From Sorbonne Université (G.C., C.E., B.F., M.-L.M., F.M., M.P., C.-S.D., G.S., A.D.), Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière; Department of Genetics (G.C., C.E., M.-L.M., P.C., F.M., G.B., G.S., A.D.), Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, Paris, France; Center for Neurology and Hertie Institute for Clinical Brain Research (R.S., M.S., L.S.), University of Tübingen, German Center for Neurodegenerative Diseases; German Center for Neurodegenerative Diseases (R.S., M.S., L.S.), Tübingen; Department of Neurology (B.P.C.v.d.W., E.G.H.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Neurogenetics Group (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), University of Antwerp; Laboratories of Neurogenetics and Neuromuscular Pathology (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), Institute Born-Bunge, University of Antwerp; Department of Neurology (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), Antwerp University Hospital, Belgium; Scientific Institute IRCCS "E. Medea" (A.M.), Conegliano, Italy; Department of Neurology (M.A.), Hôpital de Hautepierre, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (M.A.), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (M.A.), Université de Strasbourg; Department of Neurology (B.F.), Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, France; Department of Neurology (T. Klockgether, D.K.), University of Bonn; German Center for Neurodegenerative Diseases (T. Klockgether, D.K.), Bonn; Scientific Institute IRCCS E. Medea Neurorehabilitation Unit (M.G.D.), Bosisio Parini, Lecco, Italy; ULB Center of Human Genetics (I.M.), Brussels, Belgium; Scientific Institute IRCCS E. Medea Laboratory of Molecular Biology (M.T.B.), Bosisio Parini, Lecco, Italy; Department of Neurology With Friedrich-Baur Institute (T. Klopstock), University Hospital of the Ludwig-Maximilians-Universität München; German Center for Neurodegenerative Diseases (T. Klopstock); Munich Cluster for Systems Neurology (T. Klopstock), Germany; Department of Genetics (E.O.-R.), Croix-Rousse University Hospital, Lyon, France; Department of Neurology (C.K.), University of Rostock, Germany; Ecole Pratique des Hautes Etudes (M.P., G.S.), PSL Research University; Sorbonne Université (S.T.d.M.), INSERM, Institut Pierre Louis de Santé Publique, Medical Information Unit, Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris; and Raymond Escourolle Neuropathology Department (D.S., C.D.), Pitié-Salpêtrière University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, France.
Neurology. 2019 Jun 4;92(23):e2679-e2690. doi: 10.1212/WNL.0000000000007606. Epub 2019 May 8.
We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 ().
We analyzed clinical and genetic data from 241 patients with , integrating neurologic follow-up data. One case was examined neuropathologically.
Patients with had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria ( < 0.05), deep sensory loss ( < 0.01), muscle wasting ( < 0.01), ophthalmoplegia ( < 0.05), and sphincter dysfunction ( < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs ( < 0.05), diminished visual acuity due to optic atrophy ( < 0.0001), and deep sensory loss ( < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, < 0.05) and showed ataxia at onset ( < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons.
This is the largest cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.
我们利用一项大型跨国招募研究，对 7 号痉挛性截瘫基因（）的欧洲多国多中心大样本患者进行了基因型-表型相关性分析。
我们分析了 241 名患者的临床和遗传数据，整合了神经学随访数据。对 1 例病例进行了神经病理学检查。
患者发病时的平均年龄为 35.5±14.3 岁（n=233），表现为痉挛性（n=89）、共济失调（n=74）或两者兼有（n=45）。在首次就诊时，病程较长（>20 年，n=62）的患者更易出现小脑性构音障碍（<0.05）、深感觉丧失（<0.01）、肌肉萎缩（<0.01）、眼肌麻痹（<0.05）和括约肌功能障碍（<0.05）。在 30 名患者的亚组中，通过共济失调评估量表（Scale for the Assessment and Rating of Ataxia）测量的进展显示平均每年增加 1.0±1.4 分。纯合性功能丧失（LOF）变异体（n=65）患者更常出现锥体束征（<0.05）、视神经萎缩导致的视力下降（<0.0001）和深感觉丧失（<0.0001），而非至少有 1 个错义变异体的患者（n=176）。至少有 1 个 Ala510Val 变异体（58%）的患者年龄更大（37.6±13.7 岁 vs. 32.8±14.6 岁，<0.05），并且在发病时就表现出共济失调（<0.05）。神经病理学检查显示延髓锥体束减少，浦肯野细胞和黑质神经元中度缺失。
这是迄今为止最大的 队列研究，显示 LOF 变异体以痉挛为主的表型，以及携带至少 1 个 Ala510Val 变异体的患者更常出现小脑性共济失调和发病较晚。
