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Neuroanatomical differences in toddler boys with fragile x syndrome and idiopathic autism.

ABSTRACT: Autism is an etiologically heterogeneous neurodevelopmental disorder for which there is no known unifying etiology or pathogenesis. Many conditions of atypical development can lead to autism, including fragile X syndrome (FXS), which is presently the most common known single-gene cause of autism.To examine whole-brain morphometric patterns that discriminate young boys with FXS from those with idiopathic autism (iAUT) as well as control participants.Cross-sectional, in vivo neuroimaging study.Academic medical centers.Young boys (n = 165; aged 1.57-4.15 years) diagnosed as having FXS or iAUT as well as typically developing and idiopathic developmentally delayed controls.Univariate voxel-based morphometric analyses, voxel-based morphometric multivariate pattern classification (linear support vector machine), and clustering analyses (self-organizing map).We found that frontal and temporal gray and white matter regions often implicated in social cognition, including the medial prefrontal cortex, orbitofrontal cortex, superior temporal region, temporal pole, amygdala, insula, and dorsal cingulum, were aberrant in FXS and iAUT as compared with controls. However, these differences were in opposite directions for FXS and iAUT relative to controls; in general, greater volume was seen in iAUT compared with controls, who in turn had greater volume than FXS. Multivariate analysis showed that the overall pattern of brain structure in iAUT generally resembled that of the controls more than FXS, both with and without AUT.Our findings demonstrate that FXS and iAUT are associated with distinct neuroanatomical patterns, further underscoring the neurobiological heterogeneity of iAUT.

SUBMITTER: Hoeft F

PROVIDER: S-EPMC4369209 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Neuroanatomical differences in toddler boys with fragile x syndrome and idiopathic autism.

Hoeft Fumiko F Walter Elizabeth E Lightbody Amy A AA Hazlett Heather C HC Chang Catie C Piven Joseph J Reiss Allan L AL

Archives of general psychiatry 20101101 3

<h4>Context</h4>Autism is an etiologically heterogeneous neurodevelopmental disorder for which there is no known unifying etiology or pathogenesis. Many conditions of atypical development can lead to autism, including fragile X syndrome (FXS), which is presently the most common known single-gene cause of autism.<h4>Objective</h4>To examine whole-brain morphometric patterns that discriminate young boys with FXS from those with idiopathic autism (iAUT) as well as control participants.<h4>Design</h ...[more]

PMID: 21041609

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Project description:BackgroundAutism is a behavioral disorder with impaired social interaction, communication, and repetitive and stereotypic behaviors. About 5-10 % of individuals with autism have 'secondary' autism in which an environmental agent, chromosome abnormality, or single gene disorder can be identified. Ninety percent have idiopathic autism and a major gene has not yet been identified. We have assessed the incidence of chromosome abnormalities and Fragile X syndrome in a population of autistic patients referred to our laboratory.MethodsData was analyzed from 433 patients with autistic traits tested using chromosome analysis and/or fluorescence in situ hybridization (FISH) and/or molecular testing for fragile X syndrome by Southern and PCR methods.ResultsThe median age was 4 years. Sex ratio was 4.5 males to 1 female [354:79]. A chromosome (cs) abnormality was found in 14/421 [3.33 %] cases. The aberrations were: 4/14 [28%] supernumerary markers; 4/14 [28%] deletions; 1/14 [7%] duplication; 3/14 [21%] inversions; 2/14 [14%] translocations. FISH was performed on 23 cases for reasons other than to characterize a previously identified cytogenetic abnormality. All 23 cases were negative. Fragile-X testing by Southern blots and PCR analysis found 7/316 [2.2 %] with an abnormal result. The mutations detected were: a full mutation (fM) and abnormal methylation in 3 [43 %], mosaic mutations with partial methylation of variable clinical significance in 3 [43%] and a permutation carrier [14%]. The frequency of chromosome and fragile-X abnormalities appears to be within the range in reported surveys (cs 4.8-1.7%, FRAX 2-4%). Limitations of our retrospective study include paucity of behavioral diagnostic information, and a specific clinical criterion for testing.ConclusionsTwenty-eight percent of chromosome abnormalities detected in our study were subtle; therefore a high resolution cytogenetic study with a scrutiny of 15q11.2q13, 2q37 and Xp23.3 region should be standard practice when the indication is autism. The higher incidence of mosaic fragile-X mutations with partial methylation compared to FRAXA positive population [50% vs 15-40%] suggests that faint bands and variations in the Southern band pattern may occur in autistic patients.

