RISCA

The spinocerebellar ataxias (SCAs) are autosomal dominantly inherited progressive brain disorders that are characterized by motor coordination deficits, ataxia. SCAs are rare disorders affecting 3.0 to 4.2 : 100,000 inhabitants. Among the various genetic subtypes of the SCAs, SCA1, SCA2, SCA3 and SCA6 are the most common. As in all autosomal dominant disorders, 50% of the direct descendants of an SCA patient carry the mutation and will develop the disease, whereas the remaining 50% (non-carriers) will stay healthy. Since future therapies of SCAs will have to be initiated as early as possible, it is of critical importance to study the presymptomatic phase of SCAs, i.e those individuals who are still healthy, but carry the disease mutation. To study the presymptomatic phase of the common SCAs (SCA1, SCA2, SCA3, SCA6) we initiated RISCA, a longitudinal observational study of individuals at risk for one of these SCAs. RISCA enrolled 277 healthy adult individuals that descended from an SCA1, SCA2, SCA3 or SCA6 individual. Genetic testing was done anonymously. Evaluation included a number of tests of motor coordination, assessment of non-motor symptoms and brain imaging by magnetic resonance imaging (MRI).

Compared to non-carriers, (1) SCA1 and SCA2 mutations carriers had mild coordination deficits detected by clinical examination, (2) SCA3 carriers had eye movement abnormalities, (3) SCA1, SCA2 and SCA3 carriers performed worse in timed performance tests that assess motor coordination, and (4) SCA1 carriers had more non-ataxia symptoms. Coordination deficits were more pronounced, the shorter the calculated time to expected disease onset was. First deficits were detectable approximately 15 years before disease onset. In addition, cerebellar and brainstem volumes of SCA1 and SCA2 mutation carriers, as measured by magnetic resonance imaging (MRI) were reduced. There were no differences between carriers and noncarriers with respect to sleep, mood and health-related quality of life. The data of the RISCA study show that the presymptomatic stage of SCAs is characterized by mild coordination deficits and beginning tissue loss in the cerebellum and brainstem.