A substantially greater proportion of individuals may be at risk of developing a polyglutamine disease later in life than previous estimates have shown, according to a study published in JAMA Neurology.

In this observational cross-sectional study, investigators analyzed data on DNA samples obtained from individuals participating in 5 large European population-based cohorts compiled between 1997 and 2012 (N=14,196). The cohorts represented a uniform European population and included the Netherlands Study of Depression and Anxiety, the Netherlands Study of Depression in Older Persons, the Netherlands Epidemiology of Obesity, the Prospective Study of Pravastatin in the Elderly at Risk, and the Leiden 85-plus Study. None of the participants were considered to be at risk for polyglutamine disease but had certain potential risk of developing disease (advanced age, high body mass index, and being at risk for cardiovascular disorder).

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Using polymerase chain reaction, investigators applied genotyping to determine the cytosine-adenine-guanine (CAG) repeat length in 9 polyglutamine disease–associated genes (PDAGs) for each individual. For each analysis, 3 controls with known CAG repeat lengths for each PDAG were included to assure that every run was performed reliably.

The prevalence of individuals carrying the intermediate and pathological alleles was approximately 10.7% and 1.3%, respectively. No differences in age, body mass index, or distribution of individual over the cohorts, sexes, or countries were found between individuals with CAG repeat numbers within the pathological range and those with CAG repeats that were within the normal or intermediate range for any of the PDAGs.

The findings of this study are not necessarily generalizable due to the uniform sample of participants from northern Europe. Future studies should investigate more diverse cohorts. Because of the observational and cross-sectional study design, investigators did not have follow-up data on the participants to assess whether carriers of intermediate or pathological ranges of alleles developed disease symptoms later in life.

The researchers concluded that the proportion of individuals with CAG repeat numbers within the intermediate ranges of PDAGs greatly exceeded expectations, compared with existing data on prevalence of polyglutamine disease. This indicates that a substantial number of people are at risk of bearing children with a polyglutamine disease. Future studies should assess whether repeat interruptions are more abundant in disease-associated alleles from the general population compared with those from clinical series.

Disclosure: Raymond A. C. Roos, MD, PhD, reported being an advisor for UniQure.

Reference

Gardiner SL, Boogaard MW, Trompet S, et al. Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts [published online April 1, 2019]. JAMA Neurol. doi:10.1001/jamaneurol.2019.0423