RFC1 Ataxia (CANVAS): Modifiers and predictors of disease onset and severity

The scientific group from London started with a pool of over 2000 human samples to learn about the features of RFC1 ataxia. They used sequencing techniques to parse out which patients carried the double expansion in RFC1. Then they further narrowed down the list based on the availability of clinical patient data, such as records of physical and neurological symptoms. The resulting list was 392 patients who fit the criteria. The research group used this patient information to understand modifiers of disease onset and progression in RFC1 Ataxia.  

While investigating factors that impact disease, they found that the length of the repeat is strongly associated with the age of onset of symptoms and disease progression. Since this disease is caused by expansions in RFC1 on both alleles, it is important to explore the impact of repeat size on each one. One allele usually has a longer repeat than the other one. Here, the scientists looked at the impact of the repeat length of the smaller versus the larger expansion. They found that the longer the repeat, the earlier patients first experience disease symptoms. Interestingly, this was more strongly correlated with the length of the smaller repeat than the larger one. This was also seen with the progression of the disease. The longer the repeat on the smaller allele is, the earlier in time patients would experience cough, trouble speaking, and difficulty swallowing. Additionally, it was found that a later age of symptom onset is associated with faster progression. This means patients experience symptoms sooner in the duration of their disease, but will have spent longer living without any symptoms before disease onset.  

In this study, disease presentation was categorized into three groups: sensory neuropathy, complex neuropathy, and Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS). Sensory neuropathy refers to sensory impairment, tingling, numbness, feelings of vibration, and disrupted awareness of where one’s body is in space. Complex neuropathy involves trouble speaking and swallowing, dizziness, blurred vision, and headaches. CANVAS involves both sensory and complex neuropathy as well as cough, unsteadiness, and other issues with balance and space. By splitting the patients into these groups, the scientists found that smaller repeat lengths are associated with sensory neuropathy alone. As the repeat gets larger, patients experience more complex neurological symptoms and can advance to the full spectrum of CANVAS symptoms. 

Next, the researchers wanted to understand the impact of repeat length on degeneration of the cerebellum, a major brain region affected in CANVAS. Magnetic Resonance Imaging (MRI) was used to look at the structure of the cerebellum in patients. These images revealed that the length of the smaller allele is correlated with the volume of brain matter in the cerebellum. Individuals with larger repeats had less brain volume in the cerebellum, indicating that the cells are very sick. This trend has also been observed in previous studies.