Original Contribution |

New Subtype of Spinocerebellar Ataxia With Altered Vertical Eye Movements Mapping to Chromosome 1p32

Carmen Serrano-Munuera, MD; Marc Corral-Juan, BSc; Giovanni Stevanin, PhD; Hector San Nicolás, BSc; Carles Roig, MD, PhD; Jordi Corral, BSc; Berta Campos, PhD; Laura de Jorge, BSc; Carlos Morcillo-Suárez, PhD; Arcadi Navarro, PhD; Sylvie Forlani, MD, PhD; Alexandra Durr, MD, PhD; Jaime Kulisevsky, MD, PhD; Alexis Brice, MD, PhD; Ivelisse Sánchez, PhD; Victor Volpini, MD, PhD; Antoni Matilla-Dueñas, PhD
JAMA Neurol. 2013;70(6):764-771. doi:10.1001/jamaneurol.2013.2311.
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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. Electro-oculographic 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 (zmax = 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.

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Graphic Jump Location

Figure 1. Pedigree of the Spanish kindred (subtype SCA37 of spinocerebellar ataxia) showing the reconstructed haplotypes resulting from the analysis of 10 polymorphic markers spanning 20.38 cM on chromosome region 1p32.

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Graphic Jump Location

Figure 2. A and B, Sagittal and coronal T1-weighted magnetic resonance imaging scans of the brain of patient IV:5. The eye movements during vertical fixed saccades (C) (20° amplitude; top line, upward saccades; bottom line, downward saccades [arrows]) and smooth pursuit (D) (0.4 Hz; 16° amplitude; and peak velocity, 40°/s) are shown for patient IV:6. The asterisks indicate saccadic intrusions.

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Figure 3. Scale for the Assessment and Rating of Ataxia (SARA) scores of 8 affected patients.




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