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The impact of environmental factors on SCA6

Written by Tala Ortiz
Edited by Celeste Suart, PhD

Ever wonder if experiences early in life impact symptoms of a genetic disease? Researchers found that genetics isn’t the only thing to consider in SCA6

Does the environment play a role in genetic diseases? That is the question these authors aim to answer in the context of spinocerebellar ataxia type 6 (SCA6).

SCA6 is a disease caused by a genetic mutation in a gene called CACNA1A. This mutation results from an increased number of repetitive genetic building blocks called CAG repeats. A person without SCA6 usually has up to 18 CAG repeats, while a person with SCA6 has at least 20 CAG repeats if not more. It is often assumed that if someone has a disease-causing genetic mutation, they automatically get and experience the disease in the same way other people do. However, genetic diseases, especially those with repeat expansions, have proved to be much more nuanced. In this article, the authors evaluated several early life-stage factors that could impact the age a patient first experiences symptoms and how quickly their disease progresses.

Surveys were taken by 105 adult patients with SCA6 between 2021 and early 2022 at the University of Chicago. These surveys included questions about education, sports, traumatic brain injury, drug use, and whether their mother had trouble during pregnancy or labor. They also measured disease severity using the Patient-Reported Outcome Measure of Ataxia (PROM-ataxia). PROM-ataxia is a system used to assess disease in ataxia patients. It is helpful in evaluating disease progression and the effect of therapies for patients with ataxia. Age at onset and PROM-ataxia were used to calculate disease progression for the patients.

What early life factors impact the age of onset of SCA6 Symptoms?

The researchers found that there were three major factors that influenced age at disease onset for SCA6 patients, meaning different events in life can cause the disease to manifest earlier or later in life. These included: the length of the CAG repeat, patient participation in sports, and if their mother had trouble during pregnancy or birth.

First, for CAG repeat length, they found that patients with more CAG repeats began experiencing symptoms sooner than those with shorter repeats. According to their statistical model, each CAG repeat unit corresponds to symptoms three and a half years earlier, on average. This means that on average, a patient with 23 repeats would experience symptoms around seven years earlier than a patient with 21 CAG repeats.

Next, they showed that patients whose mothers had trouble during pregnancy or labor experienced symptoms an average of 13 years earlier than those whose mothers did not.

Finally, patients who played school sports at a junior varsity, varsity, or college level began symptoms 12 years earlier than those who did not. This data shows that both genetic and environmental factors have an impact on when a patient first encounters SCA6 symptoms.

What genetic and environmental factors impact disease severity and progression in SCA6?

The next disease component these researchers investigated was predictors of disease severity. They wanted to know if certain life factors impacted how harsh the disease was across patients.

Based on the surveys of this group, it is shown that age at onset and number of CAG repeats do not determine how severe the disease is. This means that a patient with 26 CAGs, who may have started symptoms earlier, does not necessarily have more severe disease symptoms than a patient with 22 CAG repeats based on their PROM-ataxia score.

There was, however, a correlation between disease severity and education level. According to their statistical model, those with higher levels of education showed lower PROM-ataxia scores, meaning their self-rated symptoms weren’t as bad as those with lower levels of education. They saw that patients who only received primary education had higher PROM-ataxia scores than those who had received secondary education, and even lower scores in those receiving post-secondary education.

Not only is severity lower in patients with higher levels of education, but disease progression is also slower. The researchers reported these individuals consistently score lower using PROM-ataxia than those with lower levels of education, whose scores increase over time at a faster rate. Overall, there is a negative correlation between education level and SCA6 severity and progression. This means patients with higher levels of education tend to have less harsh symptoms and don’t progress as quickly.

What do these results mean for SCA6 patients?

These results are very interesting and important to know because they show us that the CAG expansion is not solely responsible for disease age of onset, severity, and progression. In fact, external factors like school participation in sports and maternal struggles during pregnancy can have a greater influence over when symptoms begin compared to the genetic mutation itself.

Patients who participated in school sports early in life began experiencing symptoms around 12 years earlier than those who did not. This does not mean that exercise is bad for patients with SCA6, as there can be many explanations for this correlation. For example, individuals who played sports growing up were likely to experience more concussions and other sports-related injuries that may have seemed insignificant at the time. The authors also suggested that those who had active participation in school sports may have noticed symptoms earlier than those who did not participate in sports, which could explain the earlier age of onset. Additionally, maternal difficulties during pregnancy showed disease onset 13 years earlier on average than in patients without maternal difficulties. The reasoning behind this is not yet well understood, and more work needs to be done to fully investigate specific contributors to this correlation.

Disease severity and progression in SCA6 are correlated with education level in patients. Compared to patients with primary education, those with secondary and post-secondary education had less severe disease and slower disease progression as indicated by lower PROM-ataxia scores. This factor is heavily driven by socio-economic status, as those with higher education levels tend to have higher incomes and more access to health-related resources. The authors also mention the relationship between education level and cognitive reserve, indicating that mental stimulation may be beneficial in slowing disease progression in SCA6.

These factors taken together show that environmental conditions early in life can heavily impact when a patient begins experiencing disease symptoms, how quickly it progresses, and how bad it gets. This is important for patients to know because it can help guide their choices, especially if they are aware of a disease in the family. So far, there isn’t anything we can do to prevent SCA6, but based on this research, it may be possible to intervene and positively impact patient lives.

Conflict of Interest Statement

The author and editor have no conflicts of interest to declare.

Citation of Article Reviewed

Chen TX, Casey HL, Lin CR, Boyle TA, Schmahmann JD, L’Italien GJ, Kuo SH, Gomez CM. Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression. Cerebellum. 2024 Aug;23(4):1449-1456. doi: 10.1007/s12311-023-01655-w. https://pmc.ncbi.nlm.nih.gov/articles/PMC11269368/