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Psychiatric, Cognitive Symptoms Common in Huntington Disease Gene Carriers

Overall, 42.4% of patients with Huntington disease reported at least 1 psychiatric or cognitive symptom before motor symptoms, with depression being the most common.

In an effort to assess the timing and impact of psychiatric, cognitive, and motor abnormalities in patients with Huntington disease (HD), researchers concluded that the initial manifestation of HD is increasingly likely to be motor, and less likely to be psychiatric, as age at presentation increases, and is independent of pathogenic CAG repeat length.

Lead author Branduff McAllister, BSc, PhD, research associate, Cardiff University, and colleagues evaluated the clinical features of 6316 individuals with HD from the European REGISTRY study. Patients completed Clinical Characteristics Questionnaire (CCQ) that assessed 8 symptoms: motor, cognitive, apathy, depression, preservative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis.

They found that as age at first manifestation increased, motor presentations became more likely (odds ratio [OR] per 10-year increase in onset age, 1.06 [95% CI, 1.04-1.07]; P = 7.4 x 10-22) but psychiatric presentations became less likely (OR per 10-year increase in onset age, 0.96 [95% CI, 0.95-0.97]; P = 9.4 x 10-16).

Among patients over the age of 60 years old, 68.6% had initial motor abnormalities with far fewer having psychiatric (11.5%) or cognitive (6.7%) presentations. “The presence of psychiatric and cognitive symptoms in HD gene carriers is associated with significantly reduced functional capacity, emphasizing the importance of early recognition and management of these symptoms,” McAllister et al wrote.

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Cognitive impairment was the most significantly associated symptom with reduced total functional capacity (TFC; OR per unit decrease in TFC, 1.28 [95% CI, 1.23-1.35]; P = 1.6 x 10-25). Depression was significantly associated with total lower scores on CCQ, aligning with its prevalence early in the disease course. Significant associations were observed between depression and female sex (OR, 1.77 [95% CI, 1.44-2.17]; P = 7.0 x 10-8), as well as tobacco use and irritability (OR per extra cigarette per day, 1.02 [95% CI, 1.01-1.03]; P = 1.0 x 10-4).

McAllister and colleagues also found no significance in the relationship between CAG repeat length and the relative proportions of motor, cognitive, and psychiatric onset cases. Cases of repeat lengths of more than 59 CAG were shown to have a more balanced distribution of motor, cognitive, and psychiatric presentations, mirroring the trends seen for juvenile HD cases.

In those cases, individuals with an onset before the age of 20 were equally likely to present with motor (24.5%), cognitive (21.8%) or psychiatric features (28.2%), contrasting to patients with adult-onset HD, which had higher likely of manifestation with motor than psychiatric.

Among a subpopulation of 5609 individuals with HD, more than 99% had experienced motor symptoms compatible with HD, indicating why motor abnormalities remain the diagnostic standard for clinical onset of HD. Despite motor symptoms not explicitly defined in the CCQ, contemporaneous data from Unified Huntington’s Disease Rating Scale showed that 96.8% of the study population had chorea, alongside variable amounts of incoordination, dystonia, and rigidity.

There was a strong inverse correlation between pathogenic GAC repeat length (40-55 CAG inclusive) and mean age at symptom onset for all symptoms analyzed. Pathogenic CAG length explained 66.3% of the variance in age at onset of motor symptoms, in line with previous estimates, according to the study authors.

The timing of motor and psychiatric symptoms in HD gene carriers was shown to vary with symptom type and CAG length. Overall, 42.4% of patients with HD (2140 of 5042) reported at least 1 psychiatric or cognitive symptom in advance of motor symptoms, with a further 22.3% (1126 of 5042) reporting at least 1 of these symptoms at the same time as motor abnormalities.

McAllister B, Gusella JF, Landwehrmeyer GB, et al. Timing and impact of psychiatric, cognitive, and motor abnormalities in Huntington disease. Neurology. Published online March 25, 2021. doi: 10.1212/WNL.0000000000011893