Fragile X: leading the way for targeted treatments in autism - PubMed (original) (raw)

Review

Fragile X: leading the way for targeted treatments in autism

Lulu W Wang et al. Neurotherapeutics. 2010 Jul.

Abstract

Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.

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References

1. Hagerman RJ, Rivera SM, Hagerman PJ. The fragile X family of disorders: a model for autism and targeted treatments. Curr Pediatr Rev. 2008;4:40–52. doi: 10.2174/157339608783565770. - DOI
1. Reddy KS. Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder. BMC Med Genet. 2005;6:3–3. doi: 10.1186/1471-2350-6-3. - DOI - PMC - PubMed
1. van Karnebeek CD. Jansweijer MC, Leenders AG, Offringa M, Hennekam RC. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet. 2005;13:6–25. doi: 10.1038/sj.ejhg.5201279. - DOI - PubMed
1. Femandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn. 2009;11:324–329. doi: 10.2353/jmoldx.2009.080173. - DOI - PMC - PubMed
1. Hagerman PJ. The fragile X prevalence paradox [Erratum in: J Med Genet 2008;45:768] J Med Genet. 2008;45:498–499. doi: 10.1136/jmg.2008.059055. - DOI - PMC - PubMed

Fragile X: leading the way for targeted treatments in autism - PubMed (original) (raw)