A Systematic Review of Fragile X-Associated Neuropsychiatric Disorders.

OBJECTIVE: Fragile X premutation carriers are reported to have increased neuropsychiatric problems, and thus the term fragile X-associated neuropsychiatric disorders (FXAND) has been proposed. Unfortunately, published prevalence estimates of these phenomena are inconsistent. This systematic review clarified this issue by reviewing both fragile X premutation prevalence in patients with neurodevelopmental disorders and psychiatric disorder prevalence in premutation carriers without fragile X-associated tremor/ataxia syndrome (FXTAS). Average prevalence was derived from studies that used semistructured clinical interviews, diagnostic criteria, and validated rating scales. METHODS: Forty-six studies were reviewed. The rate of fragile X premutation in neurodevelopmental disorders was assessed from five studies. Probands with neurodevelopmental disorders were more likely than those in the general population to be premutation carriers. The rate of psychiatric disorders in premutation carriers was assessed from five studies for neurodevelopmental, 13 studies for mood, 12 studies for anxiety, and two studies for psychotic disorders. The phenotype and sex distribution among premutation carriers were similar to those with fragile X syndrome. RESULTS: Compared to control group and general population estimates, the most prevalent psychiatric disorders were neurodevelopmental disorders, anxiety disorders, and bipolar II disorder. Psychiatric disorders were also more common in males. Most studies relied only on past medical history to define the prevalence of psychiatric disorders, yielding variability in results. CONCLUSIONS: Future studies are needed to avoid bias by identifying cohorts from population-based sampling, to describe cohort demographic characteristics to elucidate differences in age and sex, and to prioritize the use of validated psychiatric assessment methods.

Misunderstood terms and concepts identified through user testing of educational materials for fragile X premutation: "Not weak or fragile?"

Complicated genetic mechanisms and unpredictable health risks associated with the FMR1 premutation can result in challenges for patient education when the diagnosis is made in a newborn. From October 15, 2018, to December 10, 2021, North Carolina parents could obtain FMR1 premutation results about their newborns through a voluntary expanded newborn screening research study. The study provided confirmatory testing, parental testing, and genetic counseling. We developed web-based educational materials to augment information about fragile X premutation conveyed by a genetic counselor. Many genetics education materials are developed for the lay population. However, relatively little research is published on how well individuals understand these materials. We conducted three rounds of iterative user testing interviews to help refine web-based educational materials that support understanding and self-paced learning. The participants included 25 parents with a 2-year college degree or less and without a child identified with fragile X syndrome, premutation, or gray-zone allele. Content analysis of interview transcripts resulted in iterative changes and ultimately saturation of findings. Across all rounds of interviews, there were two terms that were commonly misunderstood (fragile and carrier) and two terms that elicited initial misconceptions that were overcome by participants. Many also had difficulty understanding the relationship between fragile X premutation and fragile X syndrome as well as appreciating the implications of having a "fragile X gene." Website layout, formatting, and graphics also influenced comprehension. Despite iterative changes to the content, certain issues with understandability persisted. The findings support the need for user testing to identify misconceptions that may interfere with understanding and using genetic information. Here, we describe a process used to develop and refine evidence-based, understandable parental resources on fragile X premutation. Additionally, we provide recommendations to address ongoing educational challenges and discuss the potential impact of bias on the part of expert content developers.

Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan.

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

Refining reproductive risk for FMR1 premutation carriers in the general obstetric population.

Female FMR1 premutation (FMR1 PM) carriers for fragile X syndrome (FXS) are at risk to have a child with FXS based on their CGG repeat size and AGG interruption number. Studies examining this risk in unselected populations of female PM carriers are lacking. This retrospective cohort study analyzed carrier status, CGG repeat length, AGG interruption result, and reproductive risk refinement in a population of female patients who underwent routine carrier screening for FXS. A total of 1536 PM carriers (0.43%) were identified, 95% of whom had between 55 and 90 CGG repeats. A number of 1334 carriers underwent AGG interruption testing. The majority had at least one AGG interruption and received a lower reproductive risk for FXS following AGG interruption testing (89% and 85%, respectively) as compared to their risk calculated based on CGG repeat size alone. The average change in risk across the population following AGG interruption testing was -3.4%, with a range from -50.8% to 48.9%. This article describes the range of CGG repeats and AGG interruptions in an unselected population of female PM carriers and suggests that most carriers would benefit from AGG interruption testing to refine their reproductive risk of having a child with FXS.

Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. OBJECTIVE: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome. METHODS: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid ß protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid ß within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. RESULTS: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid ß in the cerebral cortex and the rate of disease progression. CONCLUSION: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society.

Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community-Based Cohort.

BACKGROUND: Premutation-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. OBJECTIVE: The 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. METHODS: Three 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. RESULTS: Although 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. CONCLUSIONS: Among 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.

'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41-200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson's disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.

Men with an FMR1 premutation and their health education needs.

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.

Inequities in diagnosis of Fragile X syndrome in Colombia.

BACKGROUND: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism spectrum disorder (ASD). In Colombia, there are no screening or testing protocols established for the diagnosis of FXS. In this study, we aimed to describe the diagnostic trends of FXS in Colombia. METHODS: Data were included on 1322 individuals obtained based on data from the only 2 databases available. Sociodemographic information and data related to the diagnostic process were obtained and included in this study. RESULTS: The average age at the time of diagnosis for individuals with the full mutation (FM) was of 26.9 ± 2.57 years and was strongly dependent on sex and socioeconomic status. Most individuals with a molecular diagnosis were from the main cities. CONCLUSION: The overall age of diagnosis of FXS is later in life than reports from other countries. Restricted access to molecular testing through the national health system might explain this discrepancy in Colombia.

Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome.

Individuals who carry a premutation (PM) allele on the FMR1 gene may experience executive limitations associated with their genetic status, including inhibition deficits. However, poor understanding of individualized risk factors has limited clinical management of this group, particularly in mothers who carry the PM allele who have children with fragile X syndrome (FXS). The present study examined CGG repeat length and age as factors that may account for variable expressivity of inhibition deficits. Participants were 134 carriers of the PM allele who were mothers of children with FXS. Inhibition skills were measured using both self-report and direct behavioral assessments. Increased vulnerability for inhibition deficits was observed at mid-range CGG lengths of approximately 80-100 repeats, with some evidence of a second zone of vulnerability occurring at approximately 130-140 CGG repeats. Risk associated with the genotype also became more pronounced with older age. This study identifies personalized risk factors that may be used to tailor the clinical management of executive deficits in carriers of the PM allele. Inhibition deficits may contribute to poor outcomes in carriers of the PM allele and their families, particularly in midlife and early old age, and clinical monitoring may be warranted.

Functional motor control deficits in older FMR1 premutation carriers.

Individuals with fragile X mental retardation 1 (FMR1) gene premutations are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. However, it is unknown whether older FMR1 premutation carriers, with or without FXTAS, exhibit functional motor control deficits compared with healthy individuals. The purpose of this study, therefore, was to determine whether older FMR1 premutation carriers exhibit impaired ability to perform functional motor tasks. Eight FMR1 premutation carriers (age: 58.88 ± 8.36 years) and eight age- and sex-matched healthy individuals (60.13 ± 9.25 years) performed (1) a steady isometric force control task with the index finger at 20% of their maximum voluntary contraction (MVC) and; (2) a single-step task. During the finger abduction task, firing rate of multiple motor units of the first dorsal interosseous (FDI) muscle was recorded. Compared with healthy controls, FMR1 premutation carriers exhibited (1) greater force variability (coefficient of variation of force) during isometric force (1.48 ± 1.02 vs. 0.63 ± 0.37%; P = 0.04); (2) reduced firing rate of multiple motor units during steady force, and; (3) reduced velocity of their weight transfer during stepping (156.62 ± 26.24 vs. 191.86 ± 18.83 cm/s; P = 0.01). These findings suggest that older FMR1 premutation carriers exhibit functional motor control deficits that reflect either subclinical issues associated with premutations independent of FXTAS, or prodromal markers of the development of FXTAS.

