Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD

Abstract

Background: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. Objective: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional and imaging outcomes between persons with CAG repeats in four ranges: normal (≤ 26), intermediate (27–35), reduced penetrance (36–39), and full penetrance (≥ 40). Methods: We examined longitudinal data from 1379 participants (280 normal [NA], 21 intermediate [IA], 88 reduced penetrance [RP], and 986 full penetrance [FP] allele ranges). We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. Results: Model 3 was the best fitting model for most outcome variables. Differences between the NA and the FP group account for the majority of significant findings. Some differences between the RP and NA groups were significant. While there were baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, we found no significant differences between the NA and IA groups. Conclusions: We did not find evidence to support differences in the IA group compared to the nongene-expanded controls. These findings are limited by a small IA sample size.

Huntington disease: Advances in the understanding of its mechanisms

“…Intermediate alleles comprise those individuals with 27–35 CAG repeats; controversial data report a mild cognitive impairment and behavioral involvement [ 6 , 7 ]. The major concern in this population is the expansion during meiosis increasing the nCAG repeats in the offspring [ 8 ] ( Table 1 ).…”