Fragile X syndrome in the largest world clustering. I. Genetic epidemiology and founder effect outline.

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

"We are not a typical family anymore": Exploring the experiences and support needs of fathers of children with Fragile X syndrome in Australia.

A diagnosis of the X-linked condition Fragile X syndrome (FXS) in a child commonly reveals the mother's carrier status. Previous research focused on the genetic counseling process for the child and maternal family, despite calls for more research on the support needs of fathers. This study explored experiences and support needs of fathers at least 1 year after their child's FXS diagnosis to understand barriers and enablers and optimize health outcomes for the family. In-depth interviews were conducted with 11 fathers recruited through the Australian Genetics of Learning Disability Service and the Fragile X Association. Deidentified transcripts were analyzed using thematic analysis guided by an inductive approach. Four themes emerged: (1) making life easier through understanding-yesterday and today, (2) the path to a new normal-today and tomorrow, (3) seeking information and support, and (4) what men want. Fathers reported diagnostic odysseys, postdiagnostic grief, and challenges adjusting. They highlighted difficulties in understanding their child's unique behaviors and needs, responding to their partner's psychological support needs, planning for their child's future, and navigating complex health and disability systems. Participants suggested health professionals facilitate father-to-father support and psychological counseling. These findings highlight the unmet needs of fathers and suggest that a strengths-based approach is critically important given the recognized mental health impact.

Phenotypic variability to medication management: an update on fragile X syndrome.

This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Predictors, Parental Views, and Concordance Across Diagnostic Sources of Autism in Male Youth with Fragile X Syndrome: Clinical Best Estimate and Community Diagnoses.

Persons with fragile X syndrome (FXS) with cooccurring autism spectrum disorder (ASD) are at risk for poorer educational, medical, employment, and independent living outcomes. Thus, the identification of ASD in those with FXS is fundamental to ensuring access to appropriate supports to achieve good quality of life. Yet, optimal diagnostic methods and the exact rate of ASD comorbidity remains controversial, and description of ASD identification in the community in FXS has been limited. This study characterized ASD in a sample of 49 male youth with FXS across multiple diagnostic sources: parent-reported community diagnoses, classification derived from ADOS-2 and ADI-R thresholds, and clinical best-estimate classifications from an expert multidisciplinary team. High concordance was found between ADOS-2/ADI-R and clinical best estimate classifications, with both methods supporting ASD in ~ 75% of male youth with FXS. In contrast, 31% had a community diagnosis. Findings supported gross under-identification of ASD in male youth with FXS in community settings; 60% of those who met clinical best estimate criteria for ASD had not received a diagnosis in the community. Moreover, community diagnoses were poorly aligned with the presence of ASD symptoms as perceived by parents and professionals and, unlike clinical best estimate diagnoses, were not associated with cognitive, behavioral, or language features. Findings highlight under-identification of ASD in community settings as a significant barrier to service access for male youth with FXS. Clinical recommendations should emphasize the benefits of seeking a professional ASD evaluation for children with FXS who are noted to display key ASD symptoms.

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.

Screening for Fragile X Syndrome Among Filipino Children with Autism Spectrum Disorder.

Individuals with autism spectrum disorder present with difficulties in social communication, restricted interests or behaviors and other co-morbidities. About 2 to 10% of cases of autism have a genetic cause, and Fragile X Syndrome (FXS) is reported in 0 to 6.5% of individuals with autism. However, the FXS and premutation prevalence among Filipino children has never been reported. The aim of the study was to establish the presence of FXS or premutation carriers among Filipino children with autism and to describe the phenotypic characteristic of cases identified. Blood was collected from 235 children aged 2-6 years old and diagnosed with autism. Samples were analyzed using PCR methods to amplify CGG repeats in the FMRI gene. The diagnosis of autism was confirmed through the Autism Diagnostic Observation Schedule-2. Additional characteristics were documented from a physical examination, Griffiths Scales of Child Development assessment and a parent-answered questionnaire using the Vineland Adaptive Behavior Scale. Fragile X testing through PCR methods in 235 children with diagnosed autism showed 220 (93.6%) were negative, no full mutations, 1 (0.436%) premutation carrier and 14 (5.95%) cases contained intermediate alleles. The FXS testing was limited to confirmed cases of autism, which is considered a high-risk group and does not provide prevalence for the general Filipino population. Subjects were self-referred or referred by clinicians, which may not represent the Filipino autism population with a bias towards those with means for clinical consultations and ability to travel to the place of testing. Samples were not measured for mosaicism, DNA methylation or AGG interspersion patterns. These may have effects on the CGG repeat expansion and overall presentation of FXS. Findings from a single premutation carrier cannot characterize features distinctly present in Filipinos with the mutation. Nevertheless, these results support the data that the prevalence of FXS in Asian populations may be lower than non-Asian populations. This can contribute to a better understanding of FXS and genetic causes of autism in the Philippines and other Asian populations.

