 patients with undiagnosed ataxia, and 455 healthy individuals. To fully characterize the structures of the expanded GAA repeats, long-range PCR products suggesting the expansion of GAA repeats were further analyzed using a long-read sequencer. Of the 548 Japanese MSA patients, we identified one MSA patient (0.2%) carrying an expanded repeat with (GAA). Among the 476 individuals with undiagnosed ataxia, (GAA) was observed in six (1.3%); this frequency was higher than that in healthy individuals (0.2%). The clinical characteristics of the MSA patient with (GAA) were consistent with those of MSA, but not with SCA27B. Further research is warranted to explore the possibility of the potential association of expanded GAA repeats in FGF14 with MSA.
多系统萎缩（MSA）是一种神经退行性疾病，其特征为自主神经系统功能障碍以及小脑性共济失调或帕金森综合征。最近研究表明，成纤维细胞生长因子14（FGF14）基因内含子1中扩展的GAA重复序列（≥250个重复单元）是导致27B型脊髓小脑共济失调（SCA27B）的原因，SCA27B是一种常染色体显性遗传的迟发性共济失调。SCA27B患者也可能表现出自主神经系统功能障碍，这可能与MSA患者的临床表现重叠。在本研究中，为了探究扩展的GAA重复序列与MSA的可能关联，我们调查了548例MSA患者、476例未确诊的共济失调患者和455名健康个体中FGF14基因扩展的GAA重复序列的频率。为了全面表征扩展的GAA重复序列的结构，我们使用长读长测序仪对提示GAA重复序列扩展的长片段PCR产物进行了进一步分析。在548例日本MSA患者中，我们鉴定出1例（0.2%）携带扩展的（GAA）重复序列的MSA患者。在476例未确诊的共济失调患者中，有6例（1.3%）观察到（GAA）；该频率高于健康个体（0.2%）。携带（GAA）的MSA患者的临床特征与MSA一致，但与SCA27B不一致。有必要进行进一步研究，以探索FGF14基因中扩展的GAA重复序列与MSA潜在关联的可能性。
