Designing clinical trials for rare diseases such as spinocerebellar ataxias (SCAs) requires us to know the timeline of disease progression. However, we remain in the dark about how symptoms of ataxia change immediately before and after onset, a prime time for intervention. Jacobi and colleagues study the progression of SCA1, SCA2, SCA3, and SCA6, starting 20 years before disease onset and ending 25 years after onset. They find that the fastest changes in symptoms occur between ataxia onset and 10 years post-onset. SCA1 was the most quickly progressing disease, followed by SCA2 and SCA3 (which were very similar), and finally SCA6. By defining the time course of disease and identifying the time of most rapid change, these scientists help us determine the most effective time to intervene with treatments.

Diving into the study, the researchers analyzed data from two European studies tracking patients with SCA1, SCA2, SCA3, and SCA6 over an extended period of time. These two studies provide complementary information. The “EUROSCA” study followed patients after the clinical onset of disease for about 4 years. The “RISCA” study studied people at risk for these diseases. We know who is at risk for these diseases because they are dominantly inherited, meaning that if your parent has the disease, you have a 50% chance of also developing the disease.  SCA1, SCA2, SCA3, and SCA6 are caused by an increased length of CAG repeats in the disease-causing gene. People develop the previously mentioned SCAs when the CAG repeat size increases past a certain threshold. Therefore, the RISCA study included people with a sufficiently large CAG repeat who will develop the disease but are not yet showing symptoms. Combining these two studies, Jacobi and colleagues had data from 677 participants to determine when ataxia symptoms appear and how quickly they worsen. 

The scientists found that each of the SCA subtypes progresses differently, which means that clinicians need to be knowledgeable about each subtype to best treat patients. Additionally, these diseases do not progress linearly, meaning they do not change at the same rate across the entire disease course. Therefore, we need to pay attention to the patient’s stage of disease to know how quickly their symptoms may progress. To study the progression of these diseases, the authors use four tests:

1. The Scale for the Assessment and Rating of Ataxia (SARA): a measure of ataxia severity that takes into account walking, standing, and coordination of movements. A higher score means more severe ataxia.
2. A subset of the SARA called the SARAaxial in which only measurements of walking, standing, sitting, and speech disturbances are included. This means that changes to hand and foot coordination are not considered because they are away from your body’s central axis and are therefore not axial. 
3. The SCA Functional Index (SCAFI): A test measuring the speed of walking, speech, and coordination. A single score is assigned based on the performance in all three of these areas.
4. The Inventory of Non-Ataxia Signs (INAS): a rough measure of non-ataxia neurological symptoms, meaning symptoms other than impaired coordination. Examples include changes to your reflexive responses (can be overactive or underactive), muscle atrophy (wasting away of the muscles), dystonia (involuntary movements), and sensory and cognitive changes.

Using four tests allows the researchers to study multiple aspects of diseases and determine the degree to which each test captures symptom changes. This is called the sensitivity of the test. 

Here’s what they found: In SCA1, SCA2, SCA3, and SCA6, symptoms represented by the SARA, SARAaxial, and SCAFI change very slowly during the 10-15 years before ataxia onset. Here, onset is defined as the start of obvious changes to how the individual walks. At the time of ataxia onset until 10 years post-onset, symptoms quickly get worse. This is where the disease course begins to look different in the SCA subtypes:

• In SCA2 and SCA3, the rate of symptom change then slows again until the end of the study period which is 25 years after disease onset. In SCA1, the SARA score continues to increase, indicating worsening ataxia, at a regular rate until the end of the study. This indicates that in SCA1, SCA2, and SCA3, the SARA, SARAaxial, and SCAFI tests perform well at detecting changes in symptom severity, even at the most advanced stages of disease.  
• In SCA6, at 10 years post-onset, symptoms measured by these three tests start to change more slowly and then plateau, meaning they don’t change at all. This suggests that the tests fail to continue capturing changes in SCA6 disease severity at advanced stages.

This brings us to the fourth test, INARS. Compared to patients with SCA1, SCA2, and SCA6, patients with SCA3 actually performed much better on the INARS across the study. In contrast, the INARS score changed similarly to the other three tests in those with SCA1, SCA2, and SCA6. This suggests that INARS may not capture non-ataxia symptoms of SCA3 patients particularly well. Overall, these findings emphasize that SCAs do not progress linearly and that the unique time course of each disease must be carefully considered. Moreover, it is important to note that these tests are estimations of disease severity and should be treated as such: they cannot perfectly capture the full scope of disease-related changes at all stages of progression for all subtypes of SCA. 

After establishing the time course of disease progression, the authors searched for factors that are associated with faster disease progression as measured by the SARA score. Looking at the size of the CAG repeat on the mutated gene, they found that the larger the repeat, the faster the disease progression in SCA1, SCA2, and SCA3, but not in SCA6. Interestingly, the impact of CAG repeat size on disease progression appeared at different times in SCA1, SCA2, and SCA3. In SCA1 and SCA3, a larger CAG repeat was associated with faster disease progression starting 5 years after disease onset. In SCA2, this relationship was observed earlier, at disease onset. Sex did not have any relation to disease progression. These findings are exciting because past studies only investigated the connection between CAG repeat size and disease progression after disease onset. Here, the authors give us a more complete picture of disease progression by tracking participants starting before disease onset. 

Overall, this study confirmed previous work showing that SCA1 disease progresses the quickest and SCA6 the slowest, with SCA2 and SCA3 sitting in the middle. The differences in disease progression, as captured by the SARA, SARAaxial, SCAFI, and INARS, are vital to consider when evaluating patient symptoms. Notably, this study only used a European sample, leaving the progression of disease in non-European populations less characterized. Future studies could harness assessments of disease severity beyond those described here. For example, scientists are investigating markers of disease detected by blood tests or MRI, called biomarkers. These are measurements of the biological changes inside a patient’s body rather than the outward symptom manifestation. Combining clinician-administered qualitative assessments of disease severity (SARA) with performance-based tests (SCAFI) and biomarkers in a wide patient population will help us gain a more complete picture of disease and determine the most effective time to intervene.