Masato Obayashi1, Giovanni Stevanin2, Matthis Synofzik3, Marie-Lorraine Monin4, Charles Duyckaerts5, Nozomu Sato1, Nathalie Streichenberger6, Alain Vighetto7, Virginie Desestret8, Christelle Tesson9, H-Erich Wichmann10, Thomas Illig11, Johanna Huttenlocher12, Yasushi Kita13, Yuishin Izumi14, Hidehiro Mizusawa1, Ludger Schöls3, Thomas Klopstock15, Alexis Brice16, Kinya Ishikawa1, Alexandra Dürr16. 1. Department of Neurology and Neurological Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. 2. Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtriére, Departement of Genetics and Cytogenetics, Paris, France Ecole Pratique des Hautes Etudes, Groupe de Neurogénétique, Paris, France. 3. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Tübingen, Germany German Centre of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. 4. Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France. 5. Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France Laboratoire de Neuropathologie R. Escourolle, Groupe Hospitalier Pitié-Salpêtrière, 47 Blvd de l'Hôpital, Paris, France. 6. Pathology and Biochemistry, Groupement Hospitalier Est, Hospices Civils de Lyon/Claude Bernard University, Lyon, France. 7. Neurology Department, Hôpital Pierre Wertheimer, Lyon, France. 8. Neurology D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France Lyon Neuroscience Research Center, INSERM U1028/CNRS UMR 5292, Lyon, France Université de Lyon-Université Claude Bernard Lyon 1, Lyon, France. 9. Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France Ecole Pratique des Hautes Etudes, Groupe de Neurogénétique, Paris, France. 10. Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. 11. Unit for Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 12. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 13. Neurology Service, Hyogo Brain and Heart Center at Himeji, Himeji, Hyogo, Japan. 14. Department of Clinical Neuroscience, The University of Tokushima Graduate School, Tokushima, Japan. 15. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München, Munich, Germany German Network for Mitochondrial Disorders (mitoNET) DZNE-German Center for Neurodegenerative Diseases, Munich, Germany German Center for Vertigo and Balance Disorders, Munich, Germany. 16. Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtriére, Departement of Genetics and Cytogenetics, Paris, France.
Abstract
OBJECTIVE: Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. METHODS: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. RESULTS: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. CONCLUSIONS: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE:Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. METHODS: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. RESULTS: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. CONCLUSIONS: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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