New Genetic Factors Determining Disease Onset Identified in Huntington’s Disease Patients

A new study recently published in the journal Cell reported the finding of new genetic variants that can accelerate or delay disease onset in patients with Huntington’s disease. The study is entitled “Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease” and was conducted by an international team of researchers from the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. The research was partly funded by the National Institutes of Health (NIH).

Huntington’s disease is a progressive, neurodegenerative, genetic disorder characterized by the lack of muscle coordination, unsteady gait, mental decline and emotional disturbances. The disease’s symptoms usually begin in midlife and the disorder is caused by an expanded CAG triplet repeat in a gene called huntingtin (chromosome 4), leading to the production of a mutant huntingtin protein that accumulates in the brain, interfering with its proper functioning. More than 35 CAG repeats in the Huntingtin gene result in disease symptoms. There is no effective treatment for Huntington’s disease and it is estimated that one in every 10,000 to 30,000 individuals in the United States suffers from the malignancy.

Researchers have now conducted the first genome-wide association (GWA) analysis to screen the genomes of 4,082 Huntington’s disease patients for chromosomal regions that might contain genetic variants linked to the disease. All the patients analyzed had 40 to 55 CAG repeats in the Huntingtin gene.

The team found that at least three genetic sites were linked to disease onset, two on chromosome 15 and one on chromosome 8. The genetic variants found at chromosome 15 were significantly associated with an early (on average six years earlier) or late (an average of a year and a half delay) symptom onset, while the variant on chromosome 8 was associated with an earlier disease onset (average of one and a half years earlier).

“This approach could have a significant impact on Huntington’s disease patients and researchers,” said the program director of the National Institute of Neurological Disorders and Stroke, part of NIH, Dr. Margaret Sutherland in a news release. “It’s an example of how precision medicine may be applied to neurological disorders.”

“Our hope is to find ways that we can slow or delay the onset of Huntington’s devastating symptoms,” added the study’s corresponding author Dr. James Gusella, director of the Center for Human Genetic Research at Massachusetts General Hospital (MGH). “This could be possible because we now have a list of clinically proven genetic factors that influence the disease.”

Although the team did not pinpoint specific genes, they reported that disease onset might be controlled by genes involved in DNA repair mechanisms, in specific cellular chemical reactions and mitochondria division. One gene in particular called MLH1, a DNA repair gene on chromosome 3, was suggested to potentially play an important role in Huntington’s disease.

The research team concluded that specific genetic variants on chromosomes 15 and 8 can modify the age at onset of the psychiatric and cognitive problems associated with Huntington’s disease, and suggest that these variants could offer new potential therapeutic targets for the disease and help in the study of other neurological disorders.

“We thank the patients and their families for their commitment to research, (…) It takes a dedicated global effort to meet the complex challenges presented by neurological disorders like Huntington’s disease.” concluded Dr. Gusella. “These results are an important step toward developing new treatments for Huntington’s disease (…) As we study more patients we hope the information we obtain will soon reduce their suffering.”