Fragile X and autism : intertwined at the molecular level leading to targeted treatments
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5’ un-translated 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 a number of 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 the 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 post-natal neuronal cell toxicity, manifest 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 metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABAA 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
ForlagUniversitetet i Tromsø
University of Tromsø
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