From the Research Division Translational Genomics of Neurodegenerative Diseases (A.T., M. Synofzik), Hertie-Institute for Clinical Brain Research and Center of Neurology, and German Center for Neurodegenerative Diseases (DZNE) (A.T., M. Synofzik), University of Tübingen; Department of Neurology and German Center for Vertigo and Balance Disorders (F.H., A.Z., M. Strupp), University Hospital, Ludwig-Maximilians University, Munich, Germany; Department of Biochemistry (M.B.), Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Institute of Medical Genetics and Applied Genomics (A.M.H., D.R.), University of Tübingen, Germany; Department of Psychiatry and Psychotherapy (M.B., C.D., O.R., T.H.), Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Austria; and Center for Rare Diseases (C.D., O.R., T.H.), University of Tübingen, Germany.
Neurology. 2023 Sep 5;101(10):e1001-e1013. doi: 10.1212/WNL.0000000000207553. Epub 2023 Jul 17.
Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP.
The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification).
Biallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34-72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6-8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease.
This study identifies RFC1 as the first-and frequent-monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution of spectrum disease, with implications for designing natural history studies and future treatment trials.
This study provides Class II evidence that RFC1 repeat expansions cause BVP.
双侧前庭病（BVP）是一种慢性致残性神经系统疾病，尽管表现相似，但目前尚未确定其单一的遗传病因。我们假设复制因子复合物亚基 1（RFC1）重复扩展可能是 BVP 的一种复发性单基因病因。
本研究涉及对来自三级平衡障碍转诊中心的 168 例特发性至少“可能 BVP”的连续患者进行 RFC1 筛查以及深入的神经病学、前庭眼动和疾病演变表型分析，其中 127 例符合当前 BVP 的诊断标准（Bárány 学会分类）。
在 127 例 BVP 患者和 41 例可能 BVP 患者中发现了 RFC1 中的双等位基因 AAGGG 重复扩展。与参考人群相比，127 例患者中有 10 例存在杂合扩展。RFC1 相关的 BVP 中位发病年龄为 60 岁（范围 34-72 岁），主要与轻度多发性神经病（10/11）共存。小脑受累（7/11）较为轻微，仅在早期出现眼动征，尚未达到经典小脑共济失调、神经病和前庭反射缺失综合征的识别水平。构音障碍、四肢共济失调或小脑萎缩在发病后 6-8 年发展。构音障碍、髌反射缺失和下跳性眼球震颤可最佳区分 RFC1 阳性 BVP 和 RFC1 阴性 BVP，但感觉症状或精细运动问题均不能区分。RFC1 阳性 BVP 患者的视频头脉冲增益低于 RFC1 阴性 BVP 患者，并且在疾病持续 10 年期间持续下降，表明这是 RFC1 疾病进展和结局的潜在标志物。
本研究确定了 RFC1 是 BVP 的第一个也是常见的单基因病因。它将 RFC1 相关的 BVP 描述为疾病谱的多系统演变的一部分，这对设计自然史研究和未来的治疗试验具有重要意义。
本研究提供了 II 级证据，证明 RFC1 重复扩展会导致 BVP。
