Pellerin David, Heindl Felix, Traschütz Andreas, Rujescu Dan, Hartmann Annette M, Brais Bernard, Houlden Henry, Dufke Claudia, Riess Olaf, Haack Tobias, Strupp Michael, Synofzik Matthis
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, UK.
J Neurol. 2024 May;271(5):2886-2892. doi: 10.1007/s00415-024-12229-z. Epub 2024 Feb 21.
The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome.
We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN.
Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients.
Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.
尽管最近研究表明，FGF14基因内含子GAA重复序列扩增可解释近50%的不明原因的下跳性眼球震颤（DBN）病例，但仍有相当一部分患者（“特发性”）的DBN病因不明。在此，我们推测双等位基因RFC1扩增可能也是DBN综合征的一个常见病因。
我们对203例DBN患者进行了RFC1重复序列基因分型，并进行了深入的表型分析，其中包括65例特发性DBN患者、102例携带FGF14基因GAA扩增的患者以及36例疑似继发性DBN患者。
在65例特发性DBN患者中，有15例（23%）检测到双等位基因RFC1 AAGGG扩增。102例FGF14基因GAA扩增阳性的患者中均未检测到，但在36例疑似继发性DBN患者中有2例（6%）检测到双等位基因RFC1扩增。RFC1基因阳性患者的DBN综合征具有以下特征：100%（15/15）存在额外的小脑功能损害、100%（15/15）存在双侧前庭病变（BVP）以及80%（12/15）存在多发性神经病。与FGF14基因GAA扩增阳性和基因未明的患者相比，RFC1基因阳性患者在检查时神经病变特征和BVP更为常见。此外，通过视频头脉冲试验测量的前庭功能在RFC1基因阳性患者中受损更为明显。
双等位基因RFC1扩增是DBN综合征常见的单基因病因。
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