Anxiety, Depression, and Social Skills in Girls with Fragile X Syndrome: Understanding the Cycle to Improve Outcomes.

OBJECTIVE: Female patients with fragile X syndrome (FXS), a genetic condition associated with a mutation in the FMR1 gene, are at significantly elevated risk for developing anxiety and depression. This study is designed to better understand these symptoms in school-age girls, particularly as they relate to age, social skills, and functional outcomes. METHODS: We compared 58 girls aged 6 to 16 years with FXS with 46 age-matched, sex-matched, and developmentally matched peers without FXS on measures of anxiety, depression, social skills, adaptive behavior, and quality of life. RESULTS: Girls with FXS 10.5 years and older demonstrated significantly higher levels of depression, withdrawal, and social avoidance than girls younger than 10.5 years with FXS ( p -values < 0.01). Girls in the comparison group did not show any age-related differences on these measures. The older FXS cohort also showed associations between social communication and interaction skills, adaptive behavior, and measures of anxiety and depression ( p -values < 0.05) not seen in the comparison group, regardless of age. CONCLUSION: We found that age seems to play an important role in the development of mood symptoms and that such symptoms are uniquely correlated with social communication and reciprocal social interaction behaviors and adaptive functioning in girls with FXS after puberty. These data suggest a critical window of intervention for girls with FXS in the improvement of social interaction skills and the prevention of social avoidance and symptoms of anxiety and depression, with the ultimate goal of improving quality of life and promoting greater independence.

The Impact of the COVID-19 Pandemic on School-Aged Children with Fragile X Syndrome.

The pandemic caused by the spread of the coronavirus disease (COVID-19), beginning in early 2020, had an impact beyond anything experienced in recent history. People with Fragile X Syndrome (FXS), the leading known heritable cause of ASD and intellectual disability, were uniquely vulnerable to pandemic-related changes. This study surveyed parent perspectives of the impact on 33 school-aged children with FXS across daily living skills, education, therapies, behaviors, health visits, and mask wearing. Academic performance was perceived to have decreased in most of the children (58%). Students in online school had the most reports of decline and those in person had the most reported improvement. Parents were significantly more satisfied with services that remained in person compared to those delivered online or in hybrid settings. Additionally, depression (75%), sleep problems (80%), attention problems (73%), and social skills (61%) were reported to have worsened the most. Parents reported that in addition to continuing with a structured schedule, the most helpful strategies were increasing face-to-face social interactions and outdoor activities. Future research should explore strategies to help online interventions and education to be more successful with individuals with FXS, given this may become a resource for families not geographically able to access in-person resources.

Descriptive analysis of seizures and comorbidities associated with fragile X syndrome.

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.

Advancing artificial intelligence-assisted pre-screening for fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, is significantly underdiagnosed in the general population. Diagnosing FXS is challenging due to the heterogeneity of the condition, subtle physical characteristics at the time of birth and similarity of phenotypes to other conditions. The medical complexity of FXS underscores an urgent need to develop more efficient and effective screening methods to identify individuals with FXS. In this study, we evaluate the effectiveness of using artificial intelligence (AI) and electronic health records (EHRs) to accelerate FXS diagnosis. METHODS: The EHRs of 2.1 million patients served by the University of Wisconsin Health System (UW Health) were the main data source for this retrospective study. UW Health includes patients from south central Wisconsin, with approximately 33 years (1988-2021) of digitized health data. We identified all participants who received a code for FXS in the form of International Classification of Diseases (ICD), Ninth or Tenth Revision (ICD9 = 759.83, ICD10 = Q99.2). Only individuals who received the FXS code on at least two occasions ("Rule of 2") were classified as clinically diagnosed cases. To ensure the availability of sufficient data prior to clinical diagnosis to test the model, only individuals who were diagnosed after age 10 were included in the analysis. A supervised random forest classifier was used to create an AI-assisted pre-screening tool to identify cases with FXS, 5 years earlier than the time of clinical diagnosis based on their medical records. The area under receiver operating characteristic curve (AUROC) was reported. The AUROC shows the level of success in identification of cases and controls (AUROC = 1 represents perfect classification). RESULTS: 52 individuals were identified as target cases and matched with 5200 controls. AI-assisted pre-screening tool successfully identified cases with FXS, 5 years earlier than the time of clinical diagnosis with an AUROC of 0.717. A separate model trained and tested on UW Health cases achieved the AUROC of 0.798. CONCLUSIONS: This result shows the potential utility of our tool in accelerating FXS diagnosis in real clinical settings. Earlier diagnosis can lead to more timely intervention and access to services with the goal of improving patients' health outcomes.

