From the Unidad de Enfermedades Neuromusculares, Department of Neurology (M.C.-S., C.P.), Instituto de Biomedicina de Sevilla (IBiS) (M.C.-S., F.M., C.P.), and Department of Pathology, Neuropathology Unit (E.R.), Hospital Universitario Virgen del Rocío, Sevilla, Spain; Laboratoire Diagnostic Génétique (V.B.), Faculté de Médecine-CHRU, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (V.B., R.Á., J.L.), Illkirch, France; Harry Perkins Institute of Medical Research and Centre for Medical Research (B.M., N.G.L., L.K.), University of Western Australia, Nedlands; Department of Pathology (Neuropathology) (A.H.-L.), Hospital Universitario 12 de Octubre, Madrid Research Institute; Neuropathology Unit (M.O.), Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona; Department of Neurology and IIS La Fe (N.M., J.J.V.), Hospital Universitari i Politècnic La Fe, Valencia; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (N.M., J.D.-M., J.J.V.); Department of Neurology (E.K.), Consulta de Enfermedades Neuromusculares y Unidad de ELA, Hospital General Universitario Santa Lucía, Cartagena, Murcia; Department of Neurology (A.C.), Hospital Virgen de las Nieves, Granada; Department of Neurology (P.Q.), Hospital Torrecárdenas, Almería; Unidad de Enfermedades Neuromusculares (J.D.-M.), Department of Neurology, Universidad Autónoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Diagnostic Genomics (M.D.), PathWest Laboratory Medicine WA, Perth, Australia; Department of Neurology (C.D.), Hospital 12 de Octubre, Madrid, Spain; Unité de Morphologie Neuromusculaire (N.B.R.), Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris; Université Sorbonne (N.B.R.), UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France; Department of Medicine (J.J.V.), Universitat de Valencia; Department of Experimental and Health Sciences (D.C.), Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain; Centre National de la Recherche Scientifique (J.L.), UMR7104, Illkirch; and Institut National de la Santé et de la Recherche Médicale (J.L.), U964, Illkirch, France.
Neurology. 2018 Jul 24;91(4):e339-e348. doi: 10.1212/WNL.0000000000005862. Epub 2018 Jun 27.
To describe a large series of patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.
Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for mutations. Clinical, histologic, radiologic, and genetic features were analyzed.
Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma.
We have identified a founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
描述一个大型患者群体，在这些患者中发现了一种西班牙南部罗马人群中的新型创始突变。
在西班牙 5 家主要神经肌肉疾病参考中心（n = 53）诊断为中心核肌病（CNM）的患者中筛选出突变。分析了临床、组织学、影像学和遗传特征。
13 个家庭的 18 名患者携带 p.Arg234Cys 变异体；其中 16 名患者为纯合子，2 名患者为复合杂合子 p.Arg234Cys/p.Arg145Cys 突变。这两种变体仅在罗马人中发现，导致我们队列中该族群 100%的 CNM。单体型分析证实所有家庭都是相关的。除了 CNM 的典型临床特征，如近端肢体无力和眼肌麻痹外，我们队列中的大多数患者还表现出明显的轴向无力，常伴有僵硬的脊柱。肌肉影像学显示椎旁肌肉严重脂肪替代。这种表型似乎是 p.Arg234Cys 突变特有的，在其他突变中没有报道过。对于 p.Arg234Cys/p.Arg145Cys 突变的 2 名复合杂合子患者，观察到极端的临床变异性，从先天性发病伴灾难性结局到迟发性疾病。对欧洲罗马人对照（n = 758）进行 p.Arg234Cys 变体筛查，发现西班牙罗马人中的携带频率为 3.5%。
我们已经确定了一个与高度特异性表型相关的罗马人创始突变，从目前的队列来看，这是西班牙 CNM 的主要原因。
