Emerging pharmacological therapies in fragile X syndrome and autism

Purpose of review Research on the pathophysiology of syndromic autism spectrum disorder (ASD) has contributed to the uncovering of mechanisms in nonsyndromic ASD. The current review aims to compare recent progress in therapeutics development for ASD with those for fragile X syndrome (FXS), the most frequent monogenic form of ASD. Recent findings Although candidates such as oxytocin, vasopressin, and cannabinoids are being tested as novel therapeutics, it remains difficult to focus on a specific molecular target of drug development for ASD core symptoms. As the pathophysiology of FXS has been well described as having a causal gene, fragile X mental retardation-1, development of therapeutic agents for FXS is focused on specific molecular targets, such as metabotropic glutamate receptor 5 and GABAB receptor. Summary There is a large unmet medical need in ASD, a heterogeneous and clinically defined behavioral syndrome, owing to its high prevalence in the general population, lifelong cognitive and behavioral deficits, and no established treatment of ASD core symptoms, such as deficits in social communication and restrictive repetitive behaviors. The molecular pathogenesis of nonsyndromic ASD is largely undefined. Lessons from initial attempts at targeted treatment development in FXS, and new designs resulting from these lessons, will inform trials in nonsyndromic ASD for development of therapeutics for its core symptoms.
Source: Current Opinion in Neurology - Category: Neurology Tags: DEVELOPMENTAL DISORDERS: Edited by Doris A. Trauner Source Type: research

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ConclusionBased on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability.
Source: Molecular Autism - Category: Molecular Biology Source Type: research
Mass Spectrometry for the Study of Autism and Neurodevelopmental Disorders. Adv Exp Med Biol. 2019;1140:477-499 Authors: Wormwood KL, Ngounou Wetie AG, Ryan JP, Darie CC, Woods AG Abstract Mass spectrometry (MS) has been increasingly used to study central nervous system (CNS) disorders, including autism spectrum disorders (ASDs). The first studies of ASD using MS focused on the identification of external toxins, but current research is more directed at understanding endogenous protein changes that occur in ASD (ASD proteomics). This chapter focuses on how MS has been used to study ASDs, with parti...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Abstract We carried out a psychometric assessment of the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS-2) in fragile X syndrome (FXS), relative to clinician DSM5-based diagnosis of autism spectrum disorder (ASD) in FXS. This was followed by instrument revisions that included: removal of non-discriminating and/or low face validity items for FXS; use of receiver operating characteristic (ROC) curves to determine optimal cut points for the original and revised measures; an exploratory factor analysis to outline subscales better representing ASD in FXS; and creation of a "tripl...
Source: Journal of Autism and Developmental Disorders - Category: Psychiatry Authors: Tags: J Autism Dev Disord Source Type: research
Abstract Fragile X syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together ...
Source: Neurobiology of Learning and Memory - Category: Neurology Authors: Tags: Neurobiol Learn Mem Source Type: research
Publication date: Available online 2 July 2019Source: Pharmacological ResearchAuthor(s): Maria Rosaria Domenici, Antonella Ferrante, Alberto Martire, Valentina Chiodi, Rita Pepponi, Maria Teresa Tebano, Patrizia PopoliAbstractAdenosine A2A receptor (A2AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the A2AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of A2ARs...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
Abstract Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. The Fmr1 knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult male Fmr1 KO mice produce fewer ultrasonic vocalizations (USVs) during mating, suggestive of abnormal social communication. Minocycline treatment for 2 months from birth alleviates a number of FXS phenotypes in mice, including USV call rate deficits. In the current study, we investigated if treatment initiated past the early developmental period would be effective, given that in many cases, individuals with FXS are treated during l...
Source: Behavioural Brain Research - Category: Neurology Authors: Tags: Behav Brain Res Source Type: research
Publication date: Available online 28 June 2019Source: Stem Cell ResearchAuthor(s): Subhajit Giri, Meera Purushottam, Biju Viswanath, Ravi S. MuddashettyAbstractMutations in FMR1 gene is the cause of Fragile X Syndrome (FXS) leading inherited cause of intellectual disability and autism spectrum disorders. FMR1 gene encodes Fragile X Mental Retardation Protein (FMRP) which is a RNA binding protein and play important role in synaptic plasticity and translational regulation in neurons. We have generated a homozygous FMR1 knockout (FMR1-KO) hESC line using CRISPR/Cas9 based genome editing. It created a homozygous 280 nucleotid...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
Conclusion This study contributes to scant knowledge of early communication phenotypes of infant ASIBs who do not meet criteria for ASD and infants with FXS. Results indicated that gesture function, not frequency, best discriminated at-risk infants from low-risk infants at 12 months of age. Findings have implications for the clinical evaluation and treatment of infants at high risk for ASD and communication disorders. PMID: 31251678 [PubMed - as supplied by publisher]
Source: Journal of speech, language, and hearing research : JSLHR - Category: Speech-Language Pathology Authors: Tags: J Speech Lang Hear Res Source Type: research
Abstract Estimates of the prevalence of speech and motor speech disorders in persons with complex neurodevelopmental disorders (CND) can inform research in the biobehavioural origins and treatment of CND. The goal of this research was to use measures and analytics in a diagnostic classification system to estimate the prevalence of speech and motor speech disorders in convenience samples of speakers with one of eight types of CND. Audio-recorded conversational speech samples from 346 participants with one of eight types of CND were obtained from a database of participants recruited for genetic and behavioural studi...
Source: Clinical Linguistics and Phonetics - Category: Speech-Language Pathology Authors: Tags: Clin Linguist Phon Source Type: research
Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: Biological Sciences Source Type: research
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