Huntington’s disease (HD) is a genetic movement disorder with dementia and psychiatric symptoms. This research is a sperm study aiming to better understand HD inheritance to improve genetic counselling of HD gene carriers. HD therapies under development may reach clinical trial stage within the next 5 years. This study will help determine whether sperm are affected by these drugs and therefore has important implications for drug development.

DNA is made up of four molecules; A(adenine), T(thymine), C(cytosine) and G(guanine) and contains ‘repeat regions’; repetitive combinations of these molecules. The huntingtin (HTT) gene is a repeat region with repeated CAG units. Normally there are up to 26 CAGs in HTT but those carrying the HD mutation have 36 or more.

Over 50 neurological human diseases exist, called repeat expansion disorders (REDs), are caused by abnormal repeat numbers in different DNA regions.

We know in HD, and many REDs, that when the mutation is inherited the gene length may change in sperm and sometimes children inherit a different sized gene compared to their parent. Expansions can lead to the child developing disease symptoms earlier than their parent, termed ‘genetic anticipation’. Although genetic anticipation is widely recognised, the reason it happens in some families and not others is unclear.

This project involves donation of blood and semen from men with HD for genetic analysis of repeat region changes in sperm and to identify potential causative genetic factors. This will improve understanding of HTT mutation inheritance risk and may reveal biological pathways for further investigation which may be applicable to other REDs.