Abstract
<strong>Background:</strong> There is emerging evidence that clinical and neuro-pathological manifestations of Huntington’s disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27–35 CAG repeats) in the <em>Huntingtin</em> (<em>HTT</em>) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. <strong>Methods:</strong> Data from the Cooperative Huntington’s Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (≤26), intermediate (27–35) and HD (≥36) groups. The motor, cognitive and behavioral scores on the Unified Huntington’s Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. <strong>Results:</strong> Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. <strong>Discussion:</strong> Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediate CAG repeats. These results have important implications for the pathogenesis of the disease and genetic counseling.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disease with a variable worldwide occurrence but the prevalence in the United States is estimated at 7–10 in 100,000.1 Inherited in an autosomal dominant manner, HD is caused by an expanded cytosineadenine-guanine (CAG) repeat length in the Huntingtin (HTT) gene on chromosome 4p16.3, resulting in accumulation of mutant huntingtin protein in the brain
The Cooperative Huntington’s Observational Research Trial (COHORT) study involved a baseline visit comprising an assessment with the Mini-Mental State Examination (MMSE), a neurological and physical examination, including body mass index (BMI), and the Unified Huntington’s Disease Rating Scale 99 (UHDRS 99), conducted by trained study personnel
This disease has been associated with stigma affecting patients with HD, and those who are at risk for developing HD.[10]
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disease with a variable worldwide occurrence but the prevalence in the United States is estimated at 7–10 in 100,000.1 Inherited in an autosomal dominant manner, HD is caused by an expanded cytosineadenine-guanine (CAG) repeat length in the Huntingtin (HTT) gene on chromosome 4p16.3, resulting in accumulation of mutant huntingtin protein in the brain. While genetically defined HD requires > 36 CAG repeats, some individuals with a mutable normal allele, or intermediate CAG range (between 27 and 35 repeats), have been reported to exhibit features of HD.[2,3,4,5,6] most subjects with CAG repeats in this range are normal, intermediate repeats have the potential to expand into the disease range within one generation.[7] In this study, we aim to further define the clinical characteristics of patients who possess CAG repeat lengths in the intermediate range as this has implications for understanding of the pathogenesis of the disease and for genetic counseling. We hypothesize that a subset of individuals with intermediate alleles demonstrates subtle clinical manifestations that resemble a mild HD phenotype. The expression of these features may be related to other, currently unidentified, genetic and non-genetic modifying factors
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