Characteristics of Baseline Huntington Disease Based on Age at Onset

Among patients with late-onset Huntington disease (LoHD), a retrospective, observational study found evidence that cognitive disorders and motor symptoms are at least, in part, related with age. These findings were published in the European Journal of Neurology.

HD is a rare, autosomal dominant disorder characterized by abnormal involuntary movement, loss of motor control, and progressive cognitive impairment. HD is caused by expansions of cytosine-adenine-guanine (CAG) triplet-repeats in the first exon of IT15. A small proportion of patients with HD (11%) have late-onset disease (age 60 years and older) which is thought to have more mild symptoms. However, there is a paucity of robust evidence about why HD onset occurs at various times or whether symptoms relate with age at onset.

This study sought to evaluate clinical characteristics of LoHD and to assess whether symptoms are influenced solely on genetics or other factors. Data were sourced from Enroll-HD, which is a multicentric, global, longitudinal, observational study of HD families. Patients with LoHD (n=663), common/typical adult-onset (CoHD; 30-59 years; n=3960), and young adult-onset (YoHD; 20-29 years; n=368) disease were evaluated for genetic, sociodemographic, clinical, neuropsychological, and behavioral characteristics.

The LoHD, CoHD, and YoHD groups were 50.7%, 51.2%, and 51.4% women; aged mean 71.6, 52.7, and 33.2 years (P <.001); and they had 40.8, 43.7, and 50.7 CAG repeats (P <.001), respectively.

LoHD was associated with more unknown or absent HD inheritance (31.2% vs 5.2%-10.0%).

The initial major symptom was motor in all groups, occurring at a higher frequency in LoHD (60.0% vs 50.8%-50.9%).

Despite symptoms manifesting later in life than other patient groups, the LoHD group had similar total motor scores (TMS; mean, 41.2 vs 41.2-44.6) and total functional capacity (TFC) scores (mean, 7.4 vs 7.3-7.7), indicating comparable severity of motor symptoms and functional impairment. The LoHD groups were associated with poorer Mini-Mental State Examination and Symbol Digit Modality Test compared with CoHD (both P ≤.002).

Fewer patients with LoHD reported a history of alcohol or substance abuse and suicidal behavior or ideation than CoHD and YoHD (all P ≤.001) and less apathy, depression, or obsessive-compulsive disorders compared with CoHD (all P ≤.004).

Among the subset of patients with more than 41 repeats (LoHD: n=233; CoHD: n=360), the LoHD cohort was associated with lower educational level, TFC, history of drug use or abuse, suicidal behavior or ideation, depression, Stroop Interference Test score, and Trail Making Test score and higher Penny Burdon of Pathology score, TMS, and unknown or absent HD ancestry (all P ≤.038), indicating probable nongenetic causes.

This study was limited by not including data on disease progression.

The study authors concluded, “It is likely that cognitive disorders and motor symptoms of LoHD are at least partly age-related and not a direct expression of the disease. In addition to CAG-triplet repeat expansion, future studies should investigate the role of other genetic and environmental factors in determining age of onset.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Petracca M, Di Tella S, Solito M, et al. Clinical and genetic characteristics of late-onset Huntington’s disease in a large European cohort. Eur J Neurol. Published online March 31, 2022. doi:10.1111/ene.15340