Impaired Energy Metabolism Linked to Age of Onset in Huntington’s Patients, Study Shows

A deficiency in energy metabolism in the cells of patients with Huntington’s disease can partly explain the variation in age of onset among individuals, a study shows.

The study, “Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset,” was published in the journal Neurology Genetics.

Huntington disease is caused by an expansion of a DNA sequence known as a CAG repeat in a region of the huntingtin (HTT) gene, leading to the production of mutant huntingtin protein.

The length of the CAG repeat sequence (i.e., how long the expansion is) — which varies among individuals with Huntington’s disease — accounts for 50-70 percent of the variation in age of onset, as patients with longer repeats tend to have an earlier age of onset.

However, there are a large number of cases in which age of onset is not explained by the length of repeat sequence.

Studies have shown that, in addition to progressive motor impairment, neuropsychiatric symptoms, and cognitive decline, patients with Huntington’s disease also experience weight loss.

Interestingly, researchers have found that this weight loss is associated with a faster rate of disease progression — independent of CAG repeat number.

Weight loss is related to energy metabolism, and several lines of evidence have shown that disturbances in energy metabolism and mitochondrial defects play a role in Huntington’s disease.

Mitochondria are responsible for fulfilling the energy needs of cells via metabolic processes. Metabolism is the way that chemical processes in the body cause food to be used in an efficient way to create energy.

Mitochondrial metabolism has been found to be impaired in certain cell types of patients with Huntington’s disease, including cells known as skin fibroblasts.

Leiden University Medical Center researchers have now investigated whether the differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease are associated with age at onset, independent of CAG repeat number.

Using the Leiden Huntington disease database, the team selected nine pairs of patients with Huntington’s disease who were matched for mutant CAG repeat size and sex, but had a difference of at least 10 years in age at onset.

Using skin biopsies, researchers isolated fibroblasts from these paired patients and measured various parameters related to energy metabolism.

Results revealed that adenosine tri-phosphate (ATP) concentration (ATP is the energy unit of the cell and the main source of energy in the body) in fibroblasts were significantly lower in patients with Huntington’s disease who had an earlier age at onset, which was independent of CAG repeat number, sex, calendar age, and disease duration.

Additionally, maximal respiration (the maximum amount of energy that can be produced), spare capacity (the difference between basal ATP production and its maximal activity — important for when the cell is under stress and needs to produce more energy), respiration dependent on complex II activity (the main energy-producing complex in the mitochondria), and other indices of mitochondrial metabolism were significantly lower in patients with Huntington disease who had an earlier age at onset — again independent of calendar age and disease duration.

“A less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset among patients with Huntington disease, whereas therapies aimed at enhancing mitochondrial function may delay disease onset,” the researchers concluded.