Cytosine-guanine-guanine Repeat Research Articles

Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Cytosine–guanine–guanine repeats of FMR1 gene negatively affect ovarian reserve and response in Chinese women

Research questionDo cytosine–guanine–guanine (CGG) repeats of the FMR1 gene affect ovarian function, ovarian response and assisted reproductive technology (ART) outcomes in Chinese women? DesignA retrospective cohort study of 5869 women who underwent 8932 ART cycles at Women's Hospital, School of Medicine, Zhejiang University between January 2018 and June 2021. Basic hormone level, oocyte yield, embryo quality and the rate of live birth were considered as main outcome measures to evaluate the effects of CGG repeats on ovarian function, ovarian response and ART outcomes. ResultsThe CGG repeats were negatively related to serum anti-Müllerian hormone (AMH), oestradiol, antral follicle count (AFC) and oocyte yield. A significant association was found between serum AMH, oestradiol and AFC even after age was controlled for. No statistically significant association, however, was found between CGG repeats and embryo quality or live birth rate. Ovarian function mediated the association between CGG repeats and ovarian response. ConclusionIncreased CGG repeats on the FMR1 gene were associated with diminished ovarian function and poor ovarian response, and ovarian function played an intermediary role in the relationship between CGG repeats and ovarian response.

Mortality in Women across the FMR1 CGG Repeat Range: The Neuroprotective Effect of Higher Education.

Higher education has been shown to have neuroprotective effects, reducing the risk of Alzheimer's and Parkinson's diseases, slowing the rate of age-related cognitive decline, and is associated with lower rates of early mortality. In the present study, the association between higher education, fragile X messenger ribonucleoprotein 1 (FMR1) cytosine-guanine-guanine (CGG) repeat number, and mortality before life expectancy was investigated in a population cohort of women born in 1939. The findings revealed a significant interaction between years of higher education and CGG repeat number. Counter to the study's hypothesis, the effects of higher education became more pronounced as the number of CGG repeats increased. There was no effect of years of higher education on early mortality for women who had 25 repeats, while each year of higher education decreased the hazard of early mortality by 8% for women who had 30 repeats. For women with 41 repeats, the hazard was decreased by 14% for each additional year of higher education. The interaction remained significant after controlling for IQ and family socioeconomic status (SES) measured during high school, as well as factors measured during adulthood (family, psychosocial, health, and financial factors). The results are interpreted in the context of differential sensitivity to the environment, a conceptualization that posits that some people are more reactive to both negative and positive environmental conditions. Expansions in CGG repeats have been shown in previous FMR1 research to manifest such a differential sensitivity pattern.

Brain Metabolomics in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study.

Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a “full mutation,” clinically Fragile X Syndrome (FXS), whereas 55 – 200 repeats result in a “premutation.” FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17–78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

Stress and genetics influence hair cortisol in FMR1 premutation carrier mothers of children with fragile X syndrome

To investigate genetic and environmental influences on cortisol levels, mothers of children with fragile X syndrome (FXS) were studied four times over a 7.5-year period. All participants (n = 84) were carriers of the FMR1 “premutation”, a genetic condition associated with impaired HPA axis functioning. Genetic variation was indicated by expansions in the number of CGG (cytosine-guanine-guanine) repeats in the FMR1 gene (67–138 repeats in the present sample). The environmental factor was cumulative exposure to adverse life events during the study period. Cortisol was measured at the beginning of the study via saliva samples and at the end of the study via hair samples; hormone values from these two specimen types were significantly correlated. The interactions between CGG repeat number and adverse life events significantly predicted hair cortisol concentration, including after accounting for the initial salivary cortisol level. For those with fewer CGG repeats, stress exposure was associated with elevated cortisol, the expected response to stress, although women with a higher number of CGGs had a reduced cortisol response to adverse events, which might be related to HPA dysfunction. These results indicate that both exogenous and endogenous factors affect HPA functioning in this population of women.

Fragile X premutation and associated health conditions: A review.

Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the FMR1 gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating individuals with FXTAS and asymptomatic premutation carriers. This study aimed to clarify the extent to which quantitative measures of gait and upper limb kinematics may serve as biobehavioral markers of FXTAS degeneration. Nineteen premutation carriers (aged 46–77 years), including 9 with possible, probable, or definite FXTAS and 16 sex- and IQ-matched healthy controls, completed tests of non-constrained walking and reaching while both standing (static reaching) and walking (dynamic reaching) to quantify gait and upper limb control, respectively. For the non-constrained walking task, participants wore reflective markers and walked at their preferred speed on a walkway. During the static reaching task, participants reached and lifted boxes of different sizes while standing. During the dynamic reaching task, participants walked to reach and lift the boxes. Movement kinematics were examined in relation to clinical ratings of neuromotor impairments and CGG repeat length. During non-constrained walking, individuals with FXTAS showed decreased stride lengths and stride velocities, increased percentages of double support time, and increased variabilities of cadence and center of mass relative to both asymptomatic premutation carriers and controls. While individuals with FXTAS did not show any static reaching differences relative to the other two groups, they showed multiple differences during dynamic reaching trials, including reduced maximum reaching velocity, prolonged acceleration time, and jerkier movement of the shoulder, elbow, and hand. Gait differences during non-constrained walking were associated with more severe clinically rated posture and gait symptoms. Reduced maximum reaching velocity and increased jerkiness during dynamic reaching were each related to more severe clinically rated kinetic dysfunction and overall neuromotor symptoms in FMR1 premutation carriers. Our findings suggest kinematic alterations consistent with gait ataxia and upper limb bradykinesia are each selectively present in individuals with FXTAS, but not asymptomatic aging premutation carriers. Consistent with neuropathological and magnetic resonance imaging (MRI) studies of FXTAS, these findings implicate cerebellar and basal ganglia degeneration associated with neuromotor decline. Our results showing associations between quantitative kinematic differences in FXTAS and clinical ratings suggest that objective assessments of gait and reaching behaviors may serve as critical and reliable targets for detecting FXTAS risk and monitoring progression.

Molecular analysis of FMR1 gene in a population in Southern Brazil: Comparison of four methods

ObjectivesFragile X syndrome (FXS) is caused by expansion of the number of cytosine-guanine-guanine (CGG) repeats in the regulatory region of the gene fragile X mental retardation 1 (FMR1). The molecular diagnoses of FXS can be performed using two tests based on two different techniques, namely polymerase chain reaction (PCR) and Southern blotting (SB). However, both of these techniques have limitations. The purpose of this study was to evaluate the performance of the commercial FragilEase™ PCR kit for FXS diagnosis comparing to other laboratory methods. Designand methods: This study had a retrospective design. We analyzed the performance of the FragilEase™ PCR kit using 90 DNA samples from patients with clinical suspicion of FXS or a family history of the syndrome using capillary electrophoresis and compared with the results obtained for the same samples using PCR, SB, and AmplideX FMR1 PCR. ResultsFragilEase™ PCR kit displayed high concordance with the results obtained using PCR, SB, and AmplideX FMR1 PCR regarding the detection of normal, intermediate/gray zone, premutation, and full mutation alleles, as well as female homozygosity and mosaicism. The replicate sizes found using the FragilEase™ PCR assay varied on average by two CGG repeats. ConclusionFragilEase™ PCR, as well as other commercially available kits, efficiently detect FMR1 mutations and simplify the workflow in laboratories that performing FXS diagnoses.

Precision Sensorimotor Control in Aging FMR1 Gene Premutation Carriers.

BackgroundIndividuals with premutation alleles of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition affecting sensorimotor function. Information on quantitative symptom traits associated with aging in premutation carriers is needed to clarify neurodegenerative processes contributing to FXTAS.Materials and Methods26 FMR1 premutation carriers ages 44–77 years and 31 age-matched healthy controls completed rapid (2 s) and sustained (8 s) visually guided precision gripping tasks. Individuals pressed at multiple force levels to determine the impact of increasing the difficulty of sensorimotor actions on precision behavior. During initial pressing, reaction time, the rate at which individuals increased their force, the duration of pressing, and force accuracy were measured. During sustained gripping, the complexity of the force time series, force variability, and mean force were examined. During relaxation, the rate at which individuals decreased their force was measured. We also examined the relationships between visuomotor behavior and cytosine-guanine-guanine (CGG) repeat length and clinically rated FXTAS symptoms.ResultsRelative to controls, premutation carriers showed reduced rates of initial force generation during rapid motor actions and longer durations of their initial pressing with their dominant hand. During sustained force, premutation carriers demonstrated reduced force complexity, though this effect was specific to younger premutation carries during dominant hand pressing and was more severe for younger relative to older premutation carriers at low and medium force levels. Increased reaction time and lower sustained force complexity each were associated with greater CGG repeat length for premutation carriers. Increased reaction time and increased sustained force variability were associated with more severe clinically rated FXTAS symptoms.ConclusionOverall our findings suggest multiple sensorimotor processes are disrupted in aging premutation carriers, including initial force control guided by feedforward mechanisms and sustained sensorimotor behaviors guided by sensory feedback control processes. Results indicating that sensorimotor issues in aging premutation carriers relate to both greater CGG repeat length and clinically rated FXTAS symptoms suggest that quantitative tests of precision sensorimotor ability may serve as key targets for monitoring FXTAS risk and progression.

