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

Serrano-Munuera C, Corral-Juan M, Stevanin G, et al. — Mon, 29 Apr 2013 00:00:00 GMT

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 (z_max = 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.

Clinical Application of Whole-Exome Sequencing A Novel Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Sequence Variation in a Child With Ataxia Whole-Exome Sequencing

Liew WM, Ben-Omran T, Darras BT, et al. — Mon, 29 Apr 2013 00:00:00 GMT

Importance

Ataxia in children is a diagnostic challenge. Besides the more common acquired causes of ataxia, there are more than 50 inherited disorders associated with ataxia. Our objective was to highlight whole-exome sequencing as a rapidly evolving clinical tool for diagnosis of mendelian disorders, and we illustrate this in the report of a single case of a novel sequence variation in the SACS gene.

Observations

A 4-year-old girl presented with delayed gross motor development, ataxia, and polyneuropathy. Results of initial testing for the common causes of inherited and acquired ataxia were unrevealing. Whole-exome sequencing showed a novel frameshift homozygous sequence variation in the SACS gene, consistent with the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Conclusions

Whole-exome sequencing is a powerful clinical tool that has been increasingly used to assist in the diagnosis of mendelian disorders. It provides a cost-effective, efficient, and expedited approach to making a clinical diagnosis and, in some cases, may be the only way to make a diagnosis.

AMA Publishing Group: Ataxia Topic Collection

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

Clinical Application of Whole-Exome Sequencing A Novel Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Sequence Variation in a Child With Ataxia Whole-Exome Sequencing