Premutation CGG repeats in FMR1 can increase the risk of Parkinsonism and ataxia in women

Women with a low level of cytosine guanine guanine (CGG) repeats in the fragile X mental retardation 1 (FMR1) gene may have an increased risk of ataxia and Parkinson’s disease, according to study results published in Movement Disorders.

Fragile X-Associated Tremor / Ataxia Syndrome (FXTAS) is caused by large CGG repeat extensions of the FMR1 gene. Most of the previous studies of the influence of these replicates used the reverse observation that the studies were inadvertently biased towards finding larger replicates. However, shorter premutation repeats (55-200) are common in the general population and occur in 1 in 150-200 women and 1 in 450 men.

To be more objective in evaluating the role of FMR1 repeats in clinical outcomes, data was obtained from the Marshfield Clinic’s Personalized Medicine Research Project, which included 1979 electronic health records from 20,353 people in northern Wisconsin. Participants who submitted a DNA sample (n = 19,989) were screened for FMR1 repeat premutation. The number of replicates was counted and the clinical results compared to a group of age-matched controls.

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Pre-mutation carriers (n = 35) and control persons (n ​​= 61) were on average 57.2 (range 26-86) years old. The mean repeat length was 31.6 (range 29-39) in the controls and 68.5 (range 55-101) in the carriers.

Overall, the FXTAS rating scale did not differ significantly between carriers and controls (P = .458). In stratifying patients based on comorbid conditions, researchers observed significant interactions between premutation status and comorbid diagnoses for the total scores and the parkinsonism and ataxia subdomains (all P <.05).

A further stratification according to age showed that the premutation status and any comorbid diagnosis were significant for the total score (b, -1.05; standard error [SE], 0.28; P <.001) and the subdomains of ataxia (b, -0.44; SE, 0.10; P <.001), parkinsonism (b, -0.32; SE, 0.11; P = .005) and tremor (b, -0.21; SE, 0.11; P = 0.052).

A similar pattern was observed in a sensitivity analysis that removed 8 participants with potentially confusing movement disorder diagnoses.

Overall, women who were carriers and had no comorbid illnesses showed increasing FXTAS Rating Scale scores with increasing age (P = 0.003). Among the women with confounding comorbidities, it was the control persons who showed increasing values ​​with increasing age (P <0.001).

This study may have been undervalued due to the small sample size.

The results showed that women with premutation CGG repeats (55-200) who have no comorbid illnesses may have an increased risk of ataxia and parkinsonism than their peers who have fewer than 55 FMR1 repeats.

“It is important that the results of the present study cannot be attributed to a determination bias. Rather, these signs were found in an unselected group of women with premutation in the general population. The severity of these signs was more subtle than that seen in previous studies in family members of children with FXS and was only evident in otherwise healthy carriers. This should give reassurance to award winners who share traits with the current cohort, ”the researchers concluded.

Disclosure: Several authors stated links to industry. For a full list of the details, see the original article.


Mailick MR, Hong J, Movaghar A, et al. Mild neurological symptoms in women with FMR1 premutation in an unselected community-based cohort. Movement disorder. Published online June 12, 2021. doi: 10.1002 / mds.28683

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