1. Akins MR, Leblanc HF, Stackpole EE, Chyung E, Fallon JR. {{Systematic mapping of Fragile X granules in the developing mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions}}. {J Comp Neurol};2012 (Apr 23)
Loss of Fragile X mental retardation protein (FMRP) leads to Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism. Although the functions of FMRP and its homologues FXR1P and FXR2P are well studied in the somatodendritic domain, recent evidence suggests that this family of RNA binding proteins also plays a role in the axonal and presynaptic compartments. Fragile X granules (FXGs) are morphologically- and genetically-defined structures containing Fragile X proteins that are expressed axonally and presynaptically in a subset of circuits. To further understand the role of presynaptic Fragile X proteins in the brain we have systematically mapped the FXG distribution in the mouse central nervous system. This analysis revealed both the circuits and the neuronal types that express FXGs. FXGs are enriched in circuits that mediate sensory processing and motor planning – functions that are particularly perturbed in FXS patients. Analysis of FXG expression in the hippocampus suggests that CA3 pyramidal neurons utilize presynaptic Fragile X proteins to modulate recurrent but not feedforward processing. Neuron-specific FMRP mutants revealed a requirement for neuronal FMRP in the regulation of FXGs. Finally, conditional FMRP ablation demonstrated that FXGs are expressed in axons of thalamic relay nuclei that innervate cortex, but not in axons of thalamic reticular nuclei, striatal nuclei, or cortical neurons that innervate thalamus. Together, these findings support the proposal that dysregulation of axonal and presynaptic Fragile X proteins contribute to the neurological symptoms of FXS. J. Comp. Neurol., 2012. (c) 2012 Wiley-Liss, Inc.
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2. Carrasco M, Volkmar FR, Bloch MH. {{Pharmacologic Treatment of Repetitive Behaviors in Autism Spectrum Disorders: Evidence of Publication Bias}}. {Pediatrics};2012 (Apr 23)
OBJECTIVE:The goal of this study was to examine the efficacy of serotonin receptor inhibitors (SRIs) for the treatment of repetitive behaviors in autism spectrum disorders (ASD).METHODS:Two reviewers searched PubMed and Clinicaltrials.gov for randomized, double-blind, placebo-controlled trials evaluating the efficacy of SRIs for repetitive behaviors in ASD. Our primary outcome was mean improvement in ratings scales of repetitive behavior. Publication bias was assessed by using a funnel plot, the Egger’s test, and a meta-regression of sample size and effect size.RESULTS:Our search identified 5 published and 5 unpublished but completed trials eligible for meta-analysis. Meta-analysis of 5 published and 1 unpublished trial (which provided data) demonstrated a small but significant effect of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.22 [95% confidence interval: 0.07-0.37], z score = 2.87, P < .005). There was significant evidence of publication bias in all analyses. When Duval and Tweedie’s trim and fill method was used to adjust for the effect of publication bias, there was no longer a significant benefit of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.12 [95% confidence interval: -0.02 to 0.27]). Secondary analyses demonstrated no significant effect of type of medication, patient age, method of analysis, trial design, or trial duration on reported SRI efficacy.CONCLUSIONS:Meta-analysis of the published literature suggests a small but significant effect of SRI in the treatment of repetitive behaviors in ASD. This effect may be attributable to selective publication of trial results. Without timely, transparent, and complete disclosure of trial results, it remains difficult to determine the efficacy of available medications.
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3. Hamlin AA, Sukharev D, Campos L, Mu Y, Tassone F, Hessl D, Nguyen DV, Loesch D, Hagerman RJ. {{Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome (FXTAS)}}. {Am J Med Genet A};2012 (Apr 23)
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72-6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82-3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease. (c) 2012 Wiley Periodicals, Inc.
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4. Pecorelli A, Leoncini S, De Felice C, Signorini C, Cerrone C, Valacchi G, Ciccoli L, Hayek J. {{Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism}}. {Brain Dev};2012 (Apr 23)
A link between oxidative stress and autism spectrum disorders (ASDs) remains controversial with opposing views on its role in the pathogenesis of the disease. We investigated for the first time the levels of non-protein-bound iron (NPBI), a pro-oxidant factor, and 4-hydroxynonenal protein adducts (4-HNE PAs), as a marker of lipid peroxidation-induced protein damage, in classic autism. Patients with classic autism (n=20, mean age 12.0+/-6.2years) and healthy controls (n=18, mean age 11.7+/-6.5years) were examined. Intraerythrocyte and plasma NPBI were measured by high performance liquid chromatography (HPLC), and 4-HNE PAs in erythrocyte membranes and plasma were detected by Western blotting. The antioxidant defences were evaluated as erythrocyte glutathione (GSH) levels using a spectrophotometric assay. Intraerythrocyte and plasma NPBI levels were significantly increased (1.98- and 3.56-folds) in autistic patients, as compared to controls (p=0.0019 and p<0.0001, respectively); likewise, 4-HNE PAs were significantly higher in erythrocyte membranes and in plasma (1.58- and 1.6-folds, respectively) from autistic patients than controls (p=0.0043 and p=0.0001, respectively). Erythrocyte GSH was slightly decreased (-10.34%) in patients compared to controls (p=0.0215). Our findings indicate an impairment of the redox status in classic autism patients, with a consequent imbalance between oxidative stress and antioxidant defences. Increased levels of NPBI could contribute to lipid peroxidation and, consequently, to increased plasma and erythrocyte membranes 4-HNE PAs thus amplifying the oxidative damage, potentially contributing to the autistic phenotype.
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5. Robinson L, Guy J, McKay L, Brockett E, Spike RC, Selfridge J, De Sousa D, Merusi C, Riedel G, Bird A, Cobb SR. {{Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome}}. {Brain};2012 (Apr 23)
Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in approximately 70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.
