中年和老年人轴索性神经病的遗传特征：重点关注.
The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .
机构信息
From the Friedrich-Baur-Institute (J.S., B.S.-W., M.W.), Department of Neurology, LMU Munich, Germany; DNA Laboratory (P.L., P.S.), Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic; Neuromuscular Unit (D.K., A.K.), Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland; Dr. John T. Macdonald Foundation Department of Human Genetics (L.A., A.R., S.Z.), John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL; Neurogenetics Group (J.B., T.D., P.D.J.), Center for Molecular Neurology, University of Antwerp; Institute Born-Bunge (J.B., T.D., P.D.J.), University of Antwerp; Neuromuscular Reference Centre (J.B., P.D.J.), Department of Neurology, Antwerp University Hospital, Belgium; Department of Clinical Chemistry and Laboratory Medicine (C.B.), Jena University Hospital; Centogene AG (C.B.), Rostock, Germany; Department of Medical Genetics (G.J.B., H.H.), Telemark Hospital Trust, Skien, Norway; Neurology Department (D.B., A.L., J. Weishaupt), Ulm University, Germany; Department of Neurology (J.D., D. Walk), University of Minnesota, Minneapolis; Department of Neurology (L.D.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Sleep Medicine and Neuromuscular Diseases (B.D., A.S., P.Y.), University of Münster; Institute of Human Genetics (K.E., I.K.), Medical Faculty, RWTH Aachen University, Germany; Sydney Medical School (M.E., M.K., G.N.), Concord Hospital, Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, Australia; Department of Orthopaedics and Trauma Surgery (C.F., K.K., D. Weinmann, R.W., S.T., M.A.-G.), Medical University of Vienna, Austria; AP-HP (T.S.), Institut de Myologie, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, G-H Pitié-Salpêtrière, Paris, France; Department of Neurology (D.N.H.), University of Rochester, NY; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Department of Neurology (S.I.), Konventhospital der Barmherzigen Brüder Linz; Karl Chiari Lab for Orthopaedic Biology (K.K., D. Weinmann, S.T.), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Austria; Stanford Center for Undiagnosed Diseases (J.N.K.), Stanford, CA; Undiagnosed Diseases Network (UDN) (J.N.K., S.Z.); Centre for Medical Research (N.G.L., R.O., G.Ravenscroft), University of Western Australia, Nedlands; Harry Perkins Institute of Medical Research (N.G.L., R.O., G. Ravenscroft), Nedlands; Neurogenetic Unit (P.J.L.), Royal Perth Hospital, Perth, Australia; Department of Neurology (W.N.L., J. Wanschitz), Medical University of Innsbruck, Austria; Department of Neurosciences and Behavior (W.M.), Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Neurology (S.P.), Hannover Medical School, Germany; Department of Clinical and Experimental Medicine (G. Ricci), University of Pisa, Italy; Institute of Human Genetics (S.R.-S.), Medical University of Innsbruck, Austria; Department of Neurodegenerative Diseases Hertie-Institute for Clinical Brain Research and Center of Neurology (L.S., R.S., M.S.), University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (L.S., R.S., M.S.), Tübingen, Germany; AP-HP (B.F.), Laboratoire de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital de Bicêtre; Le Kremlin-Bicêtre, France; Institute of Human Genetics (T.M.S.), Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg; Institute for Human Genetics (T.M.S.), Technical University Munich; and Institut für Klinische Genetik (J. Wagner), Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Germany.
出版信息
Neurology. 2020 Dec 15;95(24):e3163-e3179. doi: 10.1212/WNL.0000000000011132. Epub 2020 Nov 3.
OBJECTIVE
To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.
METHODS
We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.
RESULTS
In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance.
CONCLUSIONS
A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.
目的
为了验证单基因神经病（如遗传性运动感觉神经病，CMT）导致老年人中常见但常常无法解释的神经病这一假说，我们对 230 名发病年龄≥35 岁且病因不明的轴索性神经病患者进行了基因分析。
方法
我们招募了患者，收集了临床数据，并进行了外显子组测序（WES；n=126）和单基因测序（n=104）。我们进一步在 WES 存储库中查询了变异体，并测量了血液中 -编码蛋白 Neprilysin 的水平。
结果
在 WES 队列中，假设引起 CMT 或其他与神经病相关的疾病的基因中的致病变异的总体检出率为 18.3%（家族性病例为 26.4%，明显散发性病例为 12.3%）。 最常受累，占基因解决病例的 34.8%。在另一个独立的患者样本中检测到了类似比例的病例，患者中 变异体的比例明显高于人群频率，从 WES 存储库中检索到了额外的携带 变异体的迟发性神经病患者，以及患者血液样本中 Neprilysin 水平较低，这些都进一步支持了 与迟发性神经病的相关性。 变异体的传递通常与不完全外显的常染色体显性遗传特征一致，而较少与常染色体隐性遗传特征一致。
结论
一部分病因不明的迟发性轴索性神经病是由 CMT 基因或影响周围神经并可模拟 CMT 表型的其他疾病相关基因中的变异体引起的。 变异体可以作为完全外显的隐性等位基因起作用，但也可以在衰老人群中赋予对轴索性神经病的显性遗传易感性。
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