Multidisciplinary Approach to Phenotypic Variants in Huntington Disease

Huntington disease (HD) is a rare neurodegenerative disorder with an autosomal dominant inheritance pattern, caused by an abnormal expansion of trinucleotide cytosine-adenine-guanine (CAG) repeat in the huntingtin gene. This mutation leads to neural degeneration within the basal ganglia, particularly targeting striatum, resulting in a spectrum of motor, cognitive, and psychiatric symptoms. The first aim of this study was to explore variations across different HD stages. The second was to investigate differences among HD phenotypes based on clinical presentation at age of onset. Our research population consisted of a total of 45 participants. All participants were included in the first research sample and divided into presymptomatic (n = 4), prodromal (n = 12), and manifest stage (n = 29). Our second research sample comprised 39 participants, categorized by initial symptoms, either with (Motor +, n = 13) or without (Motor -, n = 26) motor manifestations. All data were collected from comprehensive neurological, neuropsychological, and neuroradiological assessments conducted at Padua University Hospital between 2012 and 2024. Statistical analyses were performed using R (version 4.4.1), with voxel-based morphometry used for neuroimaging data. Our results showed stastistically significant progression in motor, cognitive, and functional capacities, though no statistically significant differences were found for behavioral symptoms. Additionally, the group with initial motor manifestations showed significantly greater motor impairment, while patients without motor onset demonstrated higher functional independence. These findings suggest that motor symptoms have a greater impact on functional capacity than neuropsychiatric symptoms. Notably, attention and social cognition appeared sensitive in distinguishing between presymptomatic and prodromal stages, though further investigation is necessary.