ENOrphanet Journal of Rare Diseases | Impact of Sex Differences on Clinical Manifestations and Functional Outcomes in Huntington's Disease
Date: February 09, 2026
Classification: Frontiers
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This study reveals that female Huntington's disease patients experience irritability symptoms more frequently than males and have significantly lower employment rates, highlighting the importance of sex in disease management and social support strategies.
Literature Overview
The article titled 'Bridging the gap: sex-specific differences in Huntington’s disease,' published in the Orphanet Journal of Rare Diseases, reviews and summarizes the impact of sex on clinical manifestations, neurorehabilitation participation, and employment status within a single-center Austrian Huntington's disease cohort. Based on data from 102 genetically confirmed patients, the study analyzes gender differences in CAG repeat length, symptom distribution, use of non-pharmacological treatments, and employment status. Results indicate that although there are no significant differences between males and females in CAG repeat count or age of onset for motor/non-motor symptoms, female patients more frequently exhibit irritability symptoms and have much lower full-time employment rates than males. The study emphasizes the necessity of considering sex in clinical management and social support. The article ends with a Chinese period.Background Knowledge
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene on chromosome 4, typically pathogenic when repeat count ≥35. Core features include progressive motor dysfunction (e.g., chorea), cognitive decline, and psychiatric/behavioral abnormalities, with onset usually in mid-adulthood. Diagnosis relies on genetic testing, family history, and assessment using the Unified Huntington's Disease Rating Scale (UHDRS). In recent years, growing evidence suggests that sex may influence the clinical phenotype and disease progression trajectory in HD. For example, some large registry studies indicate that female patients may exhibit more severe psychiatric symptoms such as depression and irritability, while males more often show aggression or apathy. Additionally, some studies find that women experience faster functional decline and a more pronounced loss of independence in daily activities. However, CAG repeat length and age of onset are largely consistent between sexes, suggesting differences may stem from non-genetic factors such as biological, psychosocial, and social role factors. Current HD management emphasizes multidisciplinary collaboration, including physical, occupational, speech therapy, and psychological interventions, to maintain function and quality of life. Although pharmacological treatments have been widely studied, systematic analyses of sex differences in non-pharmacological interventions and functional outcomes remain lacking. This study fills that gap by focusing on sex-specific differences in symptom expression, rehabilitation utilization, and employment status, providing a basis for individualized intervention strategies. The paragraph ends with a Chinese period.
Research Methods and Experiments
The research team retrospectively analyzed 102 genetically confirmed Huntington’s disease patients seen at the Department of Neurology, Medical University of Innsbruck, Austria, between 2015 and March 2025. Of these, 101 patients had complete CAG repeat count data. Employment status (full-time, part-time, unemployed) and use of non-pharmacological neurorehabilitation treatments (e.g., physical therapy, occupational therapy, psychological therapy) were collected via semi-structured interviews. Clinical assessments used the UHDRS scale, and non-motor symptoms were evaluated using the PBA-s scale, covering depression, irritability, cognitive impairment, and psychotic symptoms. CAG repeat count, disease burden score (DBS), and CAG-Age Product (CAP) score were calculated and used for adjusted analyses. Data normality was assessed using the Shapiro-Wilk test; group comparisons used parametric or non-parametric tests, with Bonferroni correction for multiple testing. Due to the three-category nature of employment status, a multinomial logistic regression model was applied, adjusted for CAG repeat count and CAP score.Key Conclusions and Findings
Research Implications and Outlook
This study provides empirical support from a single-center cohort for sex differences in Huntington’s disease, emphasizing the need for greater attention to mental health and social functioning in female patients in clinical practice. The high prevalence of irritability may affect patients’ interpersonal relationships and quality of life, necessitating targeted psychological interventions. The large disparity in employment status suggests that structural societal factors (e.g., caregiving responsibilities, inadequate workplace support) may exacerbate functional decline in female patients, and future research should explore these mechanisms using a biopsychosocial model.
Although no gender difference in rehabilitation utilization was found, the overall low usage rate indicates a need to improve accessibility and promotion of multidisciplinary interventions. The findings support the importance of early and continuous rehabilitation for all patients. Future large-scale, multicenter longitudinal studies will help validate these findings and explore potential mechanisms such as hormones, neuroinflammation, or social support networks. Additionally, the effectiveness of sex-tailored intervention strategies in improving functional outcomes should be evaluated.
Conclusion
This study systematically analyzes the impact of sex on clinical manifestations and functional outcomes in Huntington’s disease patients, finding that although there are no differences between males and females in CAG repeat length and age of motor symptom onset, female patients more frequently exhibit irritability symptoms and have significantly lower employment rates. These results suggest that sex plays an important role in non-motor symptom expression and social functioning in HD. No gender differences were found in the use of non-pharmacological treatments, but the overall low rehabilitation utilization reflects insufficient support services in real-world settings. These findings emphasize that sex should be considered a key variable in the clinical management of HD, especially in the development of psychological support and vocational rehabilitation strategies. Future research should further explore the biological and sociocultural mechanisms behind these differences to advance more personalized intervention programs. This study provides an important perspective for understanding the heterogeneity of HD and offers a basis for designing social policies to optimize patients’ quality of life. The conclusion section ends completely.
