What Can We Learn about Autism from Studying Fragile X Syndrome?

Budimirović, Dejan B.; Kaufmann, Walter E.

doi:10.1159/000330213

Cited by 162 publications

(144 citation statements)

References 305 publications

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“…On the other hand, concurrent Autism Spectrum Disorder occurs in 15-60% of Fra X cases and because of such high prevalence, screening for FMR1 mutation is highly recommended in autistic children. Interestingly, psychosis and catatonia have been reported in permutation carriers where multiple genetic and environmental hits resulted in intensified involvement and significant clinical expression [21,23,24].…”

Section: Journal Of Child and Adolescent Behaviormentioning

confidence: 99%

Genotype-Phenotype Correlates in Fragile X Syndrome

Zaky¹

2018

J Child Adolesc Behav

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Fragile X syndrome is a genetic disorder that affects both males and females but males are more severely affected than females. It is characterized by intellectual and learning disabilities, behavioral and or psychiatric comorbidities, mildly dysplastic connective tissue, and large testes. Fragile X cases have more than 200 repeats of the trinucleotide CGG at a fragile locus of the X chromosome (Xq27.3) which affords the basis of the molecular diagnosis of the syndrome. Although there is no current curative treatment of Fragile X syndrome, there are many available therapeutic modalities that can be used to control its manifestations and improve the quality of life of its sufferers. Lastly but by no means least, it is well documented that the earlier the diagnosis and implementation of early intervention and individualized rehabilitation programs, the better the prognosis.

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Section: Journal Of Child and Adolescent Behaviormentioning

confidence: 99%

Genotype-Phenotype Correlates in Fragile X Syndrome

Zaky¹

2018

J Child Adolesc Behav

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“…In some studies, the severity of sleep problem was reported in children with autism and these children have a higher prevalence of sleep disorder than typically developing children [50][51][52]. And ASD with sleep problems have commonly showed the overactive and stereotypic behavior.…”

Section: Sleep Problems In Individuals With Autistic Fxsmentioning

confidence: 99%

Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

Won

Jin

Lee

et al. 2017

Preprint

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Fragile X syndrome (FXS) is the most frequent monogenic form of autism spectrum disorder (ASD). Autistic FXS is caused by loss of the fmr1 gene product, the fragile X mental retardation protein (FMRP), triggering physiological and behavioral abnormalities. It is correlated with clock components for behavioral circadian rhythm. Mutation of this gene causes the disturbances in sleep patterns and circadian behavior commonly observed in patients with autistic FXS, accompanied by frequent dysregulation of melatonin synthesis and melatonin-dependent signaling. These changes impair vigilance, learning and memory, and are also linked to autistic behavior including the abnormal anxiety response. However, although several possible causes, symptoms, and clinical features of ASD have been investigated, the correlation between an altered circadian rhythm and autistic FXS has not been extensively studied. Recent works have highlighted the impact of melatonin on the nervous, immune, and metabolic systems. Even though utilization of melatonin for sleep disorder in ASD has been considered in clinical research, further studies should be aimed at its neuroprotective role in ASD during developmental period. In this review, we focus on the regulatory circuits involved in melatonin dysregulation and circadian system disruption in those with autistic FXS. Additionally, we discuss the neuroprotective effect of melatonin intervention. This may improve neuroplasticity and physical capability. We also review the underlying molecular mechanisms, and suggest that melatonin may be a useful novel treatment for autistic FXS, countering the adverse effects of circadian variation.

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“…Hence, neurobehavioral features of FXS consist of a wide range of variable cognitive and language impairments as well as associated neurobehavioral problems (i.e., attention difficulties, hyperactivity, anxiety, and autistic features) [14,10]. Together, they constitute the major medical and educational concerns for patients with FXS.…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

“…Therefore, FXS is often "detected" after atypical behaviors and delays in skill acquisition begin to emerge [23,24]. As noted above, recent advances in understanding of the mutations of the FMR1 gene have enabled not only a model for neurodegeneration, but also more widely recognized the model for ASD [10,25].…”

Section: Neurobehavioral Features In Fxsmentioning

confidence: 99%

“…To expand on the aforementioned, on one hand, the FM leads to epigenetic (hypermethylation) silencing ("shut down") of the FMR1 gene ( Fig. 1), which results in the loss of its encoded protein (no FMRP) and clinically manifest as the most common cause of inherited form of intellectual disability (ID), and the leading known monogenetic cause of autism spectrum disorder (ASD) [10]. On the other hand, individuals with the PM present with a spectrum of unfolding genetic and clinical phenotypes [11], the best defined are early menopause due to ovarian failure (FX-POI) [7] (Sherman et al, 2014), and intention tremor, cerebellar ataxia, neuropathy and cognitive decline (FX-TAS) [8].…”

Section: Introductionmentioning

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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What Can We Learn about Autism from Studying Fragile X Syndrome?

Cited by 162 publications

References 305 publications

Genotype-Phenotype Correlates in Fragile X Syndrome

Genotype-Phenotype Correlates in Fragile X Syndrome

Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

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

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