Predictors of Comorbid Conditions in Women Who Carry an FMR1 Premutation
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SUBMITTER: Allen E
PROVIDER: S-EPMC8517131 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeEmerging 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).MethodsTo better understand premutation-associated health profiles, we collected self-reported medical histories on 355 carrier women.ResultsTwenty-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.ConclusionAlthough 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.
| S-EPMC7118023 | biostudies-literature
Project description:The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5'-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55-199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.
| S-EPMC3696495 | biostudies-literature
Project description:ObjectiveTo examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.MethodsA total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels.ResultsWe show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.ConclusionsThis is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.
| S-EPMC4409583 | biostudies-literature
Project description:BackgroundPremutation-sized (55-200) CGG repeat expansions in the FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS). Most studies of premutation carriers utilized reverse ascertainment to identify patients, leading to a selection bias for larger repeats. As shorter CGG premutation repeats are common in the population, understanding their impact on health outcomes has a potentially large public health footprint.ObjectiveThe study's objective was to compare an unselected group of premutation carriers (n = 35, 55-101 CGG repeats) with matched controls (n = 61, 29-39 CGG repeats) with respect to FXTAS-type signs using structured neurological assessments.MethodsThree neurologists independently rated signs, using an adapted version of the FXTAS Rating Scale (Leehey MA, Berry-Kravis E, Goetz CG, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008). This was a double-blind study, as genetic status (premutation vs. control) was known neither by the participants nor by any of the neurologists. Analyses controlled potentially confounding comorbid conditions in the electronic health record (eg, osteoarthritis and stroke) and probed the association of age with signs.ResultsAlthough there was no overall difference between carriers and controls, among individuals without any potentially confounding comorbid diagnoses, there was a statistically significant age-associated elevation in FXTAS-type signs in premutation carriers compared to controls.ConclusionsAmong those who do not have other comorbid diagnoses, women who have CGG repeats at the lower end of the premutation range may be at greater risk for ataxia and parkinsonism than their age peers, although their overall risk of developing such clinical features is low. This study should provide reassurance to those who share characteristics with the present cohort. © 2021 International Parkinson and Movement Disorder Society.
| S-EPMC8597892 | biostudies-literature
Project description:BACKGROUND:Fragile X premutation (Amplification of CGG number 55-200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. Recently, it has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG. This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. FMRpolyG inclusions were also found in ovary stromal cells of a FXPOI patient. The role of FMRpolyG expression has not been thoroughly examined in folliculogenesis related cells. The main goal of this study is to evaluate whether FMRpolyG accumulates in mural granulosa cells of FMR1 premutation carriers. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis. RESULTS:FMRpolyG and ubiquitin immunostained mural granulosa cells from six FMR1 premutation carriers demonstrated FMRpolyG aggregates. However, co-localization of FMRpolyG and ubiquitin appeared to vary within the FMR1 premutation carriers' group as three exhibited partial ubiquitin and FMRpolyG double staining and three premutation carriers demonstrated FMRpolyG single staining. None of the granulosa cells from the five control women expressed FMRpolyG. Additionally, human ovarian granulosa tumor, COV434, were transfected with two plasmids; both expressing 99CGG repeats but only one enables FMRpolyG expression. Like in granulosa cells from FMR1 premutation carriers, FMRpolyG aggregates were found only in COV434 transfected with expended CGG repeats and the ability to express FMRpolyG. CONCLUSIONS:Corresponding with previous studies in FXTAS, we demonstrated accumulation of FMRpolyG in mural granulosa cells of FMR1 premutation carriers. We also suggest that following further investigation, the premutation transfected COV434 might be an appropriate model for RAN translation studies. Detecting FMRpolyG accumulation in folliculogenesis related cells supports previous observations and imply a possible common protein-mediated toxic mechanism for both FXPOI and FXTAS.
| S-EPMC7045455 | biostudies-literature
Project description: Not available
| S-EPMC5714313 | biostudies-literature
Project description:The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.
| S-EPMC6660192 | biostudies-literature
Project description:Characteristics of fragile X syndrome include macroorchidism and intellectual disability, which are associated with decreased FMRP levels. FMRP is highly expressed in many tissues, but primarily in the brain and testis. The relationship between these two characteristics has not previously been studied in the premutation or carrier state. To examine this among premutation carriers and a possible association with IQ, we evaluated macroorchidism status among 213 males including 142 premutation carriers and 71 controls. The prevalence of macroorchidism among premutation carriers was 32.4% (46 out of 142), and 5.6% among controls (4 out of 71, P < 0.0001). Among premutation carriers, the age-adjusted odds ratio (OR) of macroorchidism was significantly increased with increasing FMR1 mRNA (OR 1.84, 95% confidence interval [CI] 1.04-3.25; P = 0.035). With respect to the association between macroorchidism and IQ, after adjustment for number of CGG repeats and age, premutation carriers with macroorchidism had lower verbal IQ (104.67 ± 15.86, P = 0.0152) and full scale IQ (102.98 ± 15.78, P = 0.0227) than premutation carriers without macroorchidism (verbal IQ 112.38 ± 14.14, full scale IQ 110.24 ± 14.21). Similar associations were observed for both verbal IQ (P = 0.034) and full scale IQ (P = 0.039) after being adjusted for age and FMR1 mRNA. These preliminary data support a correlation between macroorchidism and lower verbal and full scale IQ in a relevant proportion of premutation carrier males. Whether this is due to higher levels of FMR1 mRNA or to lower FMRP levels it remains to be established.
| S-EPMC4332881 | biostudies-literature
Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.
| S-EPMC2796892 | biostudies-literature
Project description:This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation.Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test.Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA.Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation.
| S-EPMC4451047 | biostudies-other