Project description:BackgroundIndividuals with autism spectrum disorder (ASD) are characterized by social communication challenges and repetitive behaviors that may be quickly detected by experts (Autism Res 10:653-62, 2017; American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013). Recent research suggests that even naïve non-experts judge a variety of human dimensions using narrow windows of experience called "first impressions." Growing recognition of sex differences in a variety of observable behaviors in ASD, combined with research showing that some autistic girls and women may "camouflage" outward symptoms, suggests it may be more difficult for naïve conversation partners to detect ASD symptoms in girls. Here, we explore the first impressions made by boys and girls with ASD and typically developing (TD) peers.MethodsNinety-three school-aged children with ASD or TD were matched on IQ; autistic girls and boys were additionally matched on autism symptom severity using the ADOS-2. Participants completed a 5-minute "get-to-know-you" conversation with a new young adult acquaintance. Immediately after the conversation, confederates rated participants on a variety of dimensions. Our primary analysis compared conversation ratings between groups (ASD boys, ASD girls, TD boys, TD girls).ResultsAutistic girls were rated more positively than autistic boys by novel conversation partners (better perceived social communication ability), despite comparable autism symptom severity as rated by expert clinicians (equivalent true social communication ability). Boys with ASD were rated more negatively than typical boys and typical girls by novel conversation partners as well as expert clinicians. There was no significant difference in the first impressions made by autistic girls compared to typical girls during conversations with a novel conversation partner, but autistic girls were rated lower than typical girls by expert clinicians.LimitationsThis study cannot speak to the ways in which first impressions may differ for younger children, adults, or individuals who are not verbally fluent; in addition, there were more autistic boys than girls in our sample, making it difficult to detect small effects.ConclusionsFirst impressions made during naturalistic conversations with non-expert conversation partners could-in combination with clinical ratings and parent report-shed light on the nature and effects of behavioral differences between girls and boys on the autism spectrum.

Project description:BackgroundThe lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder.MethodsResting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n = 11) and compared with both age-matched (n = 12) and cognitive-matched (n = 12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate.ResultsFXS participants showed increased power in the beta/gamma range (~ 25-50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors.LimitationsThe study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied.ConclusionsResting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms.

Project description:BackgroundChildren with fragile X syndrome (FXS) are at increased risk for exhibiting problem behaviors such as aggression and self-injury. However, many children with FXS have limited access to behavioral treatments that have known efficacy due to the low availability of treatment providers and the wide geographical dispersion of families with FXS across the country. Telehealth may offer a cost-effective and practical solution to overcome these significant barriers. We examined the effect of administering an established behavior analytic intervention called functional communication training (FCT) via telehealth on levels of problem behaviors exhibited by boys with FXS. We also examined treatment acceptability, as well as the effect of the treatment on levels of parenting stress.MethodsBoys with FXS, aged 3 to 10 years, who displayed problem behaviors daily, were randomized to receive FCT via telehealth (n = 30) or treatment as usual (n = 27) over 12 weeks. Outcome measures included in-session observations of problem behavior, the Aberrant Behavior Checklist-Community (ABC-C), the Treatment Acceptability Rating Form-Revised (TARF-R), and the Parenting Stress Index, 4th edition (PSI-4).ResultsIntention-to-treat analyses indicated that scores on the irritability subscale of the ABC-C, our primary outcome measure, decreased significantly for boys who received FCT via telehealth compared to boys who received treatment as usual (p < .001, Cohen's d = 0.65). In-session observations conducted for those who received treatment showed that levels of problem behavior decreased by 91% from baseline. Levels of parenting stress related to child behavioral problems were also lower following FCT treatment, and caregivers reported that the intervention was acceptable.ConclusionsThese findings support telehealth-enabled FCT as a framework for expanding access to behavioral treatments for problem behaviors in children with FXS. Expanded delivery of behavior analytic treatment via telehealth also has the potential to lower healthcare costs, improve child and family quality of life, and lead to advances in the treatment of problem behavior in the broader population of individuals with neurodevelopmental disorders.Trial registrationClinicalTrials.gov, NCT03510156 . Registered 27 April 2018.

Dataset Information

Neuroanatomical differences in toddler boys with fragile x syndrome and idiopathic autism.

Publications

Neuroanatomical differences in toddler boys with fragile x syndrome and idiopathic autism.

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