Huntington's Disease

Causes/Genetics

HD is due to a mutation in a gene that is transmitted as an autosomal dominant trait. Each child of a parent who is carrying a defective gene for HD has a 50% risk of inheriting the disease gene. In addition, although HD usually runs in certain families, the disorder may sometimes occur as the result of a spontaneous (sporadic) change in the gene for HD.

The gene responsible for HD, known as IT15, is located on chromosome 4 (4p16.3). The IT15 gene regulates, controls, or "encodes" production of a protein known as huntingtin. The protein is found in neurons throughout the brain. Mutations of the IT15 gene result in abnormally long repeats of DNA instructions. These instructions include unusual, repeated sequences of certain basic chemicals known as cytosine, adenine, and guanine or CAG trinucleotide repeats. These expanded CAG sequences result in the production of abnormal huntingtin protein.

Individuals who do not have HD tend to have about 20 CAG repeats in the IT15 gene (ranging from about 9 to 29). In contrast, those with the disorder may have about 36 to 121 CAG repeats (with most having greater than 39 repeats). Some individuals who have no symptoms (asymptomatic) may have so-called "intermediate sized" CAG repeats, ranging from approximately 30 to 39. Their relative risk of developing HD and transmitting the disease to their children requires careful assessment and is the subject of ongoing investigations.

The length of the expanded CAG repeats is thought to have some relation to the age at symptom onset. For example, those with a large number of repeats tend to develop symptoms at an earlier age. Extremely large CAG repeats of 80 or greater are often associated with a disease onset during childhood or adolescence (juvenile HD). Such a correlation may be less apparent in individuals with a shorter range of CAG repeats. For CAG repeats equal to or greater than 42, the HD gene is thought to have 100% penetrance (Brinkman, 1997).

There is great variability in the age of symptom onset and, in many cases, this may not be associated with repeat size. Therefore, interpretations of CAG repeat expansions should be restricted to determining the possibility of eventual symptom development. It is not used to estimate the age when such onset may occur.

Expanded CAG repeats are not stable and tend to expand from generation to generation. This phenomenon is known as "genetic anticipation." Evidence suggests that CAG repeats are more unstable when the disease gene is inherited from the father. Therefore, individuals with HD who inherit the disease gene from their fathers (i.e., paternal transmission) may tend to develop symptoms at an earlier age than their fathers.