Objective: To determine the association between FMR1 gray zone expansion and the presence of parkinsonism, motor, and cognitive function in community based individuals.

Background: Larger expansions, ‘premutation size’, of 55-199 CGG repeats in FMR1 cause fragile X-associated tremor/ataxia syndrome, which is manifested by intention tremor, cerebellar gait ataxia, and executive dysfunction.  It is unknown whether smaller ‘gray zone’ FMR1 41-54 CGG expansions are also associated with neurological signs. 

Methods: 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 17 cognitive tests summarized as a global measure of cognition, a modified UPDRS summarized as a global parkinsonism, and clinical diagnosis. A composite score of global motor function was also determined and included strength (using dynamometers) and nine motor performance tests of the arms and legs. 

Results: The average age of the population (n=2096) was 85.6±7.3 and average age at death (n=1048) was 88.4±6.4, with 70% women.  The prevalence of FMR1 gray zone allele carriers was 5% (109/2096).  There was no significant difference between gray zone carriers and non-carrier in the parkinsonism score (p=0.58) or global cognition (p=0.1).  Gray zone carriers had better global motor scores compared to controls (0.83+0.25 vs. 0.77+0.26, p=0.02)

Conclusions: The prevalence of FMR1 gray zone expansions is higher in these community based cohorts than other population studies in the Midwest.  Gray zone expansion carriers have better motor function compared to controls, but showed similar levels of parkinsonism and cognitive function.  This is unexpected given that larger premutation expansions are associated with neurodegenerative movement disorders and accumulation of FMR1 mRNA in neurons and warrants additional study. 

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fragile-x-gray-zone-alleles-are-associated-with-higher-global-motor-function-in-an-elderly-community-population/