The Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, an international team of scientists formed to find treatments for this disorder, identified specific genetic sites on two chromosomes that determine the beginning of neurological symptoms in Huntington’s patients. The study entitled “Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease” appeared in the journal Cell.
Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a single gene mutation, also known as a Mendelian disorder. This mutation is characterized by trinucleotide repeats (CAG-repeat) in the huntingtin gene, whose number determines disease onset. Normal individuals have six to 34 CAG-repeats, though 40 or more of these repeats cause HD with the onset of motor symptoms varying among individuals. Symptoms usually begin in midlife with a diagnosis based on motor signs such as uncontrolled movements, normally associated with emotional disturbances and dementia.
The available treatment targets symptoms to improve quality of life but no disease-modifying intervention prevents the onset or delay the progression of HD. Now, this research team investigated the pathogenic process that precedes disease by focusing on patients who had 40 to 55 CAG-repeats. “Our hope is to find ways that we can slow or delay the onset of Huntington’s devastating symptoms,” said James Gusella, the corresponding author of the study, in a press release.” This could be possible because we now have a list of clinically proven genetic factors that influence the disease,” she added.
They used genome-wide association (GWA) analysis of DNA samples collected from more than 4,000 HD patients to identify genetic variants that could determine disease initiation. Scientists also had access to clinical information to register at which age movement problems began. “We thank the patients and their families for their commitment to research,” said Gusella. “It takes a dedicated global effort to meet the complex challenges presented by neurological disorders like Huntington’s disease.”
The research team found modifications on two sites of chromosome 15: one accelerates the disease by, on average, just over six years; another site slows down the disease by about a year and a half. A site on chromosome eight was associated with earlier disease onset by nearly one and a half years. Although the individual genes have not been identified, researchers were able to conclude that they are involved in DNA repair, cellular chemical reactions, and mitochondrial function. The scientists further showed that these sites may be related with the beginning of psychiatric and cognitive problems caused by the disease.
The authors suggest that their findings may offer new therapeutic targets for HD. “These results are an important step toward developing new treatments for Huntington’s disease. They help us understand how, through evolution, nature has learned to modify the disease-causing effects of Huntington’s disease mutations,” said Gusella. “As we study more patients we hope the information we obtain will soon reduce their suffering”.