By M. Elizabeth Ross, MD, PhD

Nathan E. Cumming Professor of Neurology and Neuroscience, Chair, Neuroscience Graduate Program, Weill Cornell Medical College

Dr. Ross reports no financial relationships relevant to this field of study.

SYNOPSIS: Current genetic testing techniques with DNA sequencing can diagnose the molecular-genetic causes for the majority of dominantly inherited cerebellar ataxias.

SOURCE: Coutelier M, Coarelli G, Monin ML, et al.; for the SPATAX Network. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. Brain 2017;140:1579-1594.

Dominant, monogenic cerebellar ataxias have been associated with mutations in at least 34 genes to date. Trinucleotide, CAG repeat expansions were among the first mutations to be found in connection with this condition and include ATXN1, ATXN2, ATXN3, ATXN6 (CACNA1A), ATXN7, and TBP. A common diagnostic strategy is to test for repeat expansion mutations when an ataxia patient is newly encountered in clinic. However, this approach leaves some 40% of dominant ataxia cases unresolved. Coutelier et al tested the efficiency of a panel approach of direct sequencing known ataxia-causing genes. Investigators examined 412 cases of dominantly inherited cerebellar ataxia for which CAG/polyglutamine repeat mutations had been excluded. The investigators pursued direct sequencing of the protein-coding regions of 65 known ataxia genes and candidates.

Several significant insights were obtained. Relevant genetic variants were found in 59 patients, representing 14.3% of the study cohort, or 7.2% in the entire group that included those with CAG repeat mutations. Thus, the investigation of conventional sequence mutations is productive. Interestingly, conventional mutations were found most frequently in channel genes, namely CACNA1A, KCND3, KCNC3, and KCNA1. In addition, SPG7 and POLG were implicated as possible risk factors for cerebellar ataxia. Examination of clinical phenotypes revealed that channelopathies tended toward earlier age at onset (average 24.6 years at onset) and longer duration (20.5 years) in contrast to the CAG repeat mutations (average 40.9 years at onset, 9.3 years duration) and SPG7-associated ataxia (average 37.8 years at onset, 13.7 years duration). Especially interesting was that a particular channel, CACNA1A, caused cerebellar ataxia associated with either a CAG repeat or a conventional point mutation. Further genotype-phenotype analyses revealed that channelopathy mutations more often were accompanied by early intellectual deficiency (23% contrasting with 0% polyglutamine expansion or SPG7-related cases), while the prevalence of late-onset cognitive impairment was no different among CAG repeat, channelopathy, or SPG7 genotypes.


The study is important in that it cautions the diagnostician not to be satisfied with only trinucleotide repeat expansion testing. Together with repeat testing, direct DNA sequencing could achieve a positive diagnosis in 75% of dominantly inherited cerebellar ataxia cases. It would be of further interest to compare the diagnostic success rate of whole exome sequencing (WES) compared to a direct sequencing panel of 65 genes, since WES could identify additional potential candidate mutations as more patients are tested.