Ilaria Giordano1, Florian Harmuth1, Heike Jacobi1, Brigitte Paap1, Stefan Vielhaber1, Judith Machts1, Ludger Schöls1, Matthis Synofzik1, Marc Sturm1, Chantal Tallaksen1, Iselin M Wedding1, Sylvia Boesch1, Andreas Eigentler1, Bart van de Warrenburg1, Judith van Gaalen1, Christoph Kamm1, Ales Dudesek1, Jun-Suk Kang1, Dagmar Timmann1, Gabriella Silvestri1, Marcella Masciullo1, Thomas Klopstock1, Christiane Neuhofer1, Christos Ganos1, Alessandro Filla1, Peter Bauer1, Sophie Tezenas du Montcel1, Thomas Klockgether2. 1. From the Department of Neurology (I.G., T.K.), University Hospital of Bonn; German Center for Neurodegenerative Diseases (DZNE) (I.G., H.J., B.P., T.K.), Bonn; Institute of Medical Genetics and Applied Genomics (F.H., M.S.) and Department of Neurodegenerative Diseases (L.S., M.S.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (H.J.), Heidelberg University Hospital; Department of Neurology (S.V.), Otto-von-Guericke University Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (S.V., J.M.), Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (L.S., M.S.), Tübingen, Germany; Department of Neurology (C.T., I.M.W.), Oslo University Hospital; Faculty of Medicine (C.T.), Institute of Clinical Medicine, University of Oslo, Norway; Department of Neurology (S.B., A.E.), Medical University Innsbruck, Austria; Department of Neurology (B.v.d.W., J.v.G.), Radboud University Medical Center, Nijmegen, Netherlands; Department of Neurology (C.K., A.D.), University of Rostock; German Center for Neurodegenerative Diseases (DZNE) (C.K., A.D.), Rostock; Department of Neurology (J.-S.K.), University of Frankfurt; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Germany; Institute of Neurology (G.S.), Catholic University of Sacred Heart; SPInal REhabilitation Lab (SPIRE) (M.M.), Fondazione Santa Lucia, IRCCS, Rome, Italy; Department of Neurology (T.K., C.N.), Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich; German Center for Neurodegenerative Diseases (DZNE) (T.K., C.N.), Munich; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Munich; Department of Neurology (C.G.), University Medical Center Hamburg-Eppendorf (UKE), Germany; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University, Naples, Italy; Centogene AG (P.B.), Rostock, Germany; Pierre Louis Institute of Epidemiology and Public Health (S.T.d.M.), Pierre and Marie Curie University (UPMC); and AP-HP (S.T.d.M.), Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 2. From the Department of Neurology (I.G., T.K.), University Hospital of Bonn; German Center for Neurodegenerative Diseases (DZNE) (I.G., H.J., B.P., T.K.), Bonn; Institute of Medical Genetics and Applied Genomics (F.H., M.S.) and Department of Neurodegenerative Diseases (L.S., M.S.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (H.J.), Heidelberg University Hospital; Department of Neurology (S.V.), Otto-von-Guericke University Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (S.V., J.M.), Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (L.S., M.S.), Tübingen, Germany; Department of Neurology (C.T., I.M.W.), Oslo University Hospital; Faculty of Medicine (C.T.), Institute of Clinical Medicine, University of Oslo, Norway; Department of Neurology (S.B., A.E.), Medical University Innsbruck, Austria; Department of Neurology (B.v.d.W., J.v.G.), Radboud University Medical Center, Nijmegen, Netherlands; Department of Neurology (C.K., A.D.), University of Rostock; German Center for Neurodegenerative Diseases (DZNE) (C.K., A.D.), Rostock; Department of Neurology (J.-S.K.), University of Frankfurt; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Germany; Institute of Neurology (G.S.), Catholic University of Sacred Heart; SPInal REhabilitation Lab (SPIRE) (M.M.), Fondazione Santa Lucia, IRCCS, Rome, Italy; Department of Neurology (T.K., C.N.), Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich; German Center for Neurodegenerative Diseases (DZNE) (T.K., C.N.), Munich; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Munich; Department of Neurology (C.G.), University Medical Center Hamburg-Eppendorf (UKE), Germany; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University, Naples, Italy; Centogene AG (P.B.), Rostock, Germany; Pierre Louis Institute of Epidemiology and Public Health (S.T.d.M.), Pierre and Marie Curie University (UPMC); and AP-HP (S.T.d.M.), Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. thomas.klockgether@ukb.uni-bonn.de.
Abstract
OBJECTIVE: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. METHODS: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. RESULTS: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. CONCLUSIONS: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. CLINICALTRIALSGOV REGISTRATION: NCT02701036.
OBJECTIVE: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. METHODS: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. RESULTS: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. CONCLUSIONS: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. CLINICALTRIALSGOV REGISTRATION: NCT02701036.
Authors: Xueyan Jiang; J Faber; I Giordano; J Machts; Ch Kindler; A Dudesek; O Speck; Ch Kamm; E Düzel; F Jessen; A Spottke; St Vielhaber; H Boecker; T Klockgether; L Scheef Journal: Cerebellum Date: 2019-10 Impact factor: 3.847
Authors: T Bogdan; T Wirth; A Iosif; A Schalk; S Montaut; C Bonnard; G Carre; O Lagha-Boukbiza; C Reschwein; E Albugues; S Demuth; H Landsberger; M Einsiedler; T Parratte; A Nguyen; F Lamy; H Durand; P Fahrer; P Voulleminot; K Bigaut; J B Chanson; G Nicolas; J Chelly; C Cazeneuve; M Koenig; C Bund; I J Namer; S Kremer; N Calmels; C Tranchant; M Anheim Journal: J Neurol Date: 2022-07-23 Impact factor: 6.682
Authors: Elisabetta Indelicato; Alessandra Fanciulli; Jean Pierre Ndayisaba; Wolfgang Nachbauer; Roberta Granata; Julia Wanschitz; Michaela Wagner; Elke R Gizewski; Werner Poewe; Gregor K Wenning; Sylvia Boesch Journal: Clin Auton Res Date: 2018-02-12 Impact factor: 4.435
Authors: Alex Tiburtino Meira; Walter Oleschko Arruda; Sergio Eiji Ono; Arnolfo de Carvalho Neto; Salmo Raskin; Carlos Henrique F Camargo; Hélio Afonso G Teive Journal: Tremor Other Hyperkinet Mov (N Y) Date: 2019-09-26
Authors: Andreas Traschütz; Selina Reich; Astrid D Adarmes; Mathieu Anheim; Mahmoud Reza Ashrafi; Jonathan Baets; A Nazli Basak; Enrico Bertini; Bernard Brais; Cynthia Gagnon; Janina Gburek-Augustat; Hasmet A Hanagasi; Anna Heinzmann; Rita Horvath; Peter de Jonghe; Christoph Kamm; Peter Klivenyi; Thomas Klopstock; Martina Minnerop; Alexander Münchau; Mathilde Renaud; Richard H Roxburgh; Filippo M Santorelli; Tommaso Schirinzi; Deborah A Sival; Dagmar Timmann; Stefan Vielhaber; Michael Wallner; Bart P van de Warrenburg; Ginevra Zanni; Stephan Zuchner; Thomas Klockgether; Rebecca Schüle; Ludger Schöls; Matthis Synofzik Journal: Front Neurol Date: 2021-06-25 Impact factor: 4.003