Longitudinal changes in functional neural activation and sensitization during face processing in fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is a genetic condition associated with increased risk for social anxiety and avoidance. Using functional near-infrared spectroscopy (fNIRS), we previously demonstrated aberrant neural activity responding to faces in young girls with FXS cross-sectionally. Here, we tested the hypothesis that abnormalities in neural activation and sensitization would increase with age in 65 girls with FXS, ages 5-16 years, relative to an age-matched control group of 52 girls who had comparable cognitive function and clinical symptoms. METHODS: Functional NIRS data were collected at two time points, 2.8±0.6 years apart during a face-processing task. Linear mixed-effects models examined longitudinal neural profiles in girls with FXS and control. Correlational analysis was performed to examine associations between neural sensitization (increasing neural response to repeated stimuli), and clinical ratings. RESULTS: In girls with FXS, 32 participants had one, and 24 had two fNIRS scans. In controls, 21 had one, and 29 had two fNIRS scans. Brain activations in the right middle and superior frontal gyri were higher in FXS than controls at both time points. Neural sensitization also increased in FXS at a higher rate than controls in the superior frontal gyrus when responding to upright faces. For the FXS group, sensitization in the superior frontal gyrus positively correlated with longitudinal increases in anxiety and social avoidance scores. CONCLUSION: Girls with FXS show increasingly abnormal neural activation and sensitization responding to faces over time. Aberrant neural sensitization in girls with FXS is associated with longitudinal changes in anxiety and social skills.

Cognition, academic achievement, and adaptive behavior in school-aged girls with fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism in males and females. Females with FXS typically display a milder cognitive phenotype than males, despite experiencing significant developmental, behavioral, and social-emotional issues. AIMS: To measure and distinguish the cognitive-behavioral profile of girls with FXS relative to verbal IQ-matched peers. METHODS AND PROCEDURES: Ninety-seven participants (NFXS=55, Ncomparison=42) six to 16 years of age completed assessments evaluating cognition, academic achievement, and adaptive behavior. The comparison group consisted of age-, sex-, and verbal IQ-matched peers. OUTCOMES AND RESULTS: Consistent with previous studies, the FXS group demonstrated mean cognitive skills, academic achievement, and adaptive behavior in the borderline to low average range. On average, the FXS group showed poorer nonverbal reasoning, visual pattern recognition, verbal abstraction, math abilities, attention, inhibitory control, and working memory than the comparison group. There were no significant group differences in adaptive behavior. Different patterns of associations between cognition and selected outcomes emerged in each group. CONCLUSIONS AND IMPLICATIONS: Results highlight the importance of identifying specific cognitive-behavioral profiles in girls with FXS to inform more targeted interventions for optimizing outcomes and quality of life in this population.

Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach.

Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.

Association of Intrinsic Functional Brain Network and Longitudinal Development of Cognitive Behavioral Symptoms in Young Girls With Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Because males express a more severe phenotype than females, research has focused largely on identifying neural abnormalities in all-male or both-sex populations with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multidomain cognitive behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full-mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multidomain cognitive behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared with the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network, lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of the default mode network. These aberrant brain network characteristics map directly onto the cognitive behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (time 1) were predictive of the longitudinal development of participants' multidomain cognitive behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive behavioral symptoms in girls with FXS.

Aberrant Neural Response During Face Processing in Girls With Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies.

BACKGROUND: Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. METHODS: Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. RESULTS: Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety. CONCLUSIONS: These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition.

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.

Aberrant brain network and eye gaze patterns during natural social interaction predict multi-domain social-cognitive behaviors in girls with fragile X syndrome.