Attention/Deficit Hyperactivity Disorder in Adolescent and Young Adult Males With Fragile X Syndrome.

This study characterized the rates of attention-deficit/hyperactivity disorder (ADHD) in adolescent and young adult males with fragile X syndrome (FXS) using a multi-method approach integrating a DSM-based parent interview (Children's Interview for Psychiatric Syndromes; P-ChIPS, Fristad et al., 1998) and a parent rating scale (Child Behavior Checklist; CBCL, Achenbach, 2001). Thirty-one males with FXS, aged 16-24 years, participated. Forty-two percent met DSM-5 criteria for ADHD and 35% exceeded the CBCL cut-offs. Agreement between the two classification methods was fair (κ = 0.38). Autism symptom severity and nonverbal cognitive ability did not predict ADHD diagnoses/symptoms. Results show high rates of ADHD in males with FXS during late adolescence and young adulthood, which are not accounted for by impaired nonverbal cognitive skills or autism symptom severity. DSM-based ADHD-specific scales are recommended over broadband symptom scales to improve accurate identification.

Fragile X premutation carrier screening in Pakistani preconception women in primary care consultation.

PURPOSE: Women of reproductive age who carry fragile X premutation (PM) alleles have 56 to 200 CGG repeats in the 5'-untranslated region of FMR1 gene are at increased risk for producing children with intellectual disabilities (ID) or autism spectrum disorders (ASD) due to expansion of PM alleles to full mutation alleles (> 200 repeats) during maternal transmission. METHODS: In present study fragile X PM carrier screening was performed in total 808 women who were consulting primary health care centers for preconception care in Khyber Pakhtunkhwa region of Pakistan between April, 2018 and December, 2020. Polymerase chain reaction (PCR) was performed for detection of PM carrier women and the CGG repeats number was confirmed by Southern blotting and capillary electrophoresis. RESULTS: The prevalence rate for PM carriers among preconception women was found to be 0.7% that was contributed by 0.5% women in risk group (RG1) with family history of ID and 0.2% in risk group 2 (RG2) with family history of ASD. PM carrier women had at least one affected child or sibling. In addition, the preconception women with FMR1 PM alleles were found to be at increased risk for primary ovary insufficiency (RG1: P = 0.0265, RG2: P = 0.0389), postpartum depression (RG1: P = 0.0240, RG2: P = 0.0501) and neuropsychiatric disorders (RG1: P = 0.0389, RG2: P = 0.0432). CONCLUSIONS: Current study provides first evidence of fragile X PM carrier screening in Pakistani preconception women in primary care consultation. Findings of current study may help to improve preconception care and to reduce burden of fragile X associated disorders in our population.

Height and BMI in fragile X syndrome: A longitudinal assessment.

OBJECTIVE: Previously reported data regarding growth parameters in individuals with fragile X syndrome (FXS) are inconsistent. A longitudinal analysis of height and BMI in a large number of individuals with FXS was conducted. METHODS: Age- and sex-specific z scores for height and BMI of 1,223 individuals with FXS were calculated based on published normative data. Mixed-effect linear regression models were fit separately for males and females, and z scores for height and weight were regressed against age and adjusted for intellectual disability (ID) and psychotropic medication use. RESULTS: Mean height z score for both sexes decreased with age and was lower than normative data. Mean BMI z score was greater than normative data in both sexes, and this disparity increased with age. BMI z score in females was greater for those with moderate or severe ID than those with no or mild ID. Individuals taking antipsychotics had higher BMI z scores than those taking no or other medications; those taking anticonvulsants or stimulants had lower BMI z scores. CONCLUSIONS: Individuals with FXS are at elevated risk for overweight and obesity. The risk is higher in individuals taking antipsychotics and among females with severe ID. These findings warrant increased attention to obesity prevention for all individuals with FXS.

