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.

Daily Living Skills in Adolescent and Young Adult Males With Fragile X Syndrome.

By adulthood, most males with fragile X syndrome (FXS) require support to navigate day-to-day settings. The present study cross-sectionally: (1) characterized the profile of daily living skills in males with FXS and (2) examined associated participant characteristics (i.e., fragile X mental retardation protein [FMRP] expression, nonverbal cognition, language, autism symptomatology, and anxiety symptomatology) using the Waisman-Activities of Daily Living questionnaire. Males with FXS (n = 57, ages 15-23 years) needed more help/support in the areas of domestic and community daily livings skills, than in the area of personal daily living skills. Significant associations were observed between reduced daily living skills and lower nonverbal cognition, receptive language, expressive language, and increased autism symptomatology. Receptive language emerged as the strongest unique predictor of daily living skill performance.

Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation.

BACKGROUND: Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. METHODS: Forty-five women with the FMR1 premutation aged 35-64 years at study entry participated in 1-5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. RESULTS: Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. CONCLUSIONS: Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

Maternal Pragmatic Language Difficulties in the FMR1 Premutation and the Broad Autism Phenotype: Associations with Individual and Family Outcomes.

Broader phenotypes associated with genetic liability, including mild difficulties with pragmatic language skills, have been documented in mothers of children with autism spectrum disorder (ASD) and mothers of children with fragile X syndrome (FXS). This study investigated the relationship between pragmatic difficulties and indicators of maternal well-being and family functioning. Pragmatic difficulty was associated with loneliness in mothers of children with ASD or FXS, and with depression, decreased life satisfaction, and poorer family relationship quality in mothers of children with FXS only. Results inform subtle maternal pragmatic language difficulties as a risk factor that that may contribute to reduced health and well-being, informing tailored support services to better meet the unique needs of families of children with ASD or FXS.

Trajectories of Heart Activity Across Infancy to Early Childhood Differentially Predict Autism and Anxiety Symptoms in Fragile X Syndrome.

Background: Fragile X syndrome (FXS) is a monogenic disorder characterized by high rates of autism spectrum disorder (ASD) and anxiety. A longstanding "hyperarousal hypothesis" in FXS has argued that ANS dysfunction underpins many symptoms of FXS. However, the developmental onset and trajectory of ANS dysfunction, as well as the consequences of ANS dysfunction on later psychiatric symptoms, remain poorly understood in FXS. Insight into the emergence, trajectory, and consequences of ANS dysfunction across early development in FXS has critical implications for prevention, intervention, and optimal outcomes in both typical and atypical development. This longitudinal study investigated whether and when males with FXS evidence atypical ANS function from infancy through early childhood, and how trajectories of ANS function across infancy and early childhood predict ASD and anxiety symptom severity later in development. Methods: Participants included 73 males with FXS and 79 age-matched typically developing (TD) males. Baseline heart activity was recorded at multiple assessments between 3 and 83 months of age, resulting in 372 observations. General arousal and parasympathetic activity were indexed via interbeat interval (IBI) and respiratory sinus arrhythmia (RSA), respectively. ASD and anxiety symptoms were assessed at 36 months of age or later in a subgroup of participants (FXS n = 28; TD n = 25). Results: Males with FXS exhibited atypical patterns of developmental change in ANS function across infancy and early childhood. As a result, ANS dysfunction became progressively more discrepant across time, with the FXS group exhibiting significantly shorter IBI and lower RSA by 29 and 24 months of age, respectively. Shorter IBI at 24 months and a flatter IBI slope across development predicted elevated anxiety symptoms, but not ASD symptoms, later in childhood in both FXS and TD males. Reduced RSA at 24 months predicted elevated ASD symptoms, but not anxiety symptoms, in both groups. Developmental change in RSA across early development did not predict later anxiety or ASD symptoms. Conclusion: This is the first longitudinal study to examine the "hyperarousal hypothesis" in infants and young children with FXS. Findings suggest that hyperarousal (i.e., shorter IBI, lower RSA) is evident in males with FXS by 24-29 months of age. Interestingly, unique aspects of early ANS function differentially relate to later ASD and anxiety symptoms. General arousal, indexed by shorter IBI that becomes progressively more discrepant from TD controls, predicts later anxiety symptoms. In contrast, parasympathetic-related factors, indexed by lower levels of RSA, predict ASD symptoms. These findings support the "hyperarousal hypothesis" in FXS, in that ANS dysfunction evident early in development predicts later-emerging symptoms of ASD and anxiety. This study also have important implications for the development of targeted treatments and interventions that could potentially mitigate the long-term effects of hyperarousal in FXS.

The FMR1 Premutation Phenotype and Mother-Youth Synchrony in Fragile X Syndrome.

A subset of mothers who carry the FMR1 premutation may express a unique phenotype. The relationship between the FMR1 phenotype and mother-child interaction in families with fragile X-associated disorders has not been well characterized, despite the importance of high-quality mother-child interaction for child development. This study examined the association between the FMR1 phenotype and the quality of interactions between mothers and their adolescent/young adult sons with fragile X syndrome. Mother-youth synchrony was coded from a dyadic interaction. Maternal anxiety and depression symptoms, executive function deficits, and pragmatic language difficulties were evaluated. Results indicated that pragmatic language was associated with mother-youth synchrony. These findings highlight the importance of family-centered intervention practices for families with fragile X-associated disorders.

Concurrent Associations between Expressive Language Ability and Independence in Adolescents and Adults with Fragile X Syndrome.

