Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death

• Published in: Movement disorders Vol. 35; no. 8; pp. 1448 - 1456
• Main Authors: Hall, Deborah A., Nag, Sukriti, Ouyang, Bichun, Bennett, David A., Liu, Yuanqing, Ali, Aisha, Zhou, Lili, Berry‐Kravis, Elizabeth
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2020; Wiley Subscription Services, Inc
• Subjects: Aged; Aged, 80 and over; Aging; Alleles; Ataxia; atypical parkinsonism; Basal ganglia; Brain diseases; Central nervous system diseases; Cognition & reasoning; Cognitive ability; Death; Female; FMR1 gene; FMR1 protein; fragile X; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - genetics; FXTAS; Geriatrics; Humans; Inclusion bodies; Intellectual disabilities; Male; Movement disorders; Neurodegenerative diseases; Parkinson's disease; Parkinsonian Disorders - genetics; Polymerase chain reaction; Population genetics; Tremor; Trinucleotide Repeat Expansion - genetics; fragile X; atypical parkinsonism; FXTAS
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.28086

Background Premutation size (55–199 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene cause fragile X‐associated tremor/ataxia syndrome, but it is unclear whether smaller “gray” zone expansions of 41–54 repeats are also associated with movement disorders. The objectives of this study were to determine the association between the FMR1 gene gray zone expansions, AGG interspersions, and the presence of parkinsonism and motor and cognitive function in an elderly community‐based population. Methods Automated FMR1 polymerase chain reaction was performed on existing samples from 2 longitudinal aging studies whose subjects agreed to brain donation. A detailed clinical evaluation including a modified Unified Parkinson's Disease Rating Scale score, a composite score of global motor function, 17 cognitive tests summarized as a global measure of cognition, and neuropathological examination were obtained for genotyped participants. Results The average age of the population (n = 2362) was 85.9 ± 7.3 years, and average age at death was 88.6 ± 6.4 years (n = 1326), with 72% women. The prevalence of FMR1 gray zone alleles was 5.2% (122 of 2362). There was no difference between participants with gray zone expansions or those lacking AGG interspersions compared with normal participants in global cognition, global motor function, clinical diagnosis, or pathological changes. Gray zone alleles were associated with signs of parkinsonism in men (P = 0.01), and gray zone carrier men were more likely to die (hazard ratio, 2.34; 95% confidence interval, 1.31–4.16). Conclusions This is the largest study to investigate gray zone alleles in a community population. The key findings are that in men, the gray zone allele is associated with signs of parkinsonism and higher risk of death, but not with intranuclear neuronal inclusions. © 2020 International Parkinson and Movement Disorder Society