Asymptomatic people who carry an intermediate number (27-35) of CAG repeats on the huntingtin gene – that is, the range just below the Huntington’s disease threshold of 36 CAG repeats – may be at increased risk for mild, late-onset symptoms, according to the first report to definitely associate intermediate alleles with such symptoms.

The prevalence of this distinct category of alleles for the huntingtin (HTT) gene, termed IA (for intermediate alleles), ranges from 1.5% to 5.8% both in the general population and in affected families. The clinical manifestations of Huntington’s disease associated with IAs have remain hidden until now in part because asymptomatic family members often decline to undergo genetic testing for the disorder and so are not identified as having IAs. Emerging evidence suggests that some people with IAs are more likely than those with a smaller number of CAG repeats to develop Huntington-like neuropathologic effects, but the data are sparse, and the question is controversial, said Esther Cubo, MD, PhD, of the department of neurology, Hospital Universitario Burgos (Spain) and her associates on behalf of the European Huntington’s Disease Network (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002944 ).

To examine this issue in a large cohort of at-risk individuals, the investigators assessed clinical and sociodemographic factors for 657 people enrolled in the European Huntington’s Disease Registry , which tracks the natural course of the disease in patients and family members treated in 1998 through 2014 at 140 medical centers in 17 European and 3 other countries. They focused on individuals who were asymptomatic at baseline: 76 (11.6%) men and women who had IAs (cases) and 581 (88.4%) who had fewer than 27 CAG repeats (controls). The two groups were similar in age, body mass index, educational background, socioeconomic status, tobacco and alcohol use, and medication use, and they scored similarly on measures of health-related quality of life, functional capacity, and the Unified Huntington’s Disease Rating Scale (UHDRS) for motor, behavioral, and cognitive status.

IA status was not associated with any significant differences between cases and controls who were younger than age 60. However, after age 60, participants with IAs had higher median total UHDRS motor scores (13.0 vs. 2.0) and were more likely to show mild gait abnormalities, chorea, and bradykinesia. In the small subgroup of patients who were followed longitudinally for up to 2 years, those with IAs showed faster cognitive decline over time; however, longer follow-up of larger groups of participants is needed to confirm this trend, the investigators said.

In addition, study participants with IAs reported lower quality of life and a greater degree of apathy than those without IAs, but these differences did not reach statistical significance. Whether apathy and poor quality of life reflect Huntington’s disease or simply correlate with normal aging could not be determined.

This study was limited by the relatively small number of participants with IAs, but the findings suggest that IAs “could produce a mild phenotype” of Huntington’s disease in some carriers after age 60. Alternatively, “clinical manifestations of Huntington’s disease in patents with IA might also be potentially accelerated by medical conditions, treatments, and environmental factors” associated with normal aging, Dr. Cubo and her associates added.

This study was supported by the European Huntington’s Disease Registry. Dr. Cubo reported receiving consulting fees from UCB, Allergan, and AbbVie.


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