Complexity based measures of postural stability provide novel evidence of functional decline in fragile X premutation carriers.

BACKGROUND: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative movement disorder characterized by tremor, ataxic gait, and balance issues resulting from a premutation of the Fragile X Mental Retardation 1 (FMR1) gene. No biomarkers have yet been identified to allow early diagnosis of FXTAS, however, recent studies have reported subtle issues in the stability of younger premutation carriers, before disease onset. This study investigates the efficacy of multiscale entropy analysis (MSE) in detecting early changes in the motor system of premutation carriers without FXTAS. METHODS: Sway complexity of 12 female Premutation carriers and 15 healthy Controls were measured under four conditions: eyes open, closed, and two dual-task conditions. A Sustained Attention Response Task (SART) and a working memory based N-Back task were employed to increase cognitive load while standing on the forceplate. A Complexity Index (Ci) was calculated for anterior-posterior (AP) and mediolateral (ML) sway. Independent t-tests were used to assess between-group differences and Oneway repeated measures ANOVA were used to assess within group differences with Bonferroni corrections to adjust for multiple comparisons. RESULTS: Group performances were comparable with eyes open and closed conditions. The Carrier group's Ci was consistent across tasks and conditions while the Control group's AP Ci increased significantly during the cognitive dual-task (p = 0.001). There was also a strong correlation between CGG repeat length and complexity for the Carrier group (p = 0.004). SIGNIFICANCE: Increased sway complexity is believed to stem from reallocation of attention to facilitate the increased cognitive demands of dual-tasks. Carriers' complexity did not change during dual-tasks, possibly indicating capacity interference and inefficient division of attention. Lower sway complexity in carriers suggests diminished adaptive capacity under stress as well as degradation of motor functioning. Therefore, sway complexity may be a useful tool in identifying early functional decline in FMR1 premutation carriers as well as monitoring progression towards disease onset.

Preimplantation genetic diagnosis versus prenatal diagnosis-decision-making among pregnant FMR1 premutation carriers.

PURPOSE: To detect which factors influence decision-making among pregnant FMR1 premutation carriers regarding the preferred mode of genetic diagnosis: IVF-PGT-M (in vitro fertilization with preimplantation genetic testing for monogenic gene diseases), or CVS (chorionic villus sampling), or AC (amniocentesis) after spontaneous conception. METHODS: In Israel FMR1 premutation preconception genetic screening is offered, free of charge, to every woman in her reproductive years. FMR1 premutation carriers with ≥ 70 CGG repeats, or a history of FXS offspring, are offered IVF-PGT-M. This is a historical cohort study including all pregnant FMR1 premutation carriers who underwent prenatal diagnosis between the years 2011 and 2016 at a tertiary medical center. Data were collected from electronic charts and through phone interviews. RESULTS: One hundred seventy-five women with high-risk pregnancies who were offered IVF-PGT-M were evaluated. In 37 pregnancies (21%), the women decided to undergo IVF-PGT-M. Using the generalized estimating equations (GEE) statistical method including seven parameters, we found that previous termination of pregnancy due to FXS and advanced woman's age were significantly associated with making the decision to undergo IVF-PGT-M. Previously failed IVF was the most significant parameter in a woman's decision not to undergo IVF-PGT-M. CONCLUSION: The most dominant factor affecting the decision of FMR1 premutation carriers to choose spontaneous conception with prenatal diagnosis versus IVF-PGT-M is a previous experience of failed IVF treatments. Women whose IVF treatments failed in the past tended to try to conceive naturally and later, during the course of the pregnancy, perform CVS or AC. Conversely, women who previously experienced a termination of pregnancy (TOP) due to an affected fetus, and older women, preferred to undergo IVF-PGT-M procedures.

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism-Spectrum Quotient (AQ) questionnaires. Fifty-nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that fragile X-associated tremor/ataxia syndrome (FXTAS) patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no-FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results, a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.

The effects of optimism, religion, and hope on mood and anxiety disorders in women with the FMR1 premutation.

BACKGROUND: The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort. METHODS: Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time. RESULTS: Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later. CONCLUSIONS: In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement.

Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency.

STUDY QUESTION: Does repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue? SUMMARY ANSWER: Ovaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin. WHAT IS KNOWN ALREADY: Women who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients. STUDY DESIGN, SIZE, DURATION: Ovaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG . The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovaries from a woman with FXPOI and two control subjects and pituitaries from a man with FXTAS and a control subjects were fixed in 4% formalin. Ovaries and pituitaries of wild-type and exCGG mice were fixed in Bouin's fluid or 4% paraformaldehyde. Immunohistochemistry was performed on the human and mouse samples using FMRpolyG, ubiquitin and Fmrp antibodies. Fmr1 mRNA and protein expression were determined in mouse ovaries by quantitative RT-PCR and Western blot analysis. Follicle numbers in mouse ovaries were determined in serial sections by microscopy. MAIN RESULTS AND THE ROLE OF CHANCE: FMRpolyG-positive inclusions were present in ovarian stromal cells of a woman with FXPOI but not in the ovaries of control subjects. The FMRpolyG-positive inclusions colocalized with ubiquitin-positive inclusions. Similar inclusions were also observed in the pituitary of a man with FXTAS but not in control subjects. Similarly, ovaries of 40-week-old exCGG-KI mice, but not wild-type mice, contained numerous inclusions in the stromal cells that stained for both FMRpolyG- and ubiquitin, while the ovaries of 20-week-old exCGG-KI contained fewer inclusions. At 40 weeks ovarian Fmr1 mRNA expression was increased by 5-fold in exCGG-KI mice compared with wild-type mice, while Fmrp expression was reduced by 2-fold. With respect to ovarian function in exCGG-KI mice: (i) although the number of healthy growing follicles did not differ between wild-type and exCGG-KI mice, the number of atretic large antral follicles was increased by nearly 9-fold in 40-week old exCGG-KI mice (P < 0.001); (ii) at 40 weeks of age only 50% of exCGG-KI mice had recent ovulations compared with 89% in wild-type mice (P = 0.07) and (iii) those exCGG-KI mice with recent ovulations tended to have a reduced number of fresh corpora lutea (4.8 ± 1.74 versus 8.50 ± 0.98, exCGG-KI versus wild-type mice, respectively, P = 0.07). LIMITATIONS, REASONS FOR CAUTION: Although FMRpolyG-positive inclusions were detected in ovaries of both a woman with FXPOI and a mouse model of the FMR1 PM, we only analyzed one ovary from a FXPOI subject. Caution is needed to extrapolate these results to all women with the FMR1 PM. Furthermore, the functional consequence of FMRpolyG-positive inclusions in the ovaries for reproduction remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that a dysfunctional hypothalamic-pituitary-gonadal-axis may contribute to FXPOI in FMR1 PM carriers. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from NFXF, ZonMW, the Netherlands Brain Foundation and NIH. The authors have no conflict of interest to declare.

Carriage of One or Two FMR1 Premutation Alleles Seems to Have No Effect on Illness Severity in a FXTAS Female with an Autozygous FMR1 Premutation Allele.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS.

Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease with motor, psychiatric, and cognitive manifestations that occurs in carriers of the fragile X mental retardation 1 ( FMR1) gene premutations. This was a retrospective chart review of 196 individuals (127 men and 69 women) with FXTAS. Forty-six (23%) participants were cognitively impaired, of whom 19 (10%) had dementia. Risk factors for dementia were examined (CGG repeat size; alcohol, benzodiazepine, and opioid use; diabetes; hyperlipidemia; hypertension; hypothyroidism; obesity; sleep apnea; surgeries with general anesthesia; depression; family history of dementia). Thirteen individuals with FXTAS and dementia were then compared to 13 cognitively intact individuals matched on age, gender, and FXTAS stage. CGG repeat size was significantly higher (mean = 98.5, standard deviation [SD] = 22.2) in the dementia group, compared to the cognitively intact group (mean = 81.6, SD = 11.5; P = .0256). These results show that CGG repeat size is a risk factor for FXTAS dementia.