The Effects of the COVID-19 Pandemic on Mental Health in Mothers of Autistic Children and Mothers of Children with Fragile X Syndrome.

Background: The COVID-19 pandemic adversely affected the mental health of American mothers and mothers of children with disabilities may have been disproportionately impacted. The present study characterized psychological well-being, social support, and caregiving responsibilities during the pandemic across mothers of children with autism, fragile X syndrome (FXS), and neurotypical children. Methods: Participants were 54 mothers of children with FXS, 46 mothers of autistic children, and a control group of 80 mothers of neurotypical children. Mothers completed questionnaires on depressive and anxiety symptoms, perceived decline in psychological well-being due to the pandemic, pandemic-related changes in caregiving responsibilities, and levels of social support. Results: Over half of the mothers of children with autism and over one-third of the mothers of children with FXS reported clinically significant symptoms of depression and anxiety, with rates significantly higher than the control mothers. Though all mothers reported a surge in caregiving responsibilities, mothers of children with FXS experienced greater increases in caregiving responsibilities and social support was lower in both disability groups. Caregiving responsibilities and social support were associated with psychological well-being due to the pandemic across all groups. Conclusions: Findings highlight the harsh impact of the pandemic on the mental health of mothers of children with FXS and autism. The staggering rate of clinical depressive and anxiety symptoms reported by these groups underscores the urgent need for improved access to psychological services and family-centered supports, with increased caregiving responsibilities and inadequate social support representing important risk factors for mental health problems.

Social Communication Delay in an Unbiased Sample of Preschoolers With the FMR1 Premutation.

PURPOSE: The Fragile X Messenger Ribonucleoprotein-1 (FMR1) premutation (FXpm) is a genetic variant that is common in the general population and is associated with health symptoms and disease in adulthood. However, poor understanding of the clinical phenotype during childhood has hindered the development of clinical practice guidelines for screening and intervention. Given that social communication difficulties have been widely documented in adults with the FXpm and are linked with reduced psychosocial functioning, the present study aimed to characterize the communication profile of the FXpm during early childhood. METHOD: Eighteen children with the FXpm who were identified through cascade testing (89%) or screening at birth (11%) were compared to 21 matched typically developing children, aged 2-4 years. Participants completed standardized assessments of language (Mullen Scales of Early Learning) and adaptive communication (Vineland Adaptive Behavior Scales-II). Social communication was rated from seminaturalistic interaction samples using the Brief Observation of Social Communication Change. RESULTS: Children with the FXpm showed delayed social communication development, with the magnitude of group differences highlighting social communication as a feature that distinguishes children with the FXpm from their peers (p = .046, ηp2 = .12). The groups did not differ on the standardized language and adaptive communication measures (ps > .297, ηp2s < .03). CONCLUSIONS: Early screening and treatment of social communication delays may be key to optimizing outcomes for children with the FXpm. Further research is needed to replicate findings in a larger sample, delineate the trajectory and consequences of social communication difficulties across the life span in the FXpm, and determine the potential epidemiological significance of FMR1 as a mediator of developmental communication differences within the general population.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Atypical vocal quality in women with the FMR1 premutation: an indicator of impaired sensorimotor control.

Women with the FMR1 premutation are susceptible to motor involvement related to atypical cerebellar function, including risk for developing fragile X tremor ataxia syndrome. Vocal quality analyses are sensitive to subtle differences in motor skills but have not yet been applied to the FMR1 premutation. This study examined whether women with the FMR1 premutation demonstrate differences in vocal quality, and whether such differences relate to FMR1 genetic, executive, motor, or health features of the FMR1 premutation. Participants included 35 women with the FMR1 premutation and 45 age-matched women without the FMR1 premutation who served as a comparison group. Three sustained /a/ vowels were analyzed for pitch (mean F0), variability of pitch (standard deviation of F0), and overall vocal quality (jitter, shimmer, and harmonics-to-noise ratio). Executive, motor, and health indices were obtained from direct and self-report measures and genetic samples were analyzed for FMR1 CGG repeat length and activation ratio. Women with the FMR1 premutation had a lower pitch, larger pitch variability, and poorer vocal quality than the comparison group. Working memory was related to harmonics-to-noise ratio and shimmer in women with the FMR1 premutation. Vocal quality abnormalities differentiated women with the FMR1 premutation from the comparison group and were evident even in the absence of other clinically evident motor deficits. This study supports vocal quality analyses as a tool that may prove useful in the detection of early signs of motor involvement in this population.

