Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Paris, France.
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom.
EBioMedicine. 2024 Jan;99:104931. doi: 10.1016/j.ebiom.2023.104931. Epub 2023 Dec 27.
SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability.
We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor.
A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees.
SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling.
This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.
由 FGF14 内含子杂合 GAA 扩展引起的 SCA27B，其重复至少为 250 个，占未解决的小脑性共济失调病例的 10-60%。我们旨在评估与对照组相比，小脑性共济失调患者中 FGF14 扩增等位基因的大小和频率，并对遗传和临床变异性进行特征描述。
在这项横断面研究中，我们对来自法国的 1876 名个体进行了这种重复的研究：845 名小脑性共济失调的索引病例和 324 名受影响的亲属、475 名对照者，以及 119 名痉挛性截瘫病例和 113 名家族性特发性震颤病例。
只有在 GAA 重复数超过 300 个（10.1%，n=85）时，与对照组（1.1%，n=5）相比，索引病例中的扩增等位基因携带者的频率才具有统计学意义（p<0.0001），而在两组中均检测到了 1.7%的 GAA 等位基因。14 名 GAA 重复的索引病例中有 8 名（4/14）有其他致病变异，和/或共分离的不一致（5/14），这表明 GAA 并非因果关系。我们将 127 名 GAA 携带者的临床症状与非扩增 GAA 小脑性共济失调的病例进行了比较，从而定义了一个关键的表型三联征：45 岁以后发病、下视性眼球震颤、包括复视在内的阵发性共济失调特征；以及经常没有构音障碍。所有大于 100 个 GAA 的母系传递等位基因都是不稳定的，每代平均增加 18 个重复（r=0.44；p<0.0001）。相比之下，大于 100 个 GAA 的父系传递等位基因大多减少了 15 个 GAA（r=0.63；p<0.0001），导致了 SCA27B 家系中观察到的传递偏倚。
SCA27B 的诊断必须同时考虑表型和 GAA 扩展大小。在 GAA 重复的携带者中，如果没有记录到家族性传播，并且表现与关键的 SCA27B 表型不同，则应提示寻找其他病因。受影响的父亲生育受影响孩子的风险降低，这对遗传咨询具有潜在影响。
这项工作得到了法国医学研究基金会的支持，授予 JLM 13338 号基金，法国小脑综合征协会（Association Connaître les Syndrome Cérébelleux - France）（授予 GS）以及欧盟地平线 2020 研究与创新计划的支持，授予 GS 号项目 779257 号基金（"SOLVE-RD"）。DP 获得了加拿大卫生研究院（CIHR）的奖学金。SK 获得了德国联邦教育和研究部（01GM1905C）的资助，通过 TreatHSP 网络。这项工作得到了澳大利亚政府国家健康与医学研究理事会（GNT2001513 和 MRFF2007677）的资助，资助对象为 MB 和 PJL。
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