Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Abstract

Objective: To assess the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers, we analyzed retrospective clinical data from individuals with manifest HD.

Methods: Clinical features of patients with HD were analyzed for 6,316 individuals in an observational study of the European Huntington's Disease Network (REGISTRY) from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed 8 symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyze relationships between symptoms and functional outcomes.

Results: 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. The Clinical Characteristics Questionnaire captures data on nonmotor symptom prevalence that correlate specifically with validated clinical measures. Psychiatric and cognitive symptoms are common in HD gene carriers, with earlier onsets associated with longer CAG repeats. Of patients with HD, 42.4% reported at least 1 psychiatric or cognitive symptom before motor symptoms, with depression most common. Each nonmotor symptom was associated with significantly reduced total functional capacity scores.

Conclusions: Psychiatric and cognitive symptoms are common and functionally debilitating in HD gene carriers. They require recognition and targeting with clinical outcome measures and treatments. However, because it is impossible to distinguish confidently between nonmotor symptoms arising from HD and primary psychiatric disorders, particularly in younger premanifest patients, nonmotor symptoms should not be used to make a clinical diagnosis of HD.

Trial registration information: ClinicalTrials.gov Identifier: NCT01590589.

Figure 1. Initial Manifestation of HD Varies With Age and CAG Length

All included individuals had a pathogenic CAG length (36–93) and confirmed Huntington disease (HD) onset age determined by a rating clinician. (A) Frequency of different onset types in 4 age groups, chosen to show juvenile HD and then 20-year bins for clarity. Total n= 6,289, <20 years n = 188, 20 to 40 years n = 2,216, 40 to 60 years n = 3,276, >60 years n = 609. (B) Frequency of different onset types in 6 CAG length groups, chosen for clarity across the pathogenic range. Total n = 6,289, 36 to 39 CAG n = 156, 40 to 44 CAG n = 3,813, 45 to 49 CAG n = 1,735, 50 to 54 CAG n = 387, 55 to 59 CAG n = 97, >60 CAG n = 101.

Figure 2. Onsets of Cognitive and Psychiatric Symptoms Relative to Motor Onset in HD

Age at onset of motor symptoms was subtracted from the age at onset of each cognitive/psychiatric symptom when present. Timings of up to ± 40 years relative to motor onset shown. Only individuals with a rater-confirmed age at onset and CAG length (36–93) were included. Data from Huntington Disease (HD) Clinical Characteristics Questionnaire. (A) Cognitive impairment n = 3,225; (B) apathy n = 2,852; (C) depression n = 3,495; and (D) irritability n = 3,235.

Figure 3. Mean Ages at Onset for Motor and Psychiatric Symptoms at Different CAG Repeat Lengths

Shown are the mean ages at symptom onset as recorded by the Huntington Disease Clinical Characteristics Questionnaire for apathy (n = 2,739), cognitive impairment (n = 3,069), depression (n = 3,399), irritability (n = 3,117), and motor symptoms (n = 4,889).