Girls with fragile X syndrome (FXS) often manifest significant symptoms of avoidance, anxiety, and arousal, particularly in the context of social interaction. However, little is currently known about the associations among neurobiological, biobehavioral such as eye gaze pattern, and social-cognitive dysfunction in real-world settings. In this study, we sought to characterize brain network properties and eye gaze patterns in girls with FXS during natural social interaction. Participants included 42 girls with FXS and 31 age- and verbal IQ-matched girls (control). Portable functional near-infrared spectroscopy (fNIRS) and an eye gaze tracker were used to investigate brain network alterations and eye gaze patterns associated with social-cognitive dysfunction in girls with FXS during a structured face-to-face conversation. Compared to controls, girls with FXS showed significantly increased inter-regional functional connectivity and greater excitability within the prefrontal cortex (PFC), frontal eye field (FEF) and superior temporal gyrus (STG) during the conversation. Girls with FXS showed significantly less eye contact with their conversational partner and more unregulated eye gaze behavior compared to the control group. We also demonstrated that a machine learning approach based on multimodal data, including brain network properties and eye gaze patterns, was predictive of multiple domains of social-cognitive behaviors in girls with FXS. Our findings expand current knowledge of neural mechanisms and eye gaze behaviors underlying naturalistic social interaction in girls with FXS. These results could be further evaluated and developed as intermediate phenotypic endpoints for treatment trial evaluation in girls with FXS.

Neuroanatomical Profile of Young Females with Fragile X Syndrome: A Voxel-Based Morphometry Analysis.

Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.

Empathy and Anxiety in Young Girls with Fragile X Syndrome.

We tested whether empathy is impaired and associated with anxiety in girls with fragile X syndrome (FXS). We measured parent-reported empathy and self-reported anxiety in young girls with FXS and in a developmentally-matched comparison group. Girls with FXS received higher parent-reported scores on cognitive and affective empathy but also self-reported more severe anxiety symptoms, particularly separation anxiety and phobia symptoms, than girls in the comparison group. Girls with FXS who received higher cognitive empathy scores, however, appeared buffered against risk for separation anxiety and phobia symptoms. Girls with FXS experience elevated empathy and anxiety relative to their developmentally-matched peers. Higher cognitive empathy in girls with FXS may indicate resilience against specific forms of anxiety that are commonly observed in FXS.

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.

Glucocorticoid regulation and neuroanatomy in fragile x syndrome.

Fragile X syndrome (FXS) is the leading known inherited cause for intellectual disability. Due to mutations in the FMR1 gene, affected individuals are at risk for serious cognitive and behavioral symptoms and developmental disability. Clinical presentation varies considerably, and investigation of genetic factors not directly related to FMR1 may help better understand variability. The present study examined the BclI polymorphism of the glucocorticoid receptor gene NR3C1 in 43 individuals with FXS (28 females, age 16 to 25). Females with FXS who presented with one or more G alleles demonstrated attenuated symptoms of anxiety/depression (p = 0.038) and externalizing behaviors (p = 0.042) relative to individuals with the C/C allele. In the combined sample (males and females) structural neuroimaging data differentiated individuals with a G allele from those with the C/C genotype (p < 0.001). Key components of anxiety/fear neurocircuitry (amygdala, insula) contributed more (relative to other regions) to the model differentiating groups. These results indicate that GR polymorphisms are associated with an altered pattern of behavioral and brain development in FXS. This information is important for understanding and treating mood disorders and altered brain development among individuals with FXS. With further research, these findings could be informative for understanding anxiety and mood disorders more broadly.

Brain circuitry, behavior, and cognition: A randomized placebo-controlled trial of donepezil in fragile X syndrome.

BACKGROUND: Fragile X syndrome, the most common inherited cause for intellectual disability, is associated with alterations in cholinergic among other neurotransmitter systems. This study investigated the effects of donepezil hydrochloride, a cholinesterase inhibitor that has potential to correct aberrant cholinergic signaling. METHOD: Forty-two individuals with fragile X syndrome (mean age=19.61 years) were randomized to receive 2.5-10.0 mg of donepezil (n=20, seven females) or placebo (n=22, eight females) per day. One individual in the active group withdrew at week 7. Outcomes included the contingency naming test, the aberrant behavior checklist, and behavior and brain activation patterns during a functional magnetic resonance imaging gaze discrimination task. RESULTS: There were no significant differences between active and placebo groups on cognitive (contingency naming task) or behavioral (total score or subscales of the aberrant behavior checklist) outcomes. At baseline, the active and placebo groups did not differ in functional magnetic resonance imaging activation patterns during the gaze task. After 12 weeks of treatment the active group displayed reduced activation in response to the averted vs direct gaze contrast, relative to the placebo group, in the left superior frontal gyrus. CONCLUSIONS: Reduced functional brain activation for the active group may represent less arousal in response to direct eye gaze, relative to the placebo group. Change in functional magnetic resonance imaging activation patterns may serve as a more sensitive metric and predictor of response to treatment when compared to cognitive and behavioral assessments. Our results suggest that donepezil may have an impact on brain functioning, but longer term follow-up and concomitant behavioral intervention may be required to demonstrate improvement in cognition and behavior.

Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings.

Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.

The Influence of Hyperactivity, Impulsivity, and Attention Problems on Social Functioning in Adolescents and Young Adults With Fragile X Syndrome.

OBJECTIVE: Individuals with fragile X syndrome (FXS) present primarily with cognitive and social deficits in addition to symptoms of ADHD. The relationship between symptoms of ADHD, cognitive functioning, and social skills has never been explicitly studied. METHOD: Here, we analyzed both longitudinal ( n = 70; Time 1: ages 6-18; Time 2: ages 15-26) and cross-sectional ( n = 73; Time 2 only) data using hierarchical linear regression to assess how global intellectual functioning (IQ) and symptoms of ADHD influence social functioning in individuals with FXS. RESULTS: We found that ADHD symptoms at Times 1 and 2 consistently predict social functioning in both males and females with FXS at Time 2. CONCLUSION: Our results suggest that addressing ADHD symptoms in childhood may have positive, long-term effects on the social functioning of adolescents and young adults with FXS.

Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years.

Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex-matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function.

Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome.

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences (P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders.

The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence.

Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.

Quantifying naturalistic social gaze in fragile X syndrome using a novel eye tracking paradigm.

A hallmark behavioral feature of fragile X syndrome (FXS) is the propensity for individuals with the syndrome to exhibit significant impairments in social gaze during interactions with others. However, previous studies employing eye tracking methodology to investigate this phenomenon have been limited to presenting static photographs or videos of social interactions rather than employing a real-life social partner. To improve upon previous studies, we used a customized eye tracking configuration to quantify the social gaze of 51 individuals with FXS and 19 controls, aged 14-28 years, while they engaged in a naturalistic face-to-face social interaction with a female experimenter. Importantly, our control group was matched to the FXS group on age, developmental functioning, and degree of autistic symptomatology. Results showed that participants with FXS spent significantly less time looking at the face and had shorter episodes (and longer inter-episodes) of social gaze than controls. Regression analyses indicated that communication ability predicted higher levels of social gaze in individuals with FXS, but not in controls. Conversely, degree of autistic symptoms predicted lower levels of social gaze in controls, but not in individuals with FXS. Taken together, these data indicate that naturalistic social gaze in FXS can be measured objectively using existing eye tracking technology during face-to-face social interactions. Given that impairments in social gaze were specific to FXS, this paradigm could be employed as an objective and ecologically valid outcome measure in ongoing Phase II/Phase III clinical trials of FXS-specific interventions.

Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure.

BACKGROUND: Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals. AIMS: To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability. METHOD: We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30). RESULTS: Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. CONCLUSIONS: The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

The relationship between autistic symptomatology and independent living skills in adolescents and young adults with fragile X syndrome.

Few studies have examined the relationship between autistic symptomatology and competence in independent living skills in adolescents and young adults with fragile X syndrome (FXS). In this study, 70 individuals with FXS, aged 15-25 years, and 35 matched controls were administered direct measures of independent living skills and autistic symptomatology. Results showed that higher levels of autistic symptomatology were associated with lower levels of competence in independent living skills in individuals with FXS, but not in controls. These data indicated that the relationship between autistic symptomatology and independent living skills was syndrome-specific. Early intervention strategies that address autistic symptomatology are sorely needed to improve functional outcomes in this population.