Women with Huntington’s Experience Worse Symptoms Than Men, Global Study Suggests

Women with Huntington’s disease have worse motor, cognitive, and depressive symptoms than men with the condition, according to data from the global Enroll-HD observational study.

Notably, no sex-specific differences were found for age at diagnosis and symptom progression over the four years of follow-up.

These findings help to increase awareness of the clinical differences between women and men with Huntington’s, which may help guide management and treatment of symptoms, the researchers noted.

The study, “Sex Differences in Huntington’s disease: Evaluating the Enroll‐HD database,” was published in the journal Movement Disorders Clinical Practice.

A progressive disease, Huntington’s is caused by excessive (more than 36) repeats of a portion of DNA, called CAG triplets, within the HTT gene. This results in the production of an abnormal and toxic version of the huntingtin protein that affects brain regions responsible for movement, thought, memory, and behavior.

While sex “has been recognized as a potential contributing factor in the [development] of neurodegenerative diseases that can influence both prognosis and treatment,” the researchers wrote, “little is known about sex-related differences in the natural history of [Huntington’s disease].”

Interpretation of these potential differences may help optimize treatment and better understand the disease mechanisms behind Huntington’s.

Researchers in the U.S. have now evaluated whether sex-specific differences exist in Huntington’s by analyzing data from the international Enroll-HD study (NCT01574053) — which is following more than 20,000 people with or without disease-causative HTT mutations. This study is still recruiting participants across the U.S. and other regions.

A total of 8,043 people with a Huntington’s clinical diagnosis at any of the four analyzed annual visits were included in the longitudinal analysis. Of these patients, 2,145 (1,097 women and 1,048 men) had completed at least four annual visits, and data from visit number four were used for sex-based comparisons at a single timepoint.

Participants’ demographic information and data about their motor, cognitive, and behavioral function were retrospectively analyzed.

Because Huntington’s might be influenced by CAG length and age, potential sex differences were adjusted for the so-called CAG age product (CAP) score that considers both of these factors and is a good predictor of age of onset and disease progression.

Motor symptoms were assessed by the Unified Huntington’s Disease Rating Scale‐Total Motor Score, while cognitive function was evaluated through the verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test. The Problem Behaviors Assessment-Short Version was used to assess behavioral symptoms.

Results of the single timepoint analysis showed that men were older than women at diagnosis, but these differences were not significant after adjusting for the CAP score. There were no sex-specific differences in terms of CAG length.

History of alcohol abuse was more common in men, while smoking and history of depression was more common among women.

Notably, data from the longitudinal analysis revealed significant differences in motor, cognitive, and behavioral symptoms between men and women with Huntington’s disease.

While both sexes showed gradual motor worsening over four years, women consistently presented with more severe motor symptoms than men. Men also tended to perform better at cognitive tests than women.

Interestingly, women, but not men, performed better over time in two of the three cognitive tests. While this may be due to a repetition-associated improvement in completing the tests, it remains uncertain why men did not show the same improvement, the team noted.

Significant sex-specific differences were found for depression, with women showing worse depressive symptoms than men, despite the fact that these symptoms progressed similarly in both groups.

Notably, self-reported depressive symptoms in both sexes became less severe over time.

“It is not clear, however, if patients indeed become less depressive over the course of [Huntington’s disease] or if they fail to recognize and/or report such symptoms,” the researchers wrote.

Men had significantly worse apathy than women at visit number two, but women showed a worse progression over time. No significant differences between sexes were found for severity of irritability/aggression and psychosis.

These findings highlighted that women with Huntington’s “present with worse motor, cognitive, and depressive symptoms than males, although symptom progression over the years was similar between the two sexes,” the researchers wrote.

They also noted that most of these results are consistent with those reported in several previous studies, but in contrast with other studies showing no sex-related differences in Huntington’s.

Future studies that include different patient populations and control for potential influencing factors, such as age at disease onset and affected parent, are needed to confirm these findings, the team noted. More research is also needed to clarify the underlying mechanisms of these sex-specific differences.