Another perspective on Huntington’s Disease: Disease burden in family members and pre-manifest HD when compared to genotype-negative participants from ENROLL-HD

Background: In addition to the effects on patients suffering from motor-manifest Hunting-ton’s disease (HD), this fatal disease is devasting to people who are at risk, premanifest mutation-carriers, and especially to whole families. There is a huge burden on people in the environment of affected HD patients, and a need for further research to identify at-risk caregivers. The aim of our research was to investigate a large cohort of family members, in comparison with genotype negative and premanifest HD in order to evaluate particular cohorts more closely. Methods: We used the ENROLL-HD global registry study to compare motoric, cognitive, functional, and psychiatric manifestation in family members, premanifest HD, and genotype negative participant as controls. Cross-sectional data were analyzed using ANCOVA-analyses in IBM SPSS Statistics V.28. Results: Of \(\it N\) = 21,116 participants from the global registry study, \(\it n\) = 5174 participants had a premanifest motor-phenotype, \(\it n\) = 2358 were identified as family controls, and \(\it n\) = 2640 with a negative HD genotype. Analysis of variance revealed more motoric, cognitive, and psychiatric impairments in premanifest HD (all \(\it p\) < 0.001). Self-reported psychiatric assessments revealed a significantly higher score for depression in family controls (\(\it p\) < 0.001) when compared to genotype negative (\(\it p\) < 0.001) and premanifest HD patients (\(\it p\) < 0.05). Family controls had significantly less cognitive capacities within the cognitive test battery when compared to genotype negative participants. Conclusions: Within the largest cohort of HD patients and families, several impairments of motoric, functional, cognitive, and psychiatric components can be confirmed in a large cohort of premanifest HD, po-tentially due to prodromal HD pathology. HD family controls suffered from higher self-reported depression and less cognitive capacities, which were potentially due to loaded or stressful situations. This research aims to sensitize investigators to be aware of caregiver burdens caused by HD and encourage support with socio-medical care and targeted psychological interventions. In particular, further surveys and variables are necessary in order to implement them within the database so as to identify at-risk caregiver