Grant: Doctoral Research Award: Canada Graduate Scholarships

Huntington Disease (HD) is fatal genetic brain disorder whose symptoms include cognitive decline and uncontrollable movement. The disease occurs when part of the DNA sequence within a gene called huntingtin is repeated too many times. The larger the repeat expansion, the younger the age at which someone tends to start having disease symptoms. However, the size of the repeat does not fully explain the variation in age of onset. Someone with 39 repeats could become symptomatic as young as 30 years old or as late as their 80s or 90s. This means that even though we can genetically predict who will get HD, we cannot predict exactly when they will start showing symptoms. Recent studies have found some genetic differences in the repeat region in patients with unusually early or late disease onset. For example, patients with a particular variant in their huntingtin gene show symptoms on average 25 years earlier, while patients with a different variant show symptoms 4 years later. I want to understand why these variants cause differences in age of disease onset. Preliminary research suggests the variants may alter how much the repeated section of the huntingtin gene continues to expand in the brain during a patient's lifetime. To determine whether this causes the differences in disease onset, I will examine 1) the impact of these variants in brains of deceased patient, 2) differences in the clinical progression of patients with and without the variants, and 3) the effect of these variants in patient-derived cultured cells. A better understanding of how these variants affect onset will not only enable better disease onset predictions for HD patients, but could also suggest biological mechanisms that could be targeted to slow or prevent disease onset. Since many other diseases, collectively known as "trinucleotide repeat disorders," are caused by similar DNA repeat expansions in other genes, anything we learn may also benefit patients with these other diseases.