BACKGROUND: Few individuals with fragile X syndrome (FXS) successfully meet adult normative expectations in education, employment, peer relations, and habitation, although there is within-syndrome variability in this regard. The primary goal of this study was to determine whether expressive language skills contribute to the capacity for independent functioning in adulthood even after controlling for nonverbal cognitive ability. METHODS: Participants were 18- to 23-year-olds with FXS. Expressive language was assessed using the psychometrically validated Expressive Language Sampling (ELS) conversation and narration procedures. The language produced was transcribed and analyzed to yield measures of expressive vocabulary, syntax, and intelligibility. Parents concurrently completed questionnaires on the independent functioning of the participants with FXS. RESULTS: All three ELS measures were significantly corelated with multiple measures of independence. The magnitudes of the correlations were reduced when nonverbal IQ was controlled through partial correlation. Nonetheless, many of the partial correlations were medium to large and several were statistically significant. CONCLUSIONS: Expressive language skills appear to contribute uniquely to the capacity for independence, although longitudinal data are needed to evaluate the possibility of a bidirectional relationship between these domains. Thus, language intervention may be a prerequisite for preparing youth with FXS for an independent adult life.

Family as a Context for Child Development: Mothers with the FMR1 Premutation and Their Children with Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic disorder caused by changes of the FMR1 gene that is passed along among families. A range of developmental processes may be impacted with wide variation in abilities across individuals with FXS. Mothers of children with FXS are often carriers of a "premutation" expansion on the FMR1 gene, which is associated with its own clinical phenotype. These maternal features may increase individual and family vulnerabilities, including increased risk for depression and anxiety disorders and difficulties in social and cognitive ability. These characteristics may worsen with age, and potentially interact with a child's challenging behaviors and with family dynamics. Thus, families of children with FXS may experience unique challenges related to genetic risk, manifested across both children and parents, that should be considered in therapeutic planning to optimize outcomes for children and their families. In this article, we review core features of the FMR1 premutation as expressed in mothers and aspects of the family environment that interface with developmental outcomes of children with FXS. Recommendations for family-centered support services are discussed.

Response Inhibition Deficits in Women with the FMR1 Premutation are Associated with Age and Fall Risk.

One in 113-178 females worldwide carry a premutation allele on the FMR1 gene. The FMR1 premutation is linked to neurocognitive and neuromotor impairments, although the phenotype is not fully understood, particularly with respect to age effects. This study sought to define oculomotor response inhibition skills in women with the FMR1 premutation and their association with age and fall risk. We employed an antisaccade eye-tracking paradigm to index oculomotor inhibition skills in 35 women with the FMR1 premutation and 28 control women. The FMR1 premutation group exhibited longer antisaccade latency and reduced accuracy relative to controls, indicating deficient response inhibition skills. Longer response latency was associated with older age in the FMR1 premutation and was also predictive of fall risk. Findings highlight the utility of the antisaccade paradigm for detecting early signs of age-related executive decline in the FMR1 premutation, which is related to fall risk. Findings support the need for clinical prevention efforts to decrease and delay the trajectory of age-related executive decline in women with the FMR1 premutation during midlife.

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.

A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome.

Fragile X syndrome (FXS) is characterized by hallmark features of gaze avoidance, reduced social approach, and social anxiety. The development of therapeutics to manage these symptoms has been hindered, in part, by the lack of sensitive outcome measures. This study investigated the utility of a novel eye-tracking paradigm for indexing social avoidance-related phenotypes. Adolescent/young adult-aged males with FXS (n = 24) and typical development (n = 23) participated in the study. Participants viewed faces displaying direct or averted gaze and the first fixation duration on the eyes was recorded as an index of initial stimulus registration. Fixation durations did not differ across the direction of gaze conditions in either group, although the control group showed longer initial fixations on the eyes relative to the FXS group. Shorter initial fixation on averted gaze in males with FXS was a robust predictor of the severity of their social avoidance behavior exhibited during a social greeting context, whereas parent-reported social avoidance symptoms were not related to performance in the semi-naturalistic context. This eye-tracking paradigm may represent a promising outcome measure for FXS clinical trials because it provides a quantitative index that closely maps onto core social avoidance phenotypes of FXS, can be completed in less than 20 min, and is suitable for use with individuals with low IQ.

Gesture Frequency and Function in Infants With Fragile X Syndrome and Infant Siblings of Children With Autism Spectrum Disorder.

Purpose Infant siblings of children with autism spectrum disorder (ASIBs) and infants with fragile X syndrome (FXS) are both at risk for developing autism spectrum disorder (ASD) and communication disorders; however, very few studies have examined 1 of the earliest forms of intentional communication in infants from these groups: gestures. This study examined the frequency and function of gesture use across 12-month-old infant ASIBs, infants with FXS, and low-risk controls. Method Participants included 23 ASIBs who did not later meet diagnostic criteria for ASD, 18 infants with FXS, and 21 low-risk controls. Gestures were coded from a semistructured play-based interaction. Results Overall, infants with FXS displayed fewer gestures than low-risk infants, whereas ASIBs did not differ from the FXS or low-risk groups in overall gesture frequency. In terms of the communicative function of the gestures used, the FXS and ASIB groups displayed significantly fewer social interaction gestures than the low-risk controls, with large effect sizes. Conclusion This study contributes to scant knowledge of early communication phenotypes of infant ASIBs who do not meet criteria for ASD and infants with FXS. Results indicated that gesture function, not frequency, best discriminated at-risk infants from low-risk infants at 12 months of age. Findings have implications for the clinical evaluation and treatment of infants at high risk for ASD and communication disorders.