Unique Sex Trajectories in Huntington Disease

There is a significant sex effect on clinical and neuroimaging trajectories in Huntington disease (HD), according to results of a study published in Movement Disorders.

The number of cytosine-adenine-guanine (CAG) repeats on chromosome 4 in the huntingtin gene is an established predictor of disease severity and time to symptom onset. Despite HD’s autosomal dominant mode of inheritance, recent evidence suggests gender-based disparities in prevalence and progression.

To assess the role of sex in HD, researchers retrospectively analyzed data from 4 studies: Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD. Patients (N=19,738) with at least 40 CAG repeats were included. The researchers assessed sex effects on multiple disease metrics, including the CAG-Age Product Score (CAPS), HD Integrated Staging System (HD-ISS), Unified HD Rating Scale, Problem Behaviors Assessment (PBA), and magnetic resonance imaging outcomes.

These insights emphasize the importance of incorporating sex as a critical factor in HD research, clinical trials, and patient management.

Of the participants, 8975 were men and 10,763 were women, with a mean (SD) age of 48.2 (13.6) and 46.8 (13.9) years, respectively (P < .0001). Both groups had a mean (SD) of 43.7 (3.5) CAG repeats. However, a higher percentage of men (74.6%) had manifest HD compared with women (68.2%) (P < .0001). Men also had a higher CAPS than women (mean 1.1 vs 1.0; P < .0001).

In the linear mixed model, the researchers found that sex was significantly associated with several HD-ISS and PBA landmarks:

• PBA depression scores were higher in women than men (estimate, 1.007; P < .0001), indicating more severe depressive symptoms
• PBA apathy scores were lower in women (estimate, -0.117; P = .04)
• HD-ISS stage 2 total motor scores were lower in men (estimate, -0.266; P < .0001), suggesting greater motor impairment
• Symbol Digit Modalities Test scores were higher in men (estimate, 5.513; P < .0001), reflecting better cognitive performance
• HD-ISS stage 1 putamen volume was smaller in men (estimate, -0.988 mL; P = .0006), indicating greater striatal atrophy

Significant gender-by-CAPS interactions were observed for several HD-ISS and PBA outcomes:

• Stage 1 putamen volume (estimate, 0.868 mL; P = .008)
• Stage 2 total motor score (estimate, 0.222; P < .0001)
• Stage 2 symbol digit modalities test (estimate, -4.048; P < .0001)
• Stage 3 total functional capacity (estimate, -0.370; P = .002)
• Stage 3 independence scale (estimate, -2.582; P = .0006)

These results showed that female HD gene carriers exhibited greater CAPS-related motor, cognitive, and functional decline over time, while men demonstrated more pronounced striatal atrophy. However, behavioral symptoms such as depression and apathy were influenced primarily by sex itself, not by sex–CAPS interactions.

In the longitudinal analysis, significant time-by-gender interactions were observed:

• PBA depression (P <.001)
• Caudate volume (P <.05)
• Symbol digit modalities test (P <.05)

These findings indicated that men experienced more rapid progression of depression and caudate atrophy, while women had faster cognitive decline over time.

The major limitation of this study was that neuroimaging outcomes were only available for less than 10% of the cohort.

The study authors concluded, “The observed sex differences suggest that sex-specific considerations should be integrated into the HD staging and management. […] These insights emphasize the importance of incorporating sex as a critical factor in HD research, clinical trials, and patient management.”