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Early this year, data from the global Enroll-HD cohort showed that women with Huntington's disease experienced more severe symptoms than men.

In an observational study that followed people with manifest Huntington's disease over four annual visits, significant sex-dependent differences in motor, behavioral, and cognitive symptoms emerged, reported Natalia Rocha, PhD, of the University of Texas Health Science Center at Houston, and co-authors.

Both sexes had worsened motor symptoms over the course of four visits, but there was a significant disparity between sexes, with women consistently presenting with more motor symptoms than men, Rocha and colleagues wrote in . Women had significantly more depressive symptoms, although self-reported depressive symptoms in both sexes became less severe over time. Overall, men tended to perform better on cognitive tests than women.

Huntington's disease has a well-recognized triad of symptoms, but significant variability exists, noted co-author Erin Furr Stimming, MD, also of the University of Texas Health Science Center at Houston.

"Remarkable progress has been made in understanding the genetics, pathogenesis, and natural history of Huntington's disease; however, many questions remain and a disease-modifying therapy remains elusive," Stimming told 番茄社区. "Despite making significant advances in predicting symptom onset, we are unable to accurately determine exactly when an individual will manifest symptoms, nor are we able to accurately predict the rate of progression."

"This study suggests that women may have more severe cognitive, motor, and mood symptoms and may even have a more rapid rate of progression," Stimming continued. "Improving our understanding of the role sex hormones may play in symptom onset and rate of progression could improve our prognostic and treatment approaches."

"Enhancing our understanding of the sex differences in Huntington's disease could potentially lead us to a more effective, sex-specific approach to treatment," she added.

The analysis followed 2,145 people -- 1,097 women and 1,048 men -- with manifest Huntington's disease and a CAG repeat expansion on the huntingtin gene (HTT) of 36 or higher. At the fourth annual visit, women had a mean age of 54.4, and men had a mean age of 55.6.

There were no differences between men and women in CAG repeat length. More men (42.4%) than women (32.0%) had a history of alcohol abuse; more women (80.9%) than men (71.4%) had a history of depression (P<0.001 for both.)

Results of the Enroll-HD analysis supported findings from earlier studies. In PREDICT-HD, for example, of increased depressive symptom severity. And in a 2013 analysis of data from 1,267 people in the European Huntington's Disease Network's cohort, the rate of Huntington's than in men, even when controlled for disease burden.

In 2018, an analysis of 2,191 patients in the REGISTRY database showed that motor symptoms had the highest effect on function in Huntington's disease, reported Daniel Zielonka, MD, PhD, of Poznan University of Medical Sciences in Poland, and co-authors in . Importantly, these symptoms affected the function and independence of women with Huntington more than men, the researchers found.

"Our analysis points out the urgency to put major effort into developing treatments to alleviate the motor impairment in Huntington's disease in the attempt to symptomatically improve their quality of life, while hoping that one day neuroprotective therapies will provide a cure," Zielonka and co-authors wrote. "As it is a second study where gender differences in Huntington's disease have been confirmed, it is important to take gender into account when proposing future clinical trials and look into genetic aspect[s] of gender contribution to Huntington's disease clinical picture."

What drives sex-based differences in Huntington's disease is not clear. In Spain, research led by Jaime Kulisevsky, MD, PhD, of Sant Pau Hospital in Barcelona, investigated whether sex differences in clinical worsening could be driven by a differential impact of the underlying neurodegenerative processes on brain atrophy. If that were true, they hypothesized, women would be more vulnerable to naturally occurring neurodegeneration.

Kulisevsky and colleagues used cerebrospinal fluid neurofilament light chain (NfL) levels as a measure of neurodegeneration and assessed brain atrophy by structural MRI. Based on 41 Huntington's disease patients -- 21 women and 20 men, both groups about 44 years old -- the researchers found that larger NfL values in women reflected higher brain atrophy and clinical severity than they did in men (P<0.05 for an interaction model).

This differential vulnerability could have important implications in clinical trials, the researchers wrote in .

"This work sheds light on the biological mechanisms through which female Huntington's patients appear to have a worse clinical progression than males," Kulisevsky told 番茄社区. "The inherent neurodegeneration occurring in Huntington's disease seems to have worse clinical and neuroimaging consequences in female individuals."

"The findings suggest that sex should be taken into consideration when interpreting biomarkers of neurodegeneration in Huntington's disease," Kulisevsky added.

"Sex is an unmodifiable risk factor that may play an important role in the pathophysiology of neurodegenerative diseases," Stimming observed. Researchers have found a sex-dependent bias in risk, symptoms, and progression of diseases like Alzheimer's, Parkinson's, or multiple sclerosis, but there have been conflicting data about the role sex plays in Huntington's, an autosomal dominant disease which is independent of sex, she noted.

"While we know depression is a common psychiatric symptom in Huntington's disease, our analyses revealed that female Huntington gene carriers present with worse depressive symptoms than males," Stimming pointed out. "Therefore, it is important, especially in women, to ensure they have strong pharmacologic and nonpharmacologic support."

"Because many women are acting as caregivers for their affected parents or children at risk and may, therefore, defer their care, heightened awareness of their neuropsychiatric and motor symptoms is imperative," she added.

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