多系统 RFC1 病的自然史、表型谱和鉴别特征。
Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
机构信息
From the Department of Neurodegenerative Diseases (A.T., S.R., L.S., M. Synofzik), Hertie-Institute for Clinical Brain Research and Center of Neurology, and German Center for Neurodegenerative Diseases (DZNE) (A.T., S.R., L.S., M. Synofzik), University of Tübingen, Germany; MRC Centre for Neuromuscular Diseases (A.C., N.D., H.H.), Department of Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, London, UK; Department of Brain and Behaviour Sciences (A.C.), University Pavia, Italy; Department of Neurology (J.F., T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (J.F., H.J., T.K.), Bonn; Department of Neurology (H.J.), University Hospital of Heidelberg; Department of Psychiatry, Psychotherapy and Psychosomatics (A.M.H., D.R.), University of Halle, Germany; Département de Neurologie (S.M., M.A.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg; Department of Neurology (A.E.-L.), APHP, CHU de Bicêtre; French National Reference Center for Rare Neuropathies (NNERF) (A.E.-L.); Inserm U1195 and Paris-Sud University (A.E.-L.), Le Kremlin Bicêtre, France; Medical Faculty (S.E.), Department of Neurology, Uludag University, Bursa, Turkey; University of Zurich (V.C.S., A.A.T.); Department of Neurology (V.C.S., A.A.T.), University Hospital Zurich, Switzerland; Institute of Medical Genetics and Applied Genomics (M. Sturm, T.B.H.) and Center for Rare Diseases (T.B.H.), University of Tübingen, Germany; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (N.V.-D., H.P.); INSERM (N.V.-D., H.P.), U1258; CNRS (N.V.-D., H.P.), UMR7104, Illkirch; Université de Strasbourg (H.P.), France; Department of Neurology (B.P.v.d.W.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neurology (M.P.), Karolinska University Hospital; Department of Clinical Neuroscience (M.P.), Karolinska Institute, Stockholm, Sweden; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Essen; Department of Medical Statistics (R.-D.H.), RWTH Aachen University, Germany; Department of Neurology (J.G.), Hospital Universitario Miguel Servet. Zaragoza, Spain; Department of Neurology (M. Strupp), University Hospital, and German Center for Vertigo and Balance Disorders (M.Strupp), Ludwig Maximilians University, Munich, Germany; Neurology Service (G.M.), Hospital Unversitario Central de Asturias (HUCA), SESPA, Oviedo, Spain; Department of Neurosciences and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Institute of Genetics and Molecular and Cellular Biology (M.A.), INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch; Strasbourg Federation of Translational Medicine (M.A.), University of Strasbourg, Strasbourg, France; Service of Neurology (J.I.), University Hospital "Marqués de Valdecilla (IDIVAL)," University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)," Santander, Spain; and Suna and Inan Kıraç Foundation (A.N.B.), Neurodegeneration Research Laboratory, KUTTAM, Koç University School of Medicine, Istanbul, Turkey.
出版信息
Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25.
OBJECTIVE
To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
METHODS
Multimodal repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.
RESULTS
Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.
CONCLUSIONS
RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
目的
描绘复制因子复合物亚基 1（RFC1）重复扩增的全表型谱、鉴别特征、前瞻性进展数据，并进行样本量计算，该扩增最近被确定为导致小脑共济失调、神经病、前庭反射消失综合征（CANVAS）的病因。
方法
采用多模式重复筛查（PCR、Southern 印迹、基于全外显子/基因组测序的方法），结合（1）跨欧洲队列 A（70 个家系）的横断面和纵向深入表型研究，队列 A 中至少有 2 项 CANVAS 或慢性咳嗽共济失调（ACC）特征，或（2）土耳其队列 B（105 个家系）的未选择的晚发性共济失调。
结果
队列 A 中 RFC1 疾病的患病率为 67%，未选择的队列 B 为 14%，临床 CANVAS 为 68%，ACC 为 100%。RFC1 疾病也在西方和东方个体中被发现，甚至通过全外显子测序也可以发现。视觉代偿、感觉症状和咳嗽是强阳性鉴别预测指标（>90%），可与 RFC1 阴性患者区分。70 名 RFC1 阳性患者的表型大多为多系统（69%），包括自主神经功能障碍（62%）和运动迟缓（28%）（与小脑型多系统萎缩[MSA-C]重叠）、姿势不稳（49%）、垂直缓慢扫视（17%）和舞蹈症或肌张力障碍（11%）。共济失调进展约为每年 1.3 个共济失调评定量表（32 项横断面，17 项纵向评估，随访≤9 年[平均 3.1 年]），但也包括早期跌倒、MSA-C 样进展的可变非线性阶段（SARA 每年 2.5-5.5 分）和过早死亡。治疗试验总共需要 330 名（1 年试验）和 132 名（2 年试验）患者，以检测 50%的进展减缓。
结论
RFC1 疾病在各大洲均较为常见，CANVAS 和 ACC 为高度诊断性表型，但在一个连续的多系统疾病谱中，具有多变性和重叠性，包括 MSA-C 重叠。我们的自然病史数据有助于为未来的 RFC1 治疗试验提供信息。
分类证据
本研究提供了 II 级证据，表明 RFC1 重复扩增与 CANVAS 和 ACC 相关。
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