Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS

Abstract

Objectives: We aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study.

Methods: The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington's Disease Rating Scale (UHDRS) by investigators unaware of participants' gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27-35, and nonexpanded controls <26.

Results: Fifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group's scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups.

Conclusions: In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

Figure 1. Huntingtin allele frequency distribution in Prospective Huntington At Risk Observational Study cohort

Figure 2. Baseline mean Unified Huntington’s Disease Rating Scale behavioral scores by CAG expansion length

Figure 3. Mean total behavioral Unified Huntington’s Disease Rating Scale scores over time by CAG expansion length