Objective: To investigate the relationship between serum urea levels and clinical outcomes in people with Huntington’s disease.

Background: Several studies in people with Huntington’s disease (HD) and HD animal models have shown increased levels of urea[1-3] in brain and serum samples. Further evidence indicates that deficits in the urea cycle may already occur early in the disease [3,4] with positive effects of a low-protein diet in alleviating symptoms in HD in mouse models[5]. However, the association between serum urea levels and clinical symptoms has not been extensively investigated.

Method: We analysed data from the iMarkHD study (https://classic.clinicaltrials.gov/ct2/show/NCT03434548) and evaluated serum urea levels, determined at the time of screening for study enrolment, from 20 premanifest people with HD (PwHD), 10 perimanifest PwHD, 16 manifest PwHD, and 15 healthy controls (HC). The Shapiro-Wilk test confirmed non-normal distribution of the data, therefore we used Kruskal-Wallis test to compare urea levels between groups. To evaluate the association between serum urea levels and motor and functional components of the Unified Huntington’s Disease Rating Scale (UHDRS), Single Digit Modalities Test (SDMT) scores, and Hospital Anxiety and Depression scores (HADS), Spearman’s Rho was used.

Results: We observed that serum urea levels in manifest PwHD were significantly elevated compared to premanifest PwHD (p=0.036), but no difference was observed between the whole cohort of PwHD and HCs (p=0.466). We observed significant positive correlations between serum urea and UHDRS Total Motor Scores (TMS) scores (p=0.024) and UHDRS Total Functional Capacity (TFC) scores (p=0.007), and negative correlation between serum urea and SDMT scores (p=0.008). Moreover, we observed significant positive correlations between serum urea levels and UHDRS dystonia scores (p=0.025) within the whole cohort of PwHD. No association was revealed between serum urea levels and HADS scores.

Conclusion: The exploratory analysis of data from the iMarkHD study shows that serum urea levels were associated to several motor and non-motor outcomes, including cognitive function, in PwHD. Interestingly, there was no overall difference in serum urea levels between PwHD and HCs. These preliminary data support the hypothesis that protein degradation progresses through different disease stages and could be developed further as a potential biomarker for disease and symptom progression in PwHD.

References: 1. Patassini, S., et al., Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington’s disease human brain. Biochim Biophys Acta, 2016. 1862(9): p. 1650-62.

2. Patassini, S., et al., Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington’s disease. Biochem Biophys Res Commun, 2015. 468(1-2): p. 161-6.

3. Handley, R.R., et al., Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases. Proc Natl Acad Sci U S A, 2017. 114(52): p. E11293-e11302.

4. Skene, D.J., et al., Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers. Scientific Reports, 2017. 7(1): p. 43030.

5. Chiang, M.C., et al., Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington’s disease. Hum Mol Genet, 2007. 16(5): p. 483-98.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/serum-urea-and-clinical-outcomes-in-huntingtons-disease/