Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, Hunan, China.
EBioMedicine. 2024 Apr;102:105077. doi: 10.1016/j.ebiom.2024.105077. Epub 2024 Mar 20.
An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort.
A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar ataxia (EOCA), and 527 multiple system atrophy with predominant cerebellar ataxia (MSA-c) were enrolled. Long-range and repeat-primed PCR were performed to screen for GAA expansions in FGF14. Targeted long-read and whole-genome sequencing were performed to determine repeat size and sequence configuration. A multi-modal study including clinical assessment, MRI, and neurofilament light chain was conducted for disease assessment.
17 GAA-FGF14 positive patients with a (GAA) expansion (12 patients with a GAA-pure expansion, five patients with a (GAA)-[(GAA) (GCA)] expansion) and two possible patients with biallelic (GAA) alleles were identified. The clinical phenotypes of the 19 positive and possible positive cases covered LOCA phenotype, EOCA phenotype and MSA-c phenotype. Five of six patients with EOCA phenotype were found to have another genetic disorder. The NfL levels of patients with EOCA and MSA-c phenotypes were significantly higher than patients with LOCA phenotype and age-matched controls (p < 0.001). NfL levels of pre-ataxic GAA-FGF14 positive individuals were lower than pre-ataxic SCA3 (p < 0.001) and similar to controls.
The frequency of GAA-FGF14 expansion in a large Chinese LOCA cohort was low (1.3%). Biallelic (GAA) alleles and co-occurrence with other acquired or hereditary diseases may contribute to phenotypic variation and different progression.
This study was funded by the National Key R&D Program of China (2021YFA0805200 to H.J.), the National Natural Science Foundation of China (81974176 and 82171254 to H.J.; 82371272 to Z.C.; 82301628 to L.W.; 82301438 to Z.L.; 82201411 to L.H.), the Innovation Research Group Project of Natural Science Foundation of Hunan Province (2020JJ1008 to H.J.), the Key Research and Development Program of Hunan Province (2020SK2064 to H.J.), the Innovative Research and Development Program of Development and Reform Commission of Hunan Province to H.J., the Natural Science Foundation of Hunan Province (2024JJ3050 to H.J.; 2022JJ20094 and 2021JJ40974 to Z.C.; 2022JJ40783 to L.H.; 2022JJ40703 to Z.L.), the Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, 2020LNJJ12 to H.J.), the Central South University Research Programme of Advanced Interdisciplinary Study (2023QYJC010 to H.J.) and the Science and Technology Innovation Program of Hunan Province (2022RC1027 to Z.C.). D.P. holds a Fellowship award from the Canadian Institutes of Health Research (CIHR).
最近发现 FGF14 中的内含子 GAA 重复扩展是 GAA-FGF14 共济失调的原因。我们旨在研究一个大型中国共济失调队列中 GAA-FGF14 共济失调的频率和表型谱。
共纳入了 1216 名患者，包括 399 名典型的迟发性小脑共济失调（LOCA）、290 名早发性小脑共济失调（EOCA）和 527 名多系统萎缩伴主要小脑共济失调（MSA-c）。进行长距离和重复引物 PCR 筛选 FGF14 中的 GAA 扩展。进行靶向长读和全基因组测序以确定重复大小和序列构型。进行多模态研究，包括临床评估、MRI 和神经丝轻链，以评估疾病。
鉴定出 17 名 GAA-FGF14 阳性患者，其（GAA）扩展（12 名患者为 GAA 纯扩展，5 名患者为（GAA）-[(GAA) (GCA)] 扩展）和两名可能的双等位基因（GAA）等位基因患者。19 名阳性和可能阳性病例的临床表型涵盖了 LOCA 表型、EOCA 表型和 MSA-c 表型。六名 EOCA 表型患者中有五名发现患有另一种遗传疾病。EOCA 和 MSA-c 表型患者的 NfL 水平明显高于 LOCA 表型和年龄匹配的对照组（p<0.001）。EOCA 阳性个体的 NfL 水平低于 pre-ataxic SCA3（p<0.001），与对照组相似。
在一个大型中国 LOCA 队列中，GAA-FGF14 扩展的频率较低（1.3%）。双等位基因（GAA）等位基因和与其他获得性或遗传性疾病的共存可能导致表型变异和不同的进展。
该研究发现中国 LOCA 患者中 GAA-FGF14 扩增的频率较低，为 1.3%。双等位基因（GAA）和共突变可能导致表型的多样性和不同的疾病进展。