A Robust Polymerase Chain Reaction-based Assay for Quantifying Cytosine-guanine-guanine Trinucleotide Repeats in Fragile X Mental Retardation-1 Gene

Fragile X syndrome (FXS) and associated disorders are caused by expansion of the cytosine-guanine-guanine (CGG) trinucleotide repeat in the 5' untranslated region (UTR) of the Fragile X mental retardation-1 (FMR1) gene promoter. Conventionally, capillary electrophoresis fragment analysis on a genetic analyzer is used for the sizing of the CGG repeats of FMR1, but additional Southern blot analysis is required for exact measurement when the repeat number is higher than 200. Here, we present an accurate and robust polymerase chain reaction (PCR)-based method for quantification of the CGG repeats of FMR1. The first step of this test is PCR amplification of the repeat sequences in the 5'UTR of the FMR1 promoter using a Fragile X PCR kit, followed by purification of the PCR products and fragment sizing on a microfluidic capillary electrophoresis instrument, and subsequent interpretation of the number of CGG repeats by referencing standards with known repeats using the analysis software. This PCR-based assay is reproducible and capable of identifying the full range of CGG repeats of FMR1 promoters, including those with a repeat number of more than 200 (classified as full mutation), 55 to 200 (premutation), 46 to 54 (intermediate), and 10 to 45 (normal). It is a cost-effective method that facilitates classification of the FXS and Fragile X-associated disorders with robustness and rapid reporting time.

FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine‐guanine‐guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55–200 CGG repeats) are at risk to have an affected child. Currently, specific population‐based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan‐ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self‐reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan‐ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan‐ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic‐based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population‐wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population‐wide screening recommendations for FXS.

Prevalence of Fragile X Syndrome among children receiving special education and carrier states in first degree relatives.

Fragile X syndrome (FXS) is a genetically determined developmental disorder. Underlying genotype is cytosine-guanine-guanine (CGG) repeat expansions with over 200 repeats in the fragile X mental retardation 1 (FMR1) gene. Children with FXS are most accessible in special education institutions in Sri Lanka, with a total of approximately 6000 registered attendees. The aim of the current study was to estimate the prevalence of FXS among special school attendees and to screen first degree relatives of affected children. A nationally representative sample of 850 children (5-18 years) was selected using multi-level stratified sampling. Screening was performed by 3’ direct triplet primed PCR, followed by melting curve analysis. Expanded repeat status of the screened positives were confirmed using capillary electrophoresis, methylation specific PCR and Southern hybridization. Screening of available first degree relatives (n=12) were carried out using the same method of screening and diagnosis. Eleven had FXS. Prevalence of FXS was 1.3% (95% CI 0.9-1.6). Among the 11 with FXS 9 had more than 350 CGG repeats, while the rest had around 300. Twelve first degree relatives consisting of nine mothers, two female siblings and a male sibling were tested. All mothers and female siblings had either full mutation or premutation while the male sibling had CGG repeats in the normal range. Among the special school attendees, prevalence of FXS was 1.3% which has a high risk for autism and attention deficit hyperactivity disorder.

Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis.

There is significant morbidity associated with fragile X syndrome. Unfortunately, most maternal carriers are clinically silent during their reproductive years. Because of this, many experts have put forward the notion of preconception or prenatal fragile X carrier screening for females. This study aimed to determine the prevalence of fragile X syndrome pre-mutation and asymptomatic full-mutation carriers in a Chinese pregnant population, and the distribution of cytosine-guanine-guanine (CGG) repeat numbers using a robust fragile X mental retardation 1 (FMR1) polymerase chain reaction assay. This was a cross-sectional survey in prospectively recruited pregnant women from a university hospital in Hong Kong. Chinese pregnant women without a family history of fragile X syndrome were recruited between April 2013 and May 2015. A specific FMR1 polymerase chain reaction assay was performed on peripheral blood to determine the CGG repeat number of the FMR1 gene. Prenatal counselling was offered to full-mutation and pre-mutation carriers. In 2650 Chinese pregnant women, two individuals with pre-mutation alleles (0.08%, one in 1325) and one asymptomatic woman with full-mutation (0.04%, one in 2650) alleles were identified. The overall prevalence of pre-mutation and full-mutation alleles was 0.11% (1 in 883). Furthermore, 30 (1.1%) individuals with intermediate alleles were detected. In the 2617 women with normal CGG repeats, the most common CGG repeat allele was 30. The overall prevalence of pre-mutation and asymptomatic full-mutation carriers in the Chinese pregnant population was one in 883, detected by a new FMR1 polymerase chain reaction assay.

