Clustering of comorbid conditions among women who carry an FMR1 premutation

Abstract Purpose Emerging evidence indicates that women who carry an FMR1 premutation can experience complex health profiles beyond the two well-established premutation-associated disorders: fragile X–associated primary ovarian insufficiency (FXPOI, affects ~20–30% carriers) and fragile X–associated tremor–ataxia syndrome (FXTAS, affects ~6–15% carriers). Methods To better understand premutation-associated health profiles, we collected self-reported medical histories on 355 carrier women. Results Twenty-two health conditions were reported by at least 10% of women. Anxiety, depression, and headaches were reported by more than 30%. The number of comorbid conditions was significantly associated with body mass index (BMI) and history of smoking, but not age. Survival analysis indicated that women with FXPOI had an earlier age at onset for anxiety and osteoporosis than women without FXPOI. Cluster analysis identified eight clusters of women who reported similar patterns of comorbid conditions. The majority of carriers (63%) fell into three categories primarily defined by the presence of only a few conditions. Interestingly, a single cluster defined women with symptoms of FXTAS, and none of these women had FXPOI. Conclusion Although some women with a premutation experience complex health outcomes, most carriers report only minimal comorbid conditions. Further, women with symptoms of FXTAS appear to be distinct from women with symptoms of FXPOI.

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Predictors of Comorbid Conditions in Women Who Carry an FMR1 Premutation

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.715922 ◽

2021 ◽

Vol 12 ◽

Author(s):

Emily Graves Allen ◽

Krista Charen ◽

Heather S. Hipp ◽

Lisa Shubeck ◽

Ashima Amin ◽

...

Keyword(s):

Fragile X ◽

Health Conditions ◽

Comorbid Condition ◽

Comorbid Conditions ◽

Fmr1 Premutation ◽

Logistic Regression Models ◽

Modifiable Factors ◽

Medical Histories ◽

Ataxia Syndrome ◽

Health Profiles

Purpose: Women who carry an FMR1 premutation (PM) can experience two well-established PM-associated disorders: fragile X-associated primary ovarian insufficiency (FXPOI, affects ~20–30% carriers) and fragile X-associated tremor-ataxia syndrome (FXTAS, affects ~6–15% carriers); however, emerging evidence indicates that some of these women experience complex health profiles beyond FXPOI and FXTAS.Methods: In an effort to better understand predictors for these comorbid conditions, we collected self-reported medical histories on 413 women who carry an FMR1 PM.Results: There were 22 health conditions reported by at least 9% of women. In an exploratory analysis, 12 variables were tested in logistic regression models for each comorbid condition, including demographic variables, environmental variables, PM-associated factors, and endorsement of depression and/or anxiety. More than half of the comorbid conditions studied were associated with women who self-reported having anxiety. Age, smoking, body mass index (BMI), and depression were also significant predictor variables for specific comorbid conditions.Conclusions: Age, smoking, and BMI were significantly associated with a subset of the comorbid conditions analyzed. Importantly, depression or anxiety were also significantly associated with many of the comorbid health conditions. This work highlights some of the modifiable factors associated with complex health profiles among women with an FMR1 PM.

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Dementia in Fragile X-associated Tremor/Ataxia Syndrome

Dementia & Neuropsychologia ◽

10.1590/s1980-57642010dn40100014 ◽

2010 ◽

Vol 4 (1) ◽

pp. 79-83 ◽

Cited By ~ 1

Author(s):

Ricardo Nitrini ◽

Márcia Rúbia R. Gonçalves ◽

Leonardo P. Capelli ◽

Egberto Reis Barbosa ◽

Cláudia Sellitto Porto ◽

...

Keyword(s):

Cognitive Decline ◽

Fragile X ◽

Gait Ataxia ◽

Action Tremor ◽

Fmr1 Premutation ◽

Cerebellar Peduncles ◽

History Of ◽

Diagnostic Hypothesis ◽

Ataxia Syndrome ◽

Lateral Sclerosis

Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

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Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.742929 ◽

2021 ◽

Vol 12 ◽

Author(s):

Darren R. Hocking ◽

Danuta Z. Loesch ◽

Paige Stimpson ◽

Flora Tassone ◽

Anna Atkinson ◽

...

Keyword(s):

Executive Functioning ◽

Response Inhibition ◽

Rating Scales ◽

Psychiatric Symptoms ◽

Fragile X ◽

Fmr1 Premutation ◽

Symptom Dimensions ◽

Cgg Repeats ◽

Cerebellar Peduncles ◽

Ataxia Syndrome

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

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