Non-motor symptoms in Huntington’s disease: a systematic review

Huntington’s disease (HD) is a progressive, autosomal-dominant neurodegenerative disorder characterized by motor, cognitive, psychiatric, and behavioral disturbances. While motor symptoms are often the most clinically evident and traditionally emphasized, non-motor symptoms are increasingly recognized as major contributors to disease burden, functional impairment, reduced quality of life, caregiver distress, and healthcare utilization. Non-motor manifestations may emerge years before the onset of overt motor signs and may follow distinct trajectories throughout the disease course, yet the available evidence remains heterogeneous and scattered across multiple clinical domains. The purpose of this project is to conduct a systematic review of clinical studies assessing non-motor symptoms in cohorts of individuals with Huntington’s disease, including both premanifest and manifest stages when available. This review aims to provide an updated and structured synthesis of the prevalence and/or severity of non-motor symptoms and their clinical correlates, with particular attention to the assessment tools employed, disease stage, and study design (cross-sectional versus longitudinal). The review will include studies published within the last 30 years and will focus on studies reporting patient-level cohort data. Non-motor domains of interest include cognitive impairment (e.g., executive function, attention, memory, processing speed, social cognition), psychiatric and behavioral symptoms (e.g., depression, anxiety, apathy, irritability, obsessive-compulsive symptoms, psychosis), sleep disturbances, autonomic dysfunction and other symptoms that do not fall into the previous categories. Expected outcomes include (i) a structured overview of the clinical literature on non-motor symptoms in HD, (ii) domain-specific evidence tables summarizing key findings and assessment methodologies, (iii) identification of gaps and inconsistencies across studies, and (iv) clinically relevant conclusions regarding the burden and trajectory of non-motor symptoms. Where appropriate, associations with disease stage, motor severity measures, and genetic/biomarker indices reported in the primary studies will be summarized. The findings of this systematic review are expected to support clinicians and researchers by clarifying the current evidence base, highlighting domains requiring standardized assessment, and informing future observational and interventional research focused on improving patient-centered outcomes in Huntington’s disease. This protocol is prospectively registered to enhance transparency and to minimize reporting bias. Any amendments to the protocol will be documented and dated within the project record.