Cascade Screening for Fragile X Syndrome/CGG Repeat Expansions in Children Attending Special Education in Sri Lanka.

Fragile X syndrome (FXS) is the commonest cause of inherited mental retardation and clinically presents with learning, emotional and behaviour problems. FXS is caused by expansion of cytosine-guanine-guanine (CGG) repeats present in the 5’ untranslated region of the FMR1 gene. The aim of this study was to screen children attending special education institutions in Sri Lanka to estimate the prevalence of CGG repeat expansions. The study population comprised a representative national sample of 850 children (540 males, 310 females) with 5 to 18 years of age from moderate to severe mental retardation of wide ranging aetiology. Screening for CGG repeat expansion was carried out on DNA extracted from buccal cells using 3’ direct triplet primed PCR followed by melting curve analysis. To identify the expanded status of screened positive samples, capillary electrophoresis, methylation specific PCR and Southern hybridization were carried out using venous blood samples. Prevalence of CGG repeat expansions was 2.2%. Further classification of the positive samples into FXS full mutation, pre-mutation and grey zone gave prevalence of 1.3%, 0.8% and 0.1% respectively. All positive cases were male. No females with FXS were detected in our study may have been due to the small sample size.

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

Fragile X syndrome (FXS) is mainly caused by an expansion of a cytosine-guanine-guanine (CGG) trinucleotide repeat (greater than 200) in the 5’ untranslated region of the fragile X mental retardation 1 ( FMR1 ) gene resulting in gene silencing, methylation, and absence of FMRP. FXS involves a wide spectrum of phenotypes including intellectual disabilities, autism spectrum disorder (ASD), maladaptive behaviors or symptoms, social anxiety, mood disorders and physical features. Carriers of premutation alleles (55 - 200 CGG repeats) can manifest with neurodevelopmental phenotypes and are at risk for the neurodegenerative fragile X-associated tremor/ataxia syndrome (FXTAS) and about 20% of women with a premutation develop fragile X-associated primary ovarian insufficiency (FXPOI). These phenotypes are believed to be caused by a distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Premutation alleles are unstable and depending on the CGG length and the presence of AGG interruptions have the potential to expand to larger premutation or full mutation alleles during transmission from mothers to their children. The contraction of a CGG repeat allele, although rare, has been observed. Here, we report the case of a three-generation family, who was identified as part of a pilot study of newborn screening for FXS. Specifically, the maternal grandmother carried a premutation allele (109 CGG repeats), which contracted to an intermediate size allele (52 CGG repeats) in her son, the father of a newborn girl (proband). This allele expanded to a premutation allele of 59 CGG repeats in the proband newborn. A premutation allele of 61 CGG repeats was detected in the proband’s sister who demonstrated social phobia but normal cognition. The proband newborn showed some fragile X associated physical stigmata but normal cognition. Intriguingly, all FMR1 CGG expanded allele showed no AGG interruptions. This case shows a remarkable instability of premutation alleles throughout the three generations likely arising from different mechanisms. J Med Cases. 2015;6(12):547-553 doi: http://dx.doi.org/10.14740/jmc2301w

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with "normal" CGG repeat status.

