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Objective To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Design Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Setting Participants were recruited from academic and clinical settings. Patient(s) Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. Intervention(s) Clinical information and a DNA sample were collected for whole genome sequencing. Main Outcome Measures A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. Results The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. Conclusions In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.

Significance Expansion of 55-200 CGG repeats in the 5′ untranslated region of FMR1 predisposes carriers to fragile X–associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. FXTAS demonstrates incomplete penetrance, which strongly suggests the presence of genetic modifiers. We performed whole-genome sequencing (WGS) on male premutation carriers (CGG 55–200 ) followed by a functional screen in Drosophila and identified PSMB5 as a strong suppressor of CGG-associated neurodegeneration, thereby presenting a therapeutic strategy for FXTAS.

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 58–70 (2015); S. Jacquemont et al., JAMA 291, 460–469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55–200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila, such as Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the fly as well as in N2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS.

Purpose Approximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. Methods To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. Results As previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with 120 repeats did not have a significantly increased risk for FXPOI compared to women with

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.

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.

Men who carry an FMR1 premutation are at-risk to develop a late-onset neurodegenerative disorder called fragile X-Associated Ataxia/Tremor syndrome (FXTAS). However, little is known about their health informational needs. This qualitative study is the first to describe diagnostic experiences and identify specific health information needs of male premutation carriers. In-depth qualitative interviews were conducted by phone with ten men who carry an FMR1 premutation. Interviews were analyzed using direct content analysis. Saturation was assessed through use of the Comparative Method for Themes Saturation in qualitative interviews (CoMeTS). Five themes were identified: diagnosis experience, sources of health information, desired health information, barriers to obtaining health information, and facilitators to desired health information. Participants desired information about inheritance, symptoms, expectations for disease, and actions available to slow progression. Facilitators to obtaining health information included healthcare provider knowledge, positive experiences with providers, beneficial family dynamics, participating in research, and access to experts. Barriers to obtaining health information included lack of personal knowledge, lack of healthcare provider knowledge, negative experiences with providers, and uncertainty. Addressing the educational needs of men with/at-risk for FXTAS could improve the quality of life of men who carry a fragile X premutation.

Fragile X-associated primary ovarian insufficiency (FXPOI) occurs in about 20% of women who carry a premutation allele (55–200 CGG repeats). These women develop hypergonadotropic hypogonadism and have secondary amenorrhea before age 40. A non-linear association with repeat size and risk for FXPOI has been seen in multiple studies women with a premutation: those with a mid-range of repeats are at highest risk (∼70–100 CGG repeats). Importantly, not all carriers with 70–100 repeats experience FXPOI. We investigated whether AGG interruptions, adjusted for repeat size, impacted age at secondary amenorrhea. We have reproductive history information and AGG interruption data on 262 premutation women: 164 had an established age at amenorrhea (AAA) (for some, age at onset of FXPOI) or menopause, 16 had a surgery involving the reproductive system such as a hysterectomy, and 82 women were still cycling at the last interview. Reproductive status was determined using self-report reproductive questionnaires and interviews with a reproductive endocrinologist. For each of these 262 women, FMR1 repeat size and number of AGG interruptions were determined. We confirmed the association of repeat size with AAA or menopause among women with a premutation. As expected, both premutation repeat size and the quadratic form of repeat size (i.e., squared term) were significant in a survival analysis model predicting AAA (p < 0.0001 for both variables). When number of AGG interruptions was added to the model, this variable was not significant (p = 0.59). Finally, we used a regression model based on the 164 women with established AAA to estimate the proportion of variance in AAA explained by repeat size and its squared term. Both terms were again highly significant (p < 0.0001 for both), but together only explained 13% of the variation in AAA. The non-linear association between AAA and FMR1 repeat size has been described in several studies. We have determined that AGG interruption pattern does not contribute to this association. Because only 13% of the variation is described using repeat size, it is clear that further research of FXPOI is needed to identify other factors that affect the risk for FXPOI.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by an expansion of a CGG repeat to 55–199 in the FMR1 gene on the X chromosome. Male premutation carriers above age 50 are at higher risk of developing this syndrome, compared to women carriers. FXTAS is characterized by slowly progressive intention/action tremor, gait ataxia, variable frontal-subcortical neuropsychological deficits, and characteristic neuroimaging findings.1–3 In other trinucleotide repeat disorders, such as the spinocerebellar ataxias, and in multiple systems atrophy-C (MSA-C),4,5 olfactory identification defects, as measured by the University of Pennsylvania Smell Identification Test (UPSIT),6 are an established early finding, even in the absence of significant motor or cognitive symptoms. 7–11 The pathophysiologic explanation of these defects remains unclear. Nonetheless, the potential importance of hyposmia as an early marker of neurodegeneration is highlighted by ongoing studies in PD.12 Olfaction defects in degenerative ataxias tend to be less severe than those found in PD and Alzheimer’s disease (AD), but noteworthy compared to age-matched controls.13 Given this coincidence across different forms of neurodegeneration, we examined olfaction identification capacity as a potential clinical marker of neurodegeneration in FXTAS. Olfactory function can be measured by threshold, a function of the integrity of the olfactory bulb, and by the ability to identify and discriminate odorants that also relies on the entorhinal cortices, amygdala, and hippocampus.9,14 The UPSIT has been used extensively in the evaluation of olfaction in patients with different forms of neurodegeneration and levels of cognitive impairment.11,15–17 In this study, we used the UPSIT as a measure of above-threshold central olfactory processing and as a possible window into central neural substrates underlying FXTAS.6

