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Huntington's Disease (HD) is a neurodegenerative disorder characterized by CAG repeat expansions in the huntingtin gene that lead to progressive movement dysfunction. Though HD typically presents in adulthood (adult-onset HD, or AOHD), a subset of individuals experience symptoms before the age of 21 years. Known as juvenile-onset HD (JOHD), it is typically associated with longer CAG repeats compared to AOHD.¹

Previous trials have largely excluded patients with JOHD, either directly or indirectly.^2,3 Thus, data allowing tracking and measurement of JOHD are lacking. However, a recent study published in Parkinsonism & Related Disorders sheds new light on this critical area.¹

Using the Enroll-HD database, Nopoulos and colleagues compared motor progression in JOHD and AOHD relative to the Unified Huntington鈥檚 Disease Rating Scale (UHDRS), a widely used clinical assessment tool for AOHD, to identify which components of the scale may best distinguish JOHD. Enroll-HD is a rich resource of clinical data from individuals with HD that facilitates a wide range of research on HD, from tracking disease progression to testing potential therapies. This long-term observational study gathers valuable data annually from participants across multiple centers, empowering researchers to develop a deeper understanding of HD progression.¹

Patient demographics and clinical characteristics 

The authors of the current study included data from 9614 subjects who had 36 or more CAG repeats. They also had to have a reported age of clinical diagnosis of HD within the Enroll-HD system, which helped to limit recall bias inherent in patient-reported age of symptom onset data. The reported age of clinical diagnosis (ACD) was used to divide participant data into 2 groups: JOHD (n=90; ACD 鈮�21 years; CAG repeat length 鈮�55) or AOHD (n=9524; ACD >21 years; CAG repeat length <55).¹

To account for heterogeneity within JOHD, this group was further divided into pediatric-onset if diagnosed before age 18 (42.2%, n=38/90) and non-pediatric if diagnosed at age 18 or older. The rate of motor progression, the annual rate of change of the UHDRS total motor score (TMS), and the rate of annual change of the chorea score were compared between the JOHD and AOHD groups for 5 years while enrolled in the study. 

Motor progression in JOHD differed from AOHD

As expected, the JOHD group had longer CAG repeats (67.4, SD=10.7 vs 43.6, SD=3.0 respectively, P<.001) and were younger than the AOHD group at baseline. 

During the study period, a distinct pattern of motor progression emerged in patients with JOHD. Compared to their AOHD counterparts, all individuals with JOHD exhibited a faster increase in their TMS (2.64 points per year faster [95% confidence interval (CI) 1.65鈥�3.62], P<.001). No difference existed in TMS between pediatric and non-pediatric JOHD subcategories.¹

Interestingly, the study did not find significant differences in the rate of change of the chorea score between any of the groups. This implies that while overall motor function worsens faster in JOHD, the specific movement pattern may not differ from AOHD.¹

The investigators then focused on only the JOHD individuals. They looked at the annualized rate of change in the 31 subscales that make up the UHDRS. After corrections, no significant difference existed in the rate of change in any of the chorea subscales that comprise the UHDRS. However, the 10 variables that had the most change over time were standardized to the percent of the maximum possible total score and summed to create a new JOHD Scale, with a maximum possible score of 40. The subscales identified were dysarthria; dystonia: LUE; gait; tandem walking; pronate/supinate: R hand; dystonia: RUE; finger tapping: R hand; finger tapping: L hand; tongue protrusion; and pronate/supinate: L hand.¹

When the JOHD group was reevaluated using this new scale, the average annual rate of change in TMS score was 4.92% (95% CI [3.95鈥�5.89], P<.0001) and 5.83% (95% CI [4.77鈥�6.90], P<.0001) in the abbreviated TMS (all TMS subscales except chorea scores). The JOHD Scale changed at an annualized rate of 7.07% (95% CI [5.96鈥�8.18], P<.0001).¹

Implications for clinical practice and research

The insights gleaned from this study have significant implications for both clinical practice and research in JOHD. In the report, the authors suggest that this 鈥渟cale adequately tracks disease progression across the wide spectrum of phenotypes seen in patients with JOHD. Based on our findings, we simulated a hypothetical interventional study for patients with JOHD and found that use of the JOHD Scale as the primary outcome measure resulted in reduction in the total number of required participants by more than 33% compared to a similar study that used the TMS as the primary outcome measure. Consequently, this newly proposed JOHD Scale may represent a more clinically meaningful outcome measure鈥︹��¹

Notably, when the subscales were combined into a composite score, the new scale revealed a faster rate of progression compared to the TMS. This suggests that a more nuanced approach, focusing on specific motor domains that are particularly sensitive to change in JOHD, may provide a more accurate picture of disease progression than relying solely on the overall TMS score.¹

For clinicians, the identified subscales can inform the selection of outcome measures for monitoring disease progression and treatment response in patients with JOHD. This tailored approach can lead to more accurate assessments and personalized treatment plans. For researchers, the study provides valuable guidance for designing clinical trials in JOHD. By focusing on the identified subscales and composite score, trials can be optimized to detect subtle changes in motor function, potentially accelerating the development of effective therapies.¹

While the findings of this study offer valuable insights into motor progression in JOHD, the need for further research remains. Future studies should explore the underlying biological mechanisms driving the distinct motor phenotype observed in JOHD. Additionally, investigating the relationships between motor progression, cognitive decline, and other non-motor symptoms in JOHD is crucial for developing a comprehensive understanding of the disease.

Published: February 28, 2024