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.

Behavior Problems and Social Competence in Fragile X Syndrome: A Systematic Review.

Fragile X syndrome (FXS) causes intellectual disability and is the known leading cause of autism. Common problems in FXS include behavior and social problems. Along with syndromic characteristics and autism comorbidity, environmental factors might influence these difficulties. This systematic review focuses on the last 20 years of studies concerning behavior and social problems in FXS, considering environmental and personal variables that might influence both problems. Three databases were reviewed, leading to fifty-one studies meeting the inclusion criteria. Attention deficit hyperactivity disorder (ADHD) problems remain the greatest behavior problems, with behavioral problems and social competence being stable during the 20 years. Some developmental trajectories might have changed due to higher methodological control, such as aggressive behavior and attention problems. The socialization trajectory from childhood to adolescence remains unclear. Comorbidity with autism in individuals with FXS increased behavior problems and worsened social competence profiles. At the same time, comparisons between individuals with comorbid FXS and autism and individuals with autism might help define the comorbid phenotype. Environmental factors and parental characteristics influenced behavior problems and social competence. Higher methodological control is needed in studies including autism symptomatology and parental characteristics. More studies comparing autism in FXS with idiopathic autism are needed to discern differences between conditions.

Female fragile X premutation carriers are at increased risk for metabolic syndrome from early adulthood.

BACKGROUND AND AIMS: Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC. METHODS AND RESULTS: Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p < 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk. CONCLUSIONS: Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities.

Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM-CGG expansion of 55-199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

Sleep problems in fragile X syndrome: Cross-sectional analysis of a large clinic-based cohort.

Fragile X syndrome (FXS), the leading cause of inherited intellectual disability and autism spectrum disorder, is associated with multiple neurobehavioral abnormalities including sleep difficulties. Nonetheless, frequency, severity, and consequences of sleep problems are still unclear. The Fragile X Online Registry with Accessible Research Database (FORWARD-version-3), including Clinician Report and Parent Report forms, was analyzed for frequency, severity, relationship with behavioral problems, and impact of sleep difficulties in a mainly pediatric cohort. A focused evaluation of sleep apnea was also conducted. Six surveyed sleep difficulties were moderately frequent (~23%-46%), relatively mild, affected predominantly younger males, and considered a problem for 7%-20% of families. Snoring was more prevalent in older individuals. All sleep difficulties were associated with irritability/aggression and most also to hyperactivity. Only severe snoring was correlated with sleep apnea (loud snoring: 30%; sleep apnea: 2%-3%). Sleep difficulties are prevalent in children with FXS and, although they tend to be mild, they are associated with behavioral problems and negative impact to families. Because of its cross-sectional nature, clinic-origin, use of ad hoc data collection forms, and lack of treatment data, the present study should be considered foundational for future research aiming at better recognition and management of sleep problems in FXS.

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.

COVID-19 Pandemic: Mental Health in Girls With and Without Fragile X Syndrome.

OBJECTIVE: Children and adolescents, who have less developed coping skills, are affected by natural disasters and other traumatic events differently than adults. Emotional and behavioral effects are particularly pronounced during a pandemic-related disaster, when support networks that typically promote healthy coping, such as friends, teachers, and family members, may be less available. Children and adolescents with fragile X syndrome (FXS), who are at increased risk for developing anxiety and depression, may be particularly vulnerable to behavioral or emotional difficulties during a pandemic. This study examined the mental health outcomes of school-aged girls with FXS during the COVID-19 pandemic and associated stay-at-home orders. METHODS: Participants included 47 school-aged girls with FXS and 33 age- and developmentally matched comparison girls. Associations between COVID-19 behavioral and emotional outcomes and prior academic, adaptive, behavioral, and emotional functioning as well as prior maternal mental health and characteristics of the mother-child relationship were examined. Qualitative data from the parental report of emotional and behavioral responses to the pandemic were also obtained. RESULTS: Results indicate that school-aged girls with FXS demonstrate a distinct profile of COVID-19 related associations compared to the comparison group, such that pandemic-related worries and emotional impact of pandemic restrictions were predicted by prior mental health factors for the comparison group but by prior social, behavioral, and relational factors for the FXS group. CONCLUSIONS: Findings provide insight into factors that may confer risk or resilience for youth with special needs, suggesting potential therapeutic targets and informing public health initiatives in response to the pandemic.