The objective of this analysis is to examine the relationship between Fragile X Mental Retardation 1 gene (FMR1) cytosine-guanine-guanine (CGG) repeat number and ovarian reserve, with a particular focus exclusively on the range of CGG repeat number below the premutation (PM) range (<55 CGG repeats). Our study included female patients who underwent assessment of FMR1 CGG repeat number and serum anti-Mullerian hormone (AMH) in 2009-2014. To examine the association between FMR1 repeat number and serum AMH, we created three summary measures of CGG repeat number for the two alleles-"Sum," "Max," and "Gap" (absolute difference). Using multivariable regression models, controlling for age, we then analyzed the impact of these summary measures on AMH. A total of 566 patients were included in our study. Using multivariable regression models, we found that the relationship between CGG repeat number and AMH differed depending on age. Specifically, in younger women, AMH increased by 7-8 % (Sum p < 0.01, Max p = 0.04) for every 1 unit increase in CGG repeat number. In contrast, starting at age 40, there was a 3 to 5 % decline in AMH for every 1 unit increase in CGG repeat number (Sum p < 0.01, Max p = 0.04). This is the first study to report a statistically significant correlation of ovarian reserve and CGG repeat number in women with <55 CGG repeats. Although these women are generally considered to have a normal phenotype, our data suggest that increasing CGG repeat number within this normal range is associated with a more rapid decline in ovarian reserve.

Understanding decreased fertility in women carriers of the FMR1 premutation: a possible mechanism for Fragile X-Associated Primary Ovarian Insufficiency (FXPOI).

Fragile X syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The full mutation, defined as >200 cytosine-guanine-guanine (CGG) triplet repeats, causes FXS. Individuals with 55–199 CGG repeats, classified as premutation carriers, are affected by two distinct disorders depending on their premutation status. Disorders associated with premutation carriers include: Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The molecular similarities of FXTAS and FXPOI (e.g. overabundance of FMR1 transcript and intranuclear inclusions) suggest that similar molecular mechanisms underlie both FXTAS and FXPOI. The current hypothesis describes the underlying mechanism for FXTAS as an mRNA gain-of-function mutation, however the underlying mechanism for FXPOI remains unresolved. New data suggests that repeat associated non-AUG (RAN) translation could underlie FXPOI.

Visual motion processing deficits in infants with the fragile X premutation.

BackgroundFragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation >200 cytosine-guanine-guanine (CGG) repeats) in the FMR1 gene, leading to a reduction or absence of the gene’s protein product, fragile X mental retardation protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. In our previous work with infants and toddlers with FXS, we have been able to describe much about their cognitive and visual processing abilities. In light of recent work on the mild cognitive deficits and functional and structural brain differences that are present in adults with the fragile X (FX) premutation, in the present study we examined whether some of the low-level visual processing deficits we have observed in infants with FXS would also be present in infants with the FX premutation (55–200 CGG repeats).MethodsWe chose a contrast detection task using second-order motion stimuli on which infants with FXS previously showed significantly increased detection thresholds (Vision Res 48:1471–1478, 2008). Critically, we also included a developmental delay comparison group of infants with Down syndrome (DS), who were matched to infants with FXS on both chronological and mental age, to speak to the question of whether this second-order motion processing deficit is a FX-specific phenomenon.ResultsAs reported previously, infants with the FX full mutation showed motion contrast detection threshold levels that were significantly higher than age-matched typically developing control infants. Strikingly, the motion detection contrast levels of FX premutation infants were also significantly higher than typically developing (TD) infants and not significantly different from the group of infants with FXS or with DS.ConclusionsThese results, which are in keeping with a growing body of evidence on the mild cognitive and perceptual processing deficits and functional and structural brain differences that are present in adults and older children with the FX premutation, underscore the pressing need to study and describe the processing capabilities of infants and toddlers with the FX premutation.

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

We sought to determine the usefulness of fragile X mental retardation 1 (FMR1) carrier testing among young infertile women with or without signs of ovarian insufficiency as compared with fertile women. Three cohorts of women were recruited to determine the cytosine-guanine-guanine (CGG) repeats trinucleotide repeat length in the 5'-untranslated region of the FMR1 gene in lymphocyte DNA. A total of 199 fertile women, who were reported to have conceived within 3 months, were recruited together with 372 infertile women with ongoing menstrual cycles and 48 infertile women with primary ovarian insufficiency. The various ranges of FMR1 CGG repeat lengths among infertile women were compared with those of fertile controls. In infertile women with ongoing menstrual cycles, the serum concentrations of follicle-stimulating hormone, anti-Muellerian hormone, and inhibin B were measured during the early follicular phase. None of the three categories of FMR1 CGG repeat length expansions (premutation, intermediate range, and high normal range) were more prevalent among infertile women than among fertile women. The CGG repeat length was not correlated with any of the ovarian reserve parameters. In comparison with a generalized preconception screening strategy, infertility as a criterion, even together with reduced ovarian reserve, is not suitable for identifying a higher proportion of women with expanded FMR1 CGG repeat length.