Giulia Coarelli1, Rebecca Schule1, Bart P C van de Warrenburg1, Peter De Jonghe1, Claire Ewenczyk1, Andrea Martinuzzi1, Matthis Synofzik1, Elisa G Hamer1, Jonathan Baets1, Mathieu Anheim1, Ludger Schöls1, Tine Deconinck1, Pegah Masrori1, Bertrand Fontaine1, Thomas Klockgether1, Maria Grazia D'Angelo1, Marie-Lorraine Monin1, Jan De Bleecker1, Isabelle Migeotte1, Perrine Charles1, Maria Teresa Bassi1, Thomas Klopstock1, Fanny Mochel1, Elisabeth Ollagnon-Roman1, Marc D'Hooghe1, Christoph Kamm1, Delia Kurzwelly1, Melanie Papin1, Claire-Sophie Davoine1, Guillaume Banneau1, Sophie Tezenas du Montcel1, Danielle Seilhean1, Alexis Brice1, Charles Duyckaerts1, Giovanni Stevanin1, Alexandra Durr2. 1. 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. 2. 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. alexandra.durr@icm-institute.org.
Abstract
OBJECTIVE: 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 (SPG7). METHODS: We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. RESULTS: Patients with SPG7 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 (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 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 (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 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, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. CONCLUSIONS: This is the largest SPG7 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.
OBJECTIVE: 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 (SPG7). METHODS: We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. RESULTS:Patients with SPG7 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 (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 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 (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 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, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. CONCLUSIONS: This is the largest SPG7 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.
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