Autism spectrum disorder in Fragile X syndrome: Differential contribution of adaptive socialization and social withdrawal

Budimirović, Dejan B.; Bukelis, Irena; Cox, Christiane; Gray, Robert M.; Tierney, Elaine; Kaufmann, Walter E.

doi:10.1002/ajmg.a.31405

Cited by 96 publications

(139 citation statements)

References 48 publications

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“…Published descriptive studies of severity of SW set of behaviors as a unifying factor of ASD [31,33] and/or anxiety [32], emerging investigation of the biological basis of FXS through imaging-behavioral [29], molecular-behavioral using next generation fragile X PCR that also allows fragile X testing to be simple and more efficient [35] are examples of such helpful models. In parallel, an effort at identifying potential molecular mediators of dentritic overgrowth in FXS as new potential targets (sAPP and BDNF) of treatment [70] are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical complexity in FXS manifests with a wide array of impairments in skills in individuals with FXS (i.e., ID-features of syndromic ASD, such as deficits in social interaction and communication (e.g., eye contact, peer relationships, social withdrawal-SW) [10], and restricted and repetitive behaviors [10,14]. There is also evidence of existence of neurobehavioral subgroups in FXS based on whether individuals meet criteria for ASD [29,30], including subgroups based on severity of SW set of behaviors as a unifying factor of ASD and anxiety [31]. Indeed, the FMR1 FM (FXS) confers an especially high risk for anxiety disorders compared to general ID [32,33] (Fig.…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

“…Budimirovic and colleagues (2006) has shown that deficits in adaptive socialization is the only significant predictor of ASD in FXS and that delay in the adaptive socialization skills and degrees of SW the two primary determinants of the severity of ASD diagnosis in boys with FXS [31,33]. The most severe ASD phenotype is linked to both impaired adaptive socialization and prominent SW [31,33].…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

“…The most severe ASD phenotype is linked to both impaired adaptive socialization and prominent SW [31,33].…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

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Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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Section: Discussionmentioning

confidence: 99%

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

“…The most severe ASD phenotype is linked to both impaired adaptive socialization and prominent SW [31,33].…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

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Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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“…Approximately 30% of individuals with FXS are within the autistic spectrum with a frequency of 7-8% FXS in populations with autism [9]. Several studies have concentrated on the differentiation between boys with both FXS and autism, and those with idiopathic autism [10,11]. The results suggest similar, although milder profiles on several measures of autistic behavior in the FXS and autism group.…”

Section: Non Genetic and Genetic Conditions Associated With Autismmentioning

confidence: 96%

Genetic and Non Genetic Aspects of Autism Spectrum Disorders

Avdjieva-Tzavella¹

2008

Balkan Journal of Medical Genetics

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Chromosome abnormalities have long been recognized as an important cause of learning disabilities and multiple malformation syndromes. About 0.8% of live born infants have numerical or structural chromosomal anomalies that result in an abnormal phenotype. Identification of such anomalies is important clinically and also for accurate genetic counseling. Recently, molecular cytogenetic and array-based techniques have enabled higher resolution screens for chromosome anomalies. This brief review of the etiology of autism spectrum disorders (ASD) focuses on the heritable and non heritable risk factors that underlie this major neuro-developmental disorder. Since all patients with a chromosomal imbalance are dysmorphic, the association of ASD with a facial dysmorphism seems to be a good indication for chromosomal anomaly screening.

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Autism spectrum disorder in fragile X syndrome: A longitudinal evaluation

Hernandez

Feinberg

Vaurio

et al. 2009

American J of Med Genetics Pt A

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163

153

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The present study extends our previous work on characterizing the autistic behavior profile of boys with fragile X syndrome (FXS) who meet Diagnostic and Statistical Manual for Mental Disorders, 4 th Edition criteria for autism spectrum disorder (ASD) into a longitudinal evaluation of ASD in FXS (FXS+ASD). Specifically, we aimed to determine the stability of the diagnosis and profile of ASD in FXS over time. Through regression models, we also evaluated which autistic and social behaviors and skills were correlates of diagnosis and autistic behavior severity (i.e., Autism Diagnostic Interview-Revised total scores). Finally, we assessed the evolution of cognitive parameters in FXS+ASD. A population of 56 boys (30-88 months at baseline) with FXS was evaluated using measures of autistic, social, and cognitive behaviors and skills at three yearly evaluations. We found that the diagnosis of ASD in FXS was relatively stable over time. Further emphasizing this stability, we found a set of behaviors and skills, particularly those related to peer relationships and adaptive socialization, that differentiated FXS+ASD from the rest of the FXS cohort (FXS+None) and contributed to autistic severity at all time points. Nevertheless, the general improvement in autistic behavior observed in FXS+ASD coupled with the concurrent worsening in FXS+None resulted in less differentiation between the groups over time. Surprisingly, FXS+ASD IQ scores were stable while FXS+None non-verbal IQ scores declined. Our findings indicate that ASD is a distinctive subphenotype in FXS characterized by deficits in complex social interaction, with similarities to ASD in the general population.

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Autism spectrum disorder in Fragile X syndrome: Differential contribution of adaptive socialization and social withdrawal

Cited by 96 publications

References 48 publications

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Genetic and Non Genetic Aspects of Autism Spectrum Disorders

Autism spectrum disorder in fragile X syndrome: A longitudinal evaluation

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