Objective: To investigate the association between blood-based somatic CAG repeat expansion ratio (SER) and clinical characteristics in Huntington’s disease (HD) patients from Western China.

Background: Somatic CAG repeat expansion is a lifelong process driving neuropathogenesis in HD. The SER in blood reflects shared common effects with neuronal SER influenced by inherited CAG length and genetic modifiers. Understanding the relationship of blood-based SER and clinical characteristics of HD mutation carriers may provide in-vivo evidence for developing therapeutics targeting somatic CAG expansion.

Method: SER was quantified using capillary electrophoresis-based fragment analysis of DNA extracted from peripheral blood mononuclear cells. Clinical assessments, including motor function, cognitive performance, and functional capacities, were conducted at baseline and follow-up visits. Multivariate linear regression models were used to evaluate associations between blood-based SER and clinical characteristics. The residuals of SER after adjusting for age, CAG repeats, and their interaction term were extracted and standardized, and utilized in the sensitivity analysis.

Results: A total of 220 manifest HD patients were included in the cross-sectional analysis, and 99 patients were included in the retrospective cohort analysis, with a mean follow-up period of 5.03±3.03 years. Higher baseline SER was associated with a larger residual age of motor symptoms onset (β=-3.29, [95% CI, -6.29, -0.30], p=0.03, n=220), while exhibited no significant associations with the severity of motor and cognitive symptoms, or functional capacities cross-sectionally. Higher SER was significantly associated with slower progression of the composite UHDRS (-2.39, [-4.67, -0.11], p=0.04, n=27), and its subscales—TFC (-1.53, [-2.76, -0.30], p=0.02, n=99) and SWR (-16.22, [-29.43, -3.00], p=0.02, n=32), but not with TMS (7.38, [-1.32, 16.07], p=0.09, n=47) or SDMT (3.08, [-5.29, -11.46], p=0.45, n= 27), after adjusting for age, CAG repeat length and their interaction term. Consistent results were observed in the analysis of standardized residual SER and clinical characteristics in HD (Figure 1).

Conclusion: This study provides evidence that higher SER is associated with faster clinical progression of HD, which suggest that therapeutics targeting somatic CAG expansion may have the potential to delay disease onset and progression in HD.

Figure 1. (A-F)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/blood-based-somatic-cag-repeat-expansion-and-clinical-progression-in-huntingtons-disease-patients-from-western-china/