Objective: To determine the association between FMR1 gray zone expansions and the presence of parkinsonism, motor, and cognitive function in an elderly community-based population.

Background: ‘Premutation’ size expansions of 55-199 CGG repeats in FMR1 cause fragile X-associated tremor/ataxia syndrome (FXTAS), which is manifested by movement disorders and intra-nuclear mRNA inclusions in neurons and glia. Gray zone FMR1 expansions (41-54 CGG) have also been associated with neurological signs, but neuropathological findings in these cases have never been reported.

Method: Automated FMR1 PCR was performed on existing samples from two longitudinal aging studies at the Rush Alzheimer’s Disease Center, whose subjects agree to brain donation. A detailed clinical evaluation included a modified Unified Parkinson Disease Rating Scale score, a composite score of global motor function, and 17 cognitive tests summarized as a global measure of cognition. Neuropathological examination was performed to investigate for the presence of neuronal and glial intranuclear inclusions and other age-related pathologies.

Results: The average age of the population (n=2380) was 85.9±7.3 and average age at death was 88.6±6.4 (n=2308), with 74% women. The prevalence of FMR1 gray zone alleles was 4.5% (107/2380). There was no significant difference between gray zone participants and normal (<40 CGG) in cognitive diagnosis, global motor function, nor cognitive diagnosis; even after controlling for age, sex, education, race, and ethnicity. Gray zone alleles were associated with parkinsonism in men. There were no intranuclear neuronal or glial inclusions seen in gray zone allele carriers (n=36).

Conclusion: This is the largest study to investigate gray zone alleles in an older community population. The key outcome is that in men, the gray zone allele may be associated with parkinsonism. This is consistent with other studies that show similar results. This study did not confirm an association between a lack of FMR1 AGG interspersions and neurological signs. This study is the first to report neuropathology in FMR1 gray zone carriers, including a lack of pathological hallmarks typically associated with premutation size expansions.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fragile-x-gray-zone-alleles-in-men-are-associated-with-parkinsonism/