New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32

Carmen Serrano-Munuera, Marc Corral-Juan, Giovanni Stevanin, Hector San Nicolás, Carles Roig, Jordi Corral, Berta Campos, Laura De Jorge, Carlos Morcillo-Suárez, Arcadi Navarro, Sylvie Forlani, Alexandra Durr, Jaime Kulisevsky, Alexis Brice, Ivelisse Sánchez, Victor Volpini, Antoni Matilla-Duenãs

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24 Citations (Scopus)

Abstract

Importance: To provide clinical and genetic diagnoses for patients' conditions, it is important to identify and characterize the different subtypes of spinocerebellar ataxia (SCA). Objective: To clinically and genetically characterize a Spanish kindred with pure SCA presenting with altered vertical eye movements. Design: Family study of ambulatory patients. Electrooculographic and genetics studies were performed in 2 referral university centers. Setting: Primary care institutional center in Spain. Participants: Thirty-six participants from a large Spanish kindred were clinically examined, and 33 family members were genetically examined. Detailed clinical data were obtained from 9 affected relatives. Two ataxic siblings and 2 asymptomatic family members were examined using an enhanced clinical protocol for a follow-up period of 7 years. Main Outcomes and Measures: High-density genome-wide single-nucleotide polymorphism arrays, along with microsatellite analysis, and genetic linkage studies were performed. Whole-exome sequencing was used for 2 affected relatives. For most patients, the initial symptoms included falls, dysarthria, or clumsiness followed by a complete cerebellar syndrome. For all 9 affected relatives, we observed altered vertical eye movements, as initial ocular signs for 3 of them and for the 2 asymptomatic family members, all having inherited the risk haplotype. Neuroimaging showed isolated cerebellar atrophy. Results: Initial genome-wide linkage analysis revealed suggestive linkage to chromosome 1p32. Multipoint analysis and haplotype reconstruction further traced this SCA locus to a 0.66-cM interval flanked by D1S200 and D1S2742 (z<inf>max</inf> = 6.539; P < .0001). The causative mutation was unidentified by exome sequencing. Conclusions and Relevance: We report a new subtype of SCA presenting in patients as slow progressing ataxia with altered vertical eye movements linked to a 11-megabase interval on 1p32. The Human Genome Nomenclature Committee has assigned this subtype of ataxia the designation SCA37. ©2013 American Medical Association. All rights reserved.
Original languageEnglish
Pages (from-to)764-771
JournalJAMA Neurology
Volume70
Issue number6
DOIs
Publication statusPublished - 1 Jan 2013

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    Serrano-Munuera, C., Corral-Juan, M., Stevanin, G., San Nicolás, H., Roig, C., Corral, J., Campos, B., De Jorge, L., Morcillo-Suárez, C., Navarro, A., Forlani, S., Durr, A., Kulisevsky, J., Brice, A., Sánchez, I., Volpini, V., & Matilla-Duenãs, A. (2013). New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32. JAMA Neurology, 70(6), 764-771. https://doi.org/10.1001/jamaneurol.2013.2311