Objective: Approximately 20% of women with a premutation in the FMR1 gene experience primary ovarian insufficiency (POI). We explored diagnostic patterns, frequency of appropriate hormone replacement, obstetric outcomes, fertility treatment, reproductive decisions, and counseling of women with fragile X-associated POI (FXPOI). Methods: Semistructured interviews with 79 women with FXPOI were conducted by a single interviewer. FMR1 cytosine-guanine-guanine repeat size was determined from a blood, saliva, or buccal sample. Results: The median age of POI onset for women in our study was 33 years. Seventy-two percent of the women had an FMR1 cytosine-guanine-guanine repeat length of 80 to 100. Mean length of time from symptom onset to POI diagnosis was 1.12 years, longer in women with a younger age of POI onset and shorter in women who knew they were carriers. After diagnosis, 52% of women never took hormone therapy, started it years after POI diagnosis, or stopped it before 45 years of age. Forty-nine percent of the women had infertility, but 75% had had at least one genetically related child. Obstetric outcomes were similar to the general population. Forty-six percent of women had a diagnosis of low bone mineral density or osteoporosis, and an additional 19% had never had a bone density assessment. Conclusions: Women with FXPOI are at significant risk for delayed POI diagnosis and undertreatment with hormone therapy. Although approximately 50% of women had infertility, most were able to conceive at least one child and had no elevated risk of adverse obstetric outcomes.

FMR1 premutation cytosine-guanine-guanine repeat expansion alleles are relatively common mutations in the general population that are associated with a neurodegenerative disease (fragile X-associated tremor/ataxia syndrome), reproductive health problems and potentially a wide range of additional mental and general health conditions that are not yet well-characterised. The International Fragile X Premutation Registry (IFXPR) was developed to facilitate and encourage research to better understand the FMR1 premutation and its impact on human health, to facilitate clinical trial readiness by identifying and characterising diverse cohorts of individuals interested in study participation, and to build community and collaboration among carriers, family members, researchers and clinicians around the world. Here, we describe the development and content of the IFXPR, characterise its first 747 registrants from 32 countries and invite investigators to apply for recruitment support for their project(s). With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies.

Background People with Down syndrome (DS) are one of the highest risk groups for mortality associated with COVID-19, but outcomes may differ across countries due to different co-morbidity profiles, exposures, and societal practices, which could have implications for disease management. This study is designed to identify differences in clinical presentation, severity, and treatment of COVID-19 between India and several high-income countries (HICs). Methods We used data from an international survey to examine the differences in disease manifestation and management for COVID-19 patients with DS from India vs HIC. De-identified survey data collected from April 2020 to August 2021 were analysed. Results COVID-19 patients with DS from India were on average nine years younger than those from HICs. Comorbidities associated with a higher risk for severe COVID-19 were more frequent among the patients from India than from HICs. Hospitalizations were more frequent among patients from India as were COVID-19-related medical complications. Treatment strategies differed between India and HICs, with more frequent use of antibiotics in India. The average severity score of 3.31 was recorded for Indian DS in contrast to 2.3 for European and 2.04 for US cases. Conclusions Presentation and outcomes of COVID-19 among individuals with DS were more severe for patients from India than for those from HIC. Global efforts should especially target vaccination campaigns and other risk-reducing interventions for individuals with DS from low-income countries.

Background: Fragile X syndrome is characterized by a myriad of physical features, behavioral features, and medical problems. Commonly found behavioral features are hyperactivity, anxiety, socialization difficulties, and ASD. There is also a higher incidence than in the general population of strabismus, otitis media, and mitral valve prolapse. In addition, one of the most common medical problems associated with FXS is an increased risk of seizures. A subset of individuals carrying the full mutation of the FMR1 gene and diagnosed with fragile X syndrome (FXS) are reported to experience seizures, mostly during the first 10 years of their life span. Methods: As part of a larger project to identify genetic variants that modify the risk of seizures, we collected clinical information from 49 carriers with FXS who experienced seizures and 46 without seizures. We compared seizure type and comorbid conditions based on the source of data as well as family history of seizures. Results: We found that the concordance of seizure types observed by parents and medical specialists varied by type of seizure. The most common comorbid condition among those with seizures was autism spectrum disorder (47% per medical records vs. 33% per parent report compared with 19% among those without seizures per parent report); the frequency of other comorbid conditions did not differ among groups. We found a slightly higher frequency of family members who experienced seizures among the seizure group compared with the nonseizure group. Conclusion: This study confirms previously reported features of seizures in FXS, supports additional genetic factors, and highlights the importance of information sources, altogether contributing to a better understanding of seizures in FXS.

