Abstract
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.
Highlights
Fragile X syndrome (FXS) is an important subtype of autism, both because of its frequency and because knowledge of the molecular mechanisms involved in its pathogenesis has facilitated the development of targeted treatments with the potential to reverse or dramatically improve both behavioral and cognitive deficits
Because of concern about the genetic factors that underlie both autoimmune disease and autism, we studied whether there is an increase in autism spectrum disorder (ASD) with FXS in the children of female carriers who have autoimmune disease, compared with carriers who do not have autoimmune disease [128]
FX syndrome and autism are intertwined, because FMR1 protein (FMRP) regulates the translation of many messages that affect synaptic plasticity and connectivity in the central nervous system
Summary
Fragile X syndrome (FXS) is an important subtype of autism, both because of its frequency and because knowledge of the molecular mechanisms involved in its pathogenesis has facilitated the development of targeted treatments with the potential to reverse or dramatically improve both behavioral and cognitive deficits. FXTAS was originally described as a late adult-onset neurodegenerative disorder; there is an emerging view that FXTAS, and probably FXPOI, is the end stage of a process that begins in early development, and that may be responsible for the emotional and behavioral problems, cognitive impairment, ASD and seizure activity experienced by children who are carriers of premutation alleles [21,25,87]. This view is based on a combination of animal and cell-based studies for early abnormalities resulting from expression of a premutation allele. Because of the shared neurobiological and molecular pathways, these interventions will hopefully prove helpful in a subset of patients with idiopathic autism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
