Overall, HDL syndromes are rare.  They are much less common than Huntington disease, which affects an estimated 3 to 7 per 100,000 people of European ancestry.

Of the four described HDL syndromes, HDL4 appears to be the most common.  HDL2 is the second most common and occurs almost exclusively in people of African heritage (especially Black South Africans).  HDL1 has been reported in only one family.  HDL3 has been found in two families, both of which were from Saudi Arabia.

In about one percent of people with the characteristic features of Huntington disease, no mutation in the HD gene has been identified. Mutations in the PRNP, JPH3, and TBP genes have been found to cause the signs and symptoms in some of these individuals. HDL1 is caused by mutations in the PRNP gene, while HDL2 results from mutations in JPH3. Mutations in the TBP gene are responsible for HDL4 (also known as spinocerebellar ataxia type 17). The genetic cause of HDL3 is unknown.

The PRNP, JPH3, and TBP genes provide instructions for making proteins that are important for normal brain function. The features of HDL syndromes result from a particular type of mutation in any one of these genes. This mutation increases the length of a repeated segment of DNA within the gene, which leads to the production of an abnormal PRNP, JPH3, or TBP protein. The abnormal protein can build up in nerve cells (neurons) and disrupt the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of HDL syndromes.

Other medical conditions and gene mutations may also cause signs and symptoms resembling Huntington disease. In some affected people, the cause of the disorder is never identified.