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.

Objective 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). The primary features of FXTAS are late-onset intention tremor and gait ataxia. Previous reports have shown global deficits in neuropsychological measures among males with FXTAS, particularly those related to executive functioning. The purpose of this study was to investigate the neuropsychological profile among older males with the premutation who are at risk for FXTAS. Method Premutation carriers, 66 with motor symptoms and 23 without, and 18 non-carrier siblings were recruited from pedigrees diagnosed with fragile X syndrome, all over age 50. Subjects were examined with a neurological test battery to identify symptoms of FXTAS and a neuropsychological test battery to investigate cognitive and behavioral profiles. Linear regression and ANCOVA were used to determine the effect of the premutation on outcome measures adjusting for age and education. Results We identified a significant decrease in scores of general intelligence and a marginally significant decrease in scores of logical memory among premutation carrier males with motor symptoms compared to the non-carrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. Discussion Similar to other reports, we found that the FMR1 premutation is associated with deficits in general intelligence and memory among older males with symptoms of FXTAS. However, our results differed in that we found no evidence of premutation-associated executive dysfunction. We provide possible explanations for this difference.

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<0.05. All FMR1 premutation carriers were men of mean age 65±7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869–878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6±6) compared to the other groups (p<0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p<0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor-and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.

Introduction 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. Methods 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. Results 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. Conclusions 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.

Instability of the FMR1 repeat, commonly observed in transmissions of premutation alleles (55–200 repeats), is influenced by the size of the repeat, its internal structure and the sex of the transmitting parent. We assessed these three factors in unstable transmissions of 14/3,335 normal (~5 to 44 repeats), 54/293 intermediate (45–54 repeats), and 1561/1,880 premutation alleles. While most unstable transmissions led to expansions, contractions to smaller repeats were observed in all size classes. For normal alleles, instability was more frequent in paternal transmissions and in alleles with long 3′ uninterrupted repeat lengths. For premutation alleles, contractions also occurred more often in paternal than maternal transmissions and the frequency of paternal contractions increased linearly with repeat size. All paternal premutation allele contractions were transmitted as premutation alleles, but maternal premutation allele contractions were transmitted as premutation, intermediate, or normal alleles. The eight losses of AGG interruptions in the FMR1 repeat occurred exclusively in contractions of maternal premutation alleles. We propose a refined model of FMR1 repeat progression from normal to premutation size and suggest that most normal alleles without AGG interruptions are derived from contractions of maternal premutation alleles.

We investigated the effect of AGG interruptions on fragile X repeat instability upon transmission of fragile X intermediate and small premutation alleles with 45-69 CGG repeats. The FMR1 repeat structure was determined for 375 mothers, 48 fathers, and 538 offspring (457 maternal and 81 paternal transmissions) using a novel PCR assay to determine repeat length and AGG interruptions. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3′ end were correlated with repeat instability on transmission. Maternal alleles with no AGGs conferred the greatest risk for unstable transmissions. All nine full mutation expansions were inherited from maternal alleles with no AGGs. Furthermore, the magnitude of repeat expansion was larger for alleles lacking AGG interruptions. Transmissions from paternal alleles with no AGGs also exhibited greater instability than those with one or more AGGs. Our results demonstrate that characterization of the AGG structure within the FMR1 repeat allows more accurate risk estimates of repeat instability and expansion to full mutations for intermediate and small premutation alleles.