FMR1 premutation and full mutation molecular mechanisms related to autism

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has 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

Unplanned medication discontinuation as a potential pharmacovigilance signal : a nested young person cohort study

Because of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people. Using orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation. During the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1-2 compared to SIMD 9-10 OR 0.09 (95% CI0.01 - 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 - 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients. Identification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people