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Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington’s disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington’s Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants’ motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD.

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

Patients with adult-onset Huntington’s Disease (AOHD) have been found to have dysfunction of the autonomic nervous system that is thought to be secondary to neurodegeneration causing dysfunction of the brain–heart axis. However, this relationship has not been investigated in patients with juvenile-onset HD (JOHD). The aim of this study was to compare simple physiologic measures between patients with JOHD (n = 27 participants with 64 visits) and participants without the gene expansion that causes HD (GNE group; n = 259 participants with 395 visits). Using data from the Kids-JOHD study, we compared mean resting heart rate (rHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the JOHD and GNE groups. We also divided the JOHD group into those with childhood-onset JOHD (motor diagnosis received before the age of 13, [n = 16]) and those with adolescent-onset JOHD (motor diagnosis received at or after the age of 13 [n = 11]). We used linear mixed-effects models to compare the group means while controlling for age, sex, and parental socioeconomic status and including a random effect per participant and family. For the primary analysis, we found that the JOHD group had significant increases in their rHR compared to the GNE group. Conversely, the JOHD group had significantly lower SBP compared to the GNE group. The JOHD group also had lower DBP compared to the GNE group, but the results did not reach significance. SBP and DBP decreased as disease duration of JOHD increased, but rHR did not continue to increase. Resting heart rate is more sensitive to changes in autonomic function as compared to SBP. Therefore, these results seem to indicate that early neurodegenerative changes of the central autonomic network likely lead to an increase in rHR while later progression of JOHD leads to changes in blood pressure. We hypothesize that these later changes in blood pressure are secondary to neurodegeneration in brainstem regions such as the medulla.