Longitudinal Profiles of Adaptive Behavior in Fragile X Syndrome

Klaiman, Cheryl; Quintin, Eve Marie; Jo, Booil; Lightbody, Amy A.; Hazlett, Heather C.; Piven, Joseph; Hall, Scott S.; Reiss, Allan L.

doi:10.1542/peds.2013-3990

Cited by 78 publications

(99 citation statements)

References 27 publications

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“…Standard scores on the Vineland Adaptive Behavior Scale for overall adaptive behavior as well as subdomains have also been shown to decline with age during childhood, in males more so than in females with FXS [14]. Decline in standard scores for intelligence and adaptive function is not the results of loss of skills or regression but rather failure to keep pace with the normal rate of intellectual development.…”

Section: Cognitive Behavioral and Language Features Of Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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Section: Cognitive Behavioral and Language Features Of Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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“…While full analyses are pending, preliminary findings showed that many areas of positive response have not been well captured by the primarily parent-based outcome measures; thus, we are seeing only part of response. Arbaclofen 1 year (Vineland) data that showed change in the FXS disease trajectory in terms of participant adaptive skill has much relevance given that longitudinal have shown that the acquisition of adaptive skills slows, especially in male, as individuals with fragile X syndrome age [108].…”

Section: Discussionmentioning

confidence: 99%

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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“…It is hoped that future research efforts will evaluate these intensive early intervention strategies in children with FXS, perhaps in combination with pharmacological approaches. A recent large-scale longitudinal study of adaptive behavior profiles shown by individuals with FXS over childhood to adulthood indicated that the most meaningful improvements in daily living skills occurred after 14 years of age (Klaiman et al, 2014). These data indicate that the developmental period from childhood to early adolescence is critical and that intervention strategies that address autistic symptomatology (and underlying symptoms of social anxiety) in FXS during this period are sorely needed.…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Autistic Symptomatology and Independent Living Skills in Adolescents and Young Adults with Fragile X Syndrome

Hustyi

Hall

Quintin

et al. 2014

J Autism Dev Disord

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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 to 25 years, and 35 age- and IQ-matched controls were administered the Independent Living Scales (Loeb, 1996) and the Autism Diagnostic Observation Schedule (Lord et al., 2000). 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.

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Longitudinal Profiles of Adaptive Behavior in Fragile X Syndrome

Cited by 78 publications

References 27 publications

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

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

The Relationship Between Autistic Symptomatology and Independent Living Skills in Adolescents and Young Adults with Fragile X Syndrome

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