Clinical implications of malnutrition in Huntington's disease progression: evidence from a Chinese cohort and Mendelian randomization

Background Huntington's disease (HD) is a neurodegenerative disorder associated with progressive motor, cognitive, and psychiatric dysfunction. Peripheral metabolic disturbances, including malnutrition, are commonly observed in HD. However, the prevalence, clinical correlations, and prognostic value of malnutrition in HD, especially among Chinese patients, remain inadequately explored. Methods This cohort study recruited 113 genetically confirmed HD patients and 113 age/sex-matched healthy controls (HCs). Nutritional status was assessed using the Controlling Nutritional Status (CONUT) score, Geriatric Nutritional Risk Index (GNRI), and Prognostic Nutritional Index (PNI). Clinical evaluations included Unified Huntington's Disease Rating Scale (UHDRS), cognitive tests, and psychiatric assessments. Kaplan-Meier survival analysis and Cox regression models were used to evaluate the prognostic significance of malnutrition. Mendelian randomization (MR) analysis was employed to explore causal relationships between nutritional indicators and HD progression using genome-wide association study (GWAS) data. Results During a mean follow-up of 5.74 years, 44 patients reached composite endpoints of death or loss of independent function [total functional capacity (TFC) ≤ 2]. HD patients showed higher malnutrition prevalence than HCs (CONUT: 34.51 vs. 13.27%; GNRI: 7.96 vs. 2.65%). Malnutrition correlated with functional decline, cognitive impairment, advanced disease stage, and lower composite Unified Huntington's Disease Rating Scale (cUHDRS) score, but not with survival outcomes. MR analysis suggests a causal relationship between lymphocyte count and delayed motor progression in HD patients. Conclusion Malnutrition was highly prevalent in Chinese HD patients and was associated with functional and cognitive decline. Although malnutrition did not independently predict survival, MR analysis suggests that lymphocytes delay motor progression, implying that immunonutritional pathways may warrant further investigation as potential targets for future mechanistic and interventional research.