Sir: The fragile X premutation, an expansion of a CGG triplet repeat in the 5′-untranslated region of the FMR1 gene (55–200 repeats), is one of the most common aetiologies of primary ovarian insufficiency: fragile X-associated primary ovarian insufficiency (FXPOI).1–3 Men who carry the premutation are at increased risk for a late-onset neurodegenerative disorder termed fragile X tremor/ataxia syndrome (FXTAS).4 In premutation carriers, FMR1 is transcribed at increased levels, and the large rCGG tracks may cause disease by acting in a toxic gain of function manner.5–8

The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (approximately 55-199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18-50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.

Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) with respect to the molecular etiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy. Our primary goal in this work was to investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrumentation to identify pre-clinical symptoms of FXTAS. We have tested both premutation carriers with 70-199 repeats (N=62 males) and their low-repeat allele carrier siblings (N=27 males) identified through families with an individual affected with FXS. As expected, due to the sensitivity of the instrument, we were able to identify tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not endorsed ataxia. Among subjects who self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and self-report. Comparison of rates of these traits among premutation carriers and low-repeat allele carrier siblings are presented along with the minimum estimates of age-related prevalence.

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. © 2012 Wiley Periodicals, Inc.

We investigated olfactory defects in fragile X-associated tremor/ataxia syndrome (FXTAS), a finding reported on in other neurodegenerative disorders with clinical features that overlap those of FXTAS.We measured olfactory identification capacity in 41 FMR1 premutation carriers and 42 controls using the University of Pennsylvania Smell Identification Test (UPSIT). Carriers received neurologic evaluations using motor rating scales for tremor, ataxia, and parkinsonism. Cognitive function was measured using the Montreal Cognitive Assessment test.Frequency of olfactory defects was higher in carriers, compared to controls (61% versus 29%; P = 0.003). There was no statistically significant group difference in severity of olfaction defects, after accounting for differences in age, and in rates of head injury and smoking. However, both the frequency (odds ratio = 3.9; 95% confidence interval: 0.81-19.1) and severity (28.6 versus 33.4; P = 0.01) of these defects were greater in cognitively impaired, compared to cognitively intact, carriers. There was no correlation between UPSIT scores and the above-mentioned motor rating scales.FMR1 premutation carriers are susceptible to olfactory identification defects. The severity of these defects is comparable to that reported in hereditary ataxias, but less than that in PD and Alzheimer's disease. This concurrence across neurodegenerative disorders suggests a shared system vulnerability that correlates with, but is not limited to, cognitive impairment, because it is also found in cognitively intact carriers. These results need to be corroborated in a larger prospective study of FMR1 premutation carriers that extends beyond olfactory identification to include measures of smell thresholds.

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype–phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype–phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher’s exact test with p

The 5' untranslated region of the fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat. Expansions of this repeat are associated with a spectrum of disorders. Full mutation alleles, repeatsor= 200, are associated with fragile X syndrome. Premutation alleles, repeats of approximately 55-199, are associated with a tremor-ataxia syndrome most commonly in older males and primary ovarian insufficiency in females. However, the neuropsychological impact of carrying a premutation allele is presently unclear in younger adults. In this study, we analyzed neuropsychological scores for 138 males and 506 females ascertained from the general population and from families with a history of fragile X syndrome. Subjects were age 18-50 years and had varying repeat lengths. Neuropsychological scores were obtained from measures of general intelligence, memory, and executive functioning, including attention. Principal component analysis followed by varimax rotation was used to create independent factors for analysis. These factors were modeled for males and females separately via a general linear model that accounted for correlation among related subjects. All models were adjusted for potential confounders, including age at testing, ethnicity, and household income. Among males, no repeat length associations were detected for any factor. Among females, only a significant association with repeat length and self-report attention (p0.01) was detected, with premutation carriers self-reporting significantly more attention-related problems compared to noncarriers. No significant interactions between repeat length and age were detected. Overall, these results indicate the lack of a global neuropsychological impact of carrying a premutation allele among adults under the age of 50.