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.

Low normal FMR1 genotype in older adult women: Psychological well-being and motor function.

The FMR1 gene plays a key role in adult neurogenesis and neuroplasticity, and thus may contribute to age-related health in the population. The current study focused on the "low normal" FMR1 genotype, defined by lower-than-typical numbers of FMR1 CGG repeats (<26), as a potential genetic determinant of age-related health. We characterized the effect of the low normal FMR1 genotype on psychological well-being and motor function in a racially diverse non-clinical sample of older adult women. Women with low CGG repeats were distinguished from those with CGGs falling within the mid-high end of the normal range by reduced performance on multimodal assessments of motor function and psychological well-being, with large effect sizes. Robust continuous associations were also detected between lower CGG repeat length and reduced psychological well-being, balance, and dexterity. Findings suggest that FMR1 may represent an important mediator of individual differences in age-related health; larger epidemiological studies are needed. Given that approximately 23-35% of females carry the low normal genotype, efforts to understand its clinical effects have relevance a broad swath of the aging population.

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.

Verbal inhibition declines among older women with high FMR1 premutation expansions: A prospective study.

The FMR1 premutation has been associated with difficulties in executive functioning, including verbal inhibition. However, little is known about the longitudinal profiles of verbal inhibition among FMR1 premutation carriers, particularly in women, and how individual factors such as aging and CGG repeat length may contribute to changes in verbal inhibition over time. The present study examined verbal inhibition performance (i.e., inhibition errors) on the Hayling Sentence Completion Task in a cohort of 92 women with the FMR1 premutation across two timepoints approximately three years apart. We examined the effects of age, CGG repeat length, and their interactions on verbal inhibition over time. We also evaluated whether response latency affected verbal inhibition errors. We found no significant change in verbal inhibition in the full cohort during the three-year study period. However, a subset of FMR1 premutation carriers, namely older participants with higher CGG repeats, evidenced greater declines in verbal inhibition over time. Longer response latencies did not compensate for verbal inhibition errors. The findings suggest that a subset of women with the FMR1 premutation may be at earlier, increased risk for changes in executive functioning, which if confirmed, should be considered as part of the clinical profile associated with the premutation.

Cluttering in the Speech of Young Men With Fragile X Syndrome.

PURPOSE: Cluttering is a fluency disorder that has been noted clinically in individuals with fragile X syndrome (FXS). Yet, cluttering has not been systematically characterized in this population, hindering identification and intervention efforts. This study examined the rates of cluttering in male young adults with FXS using expert clinical opinion, the alignment between expert clinical opinion and objectively quantified features of cluttering from language transcripts, and the association between cluttering and aspects of the FXS phenotype. METHOD: Thirty-six men with FXS (aged 18-26 years; M = 22, SD = 2.35) contributed language samples and completed measures of nonverbal cognition, autism symptoms, anxiety, and symptoms of attention-deficit/hyperactivity disorder (ADHD). The presence of cluttering was determined by the consensus of two clinical experts in fluency disorders based on characteristics exhibited in the language sample. Cluttering features (speech rate, disfluencies, etc.) were also objectively quantified from the language transcripts. RESULTS: Clinical experts determined that 50% of participants met the criteria for a cluttering diagnosis. Phrase repetitions were the most salient feature that distinguished individuals who cluttered. Although the presence of cluttering was not associated with autism symptoms or mean length of utterance, cluttering was more likely to occur when nonverbal cognitive ability was higher, ADHD symptoms were elevated, and anxiety symptoms were low. CONCLUSIONS: Half of the male young adults with FXS exhibited cluttering, which supports FXS as a genetic diagnosis that is highly enriched for risk of cluttering. Cluttering was associated with increased ADHD symptoms and cognitive ability and reduced anxiety symptoms. This study contributes a new description of the clinical presentation of cluttering in men with FXS and may lead to improved understanding of the potential underlying mechanisms of cluttering and eventual refinements to treatment and diagnosis.