1. Pacey LK, Xuan IC, Guan S, Sussman D, Henkelman RM, Chen Y, Thomsen C, Hampson DR. {{Delayed myelination in a mouse model of fragile X syndrome}}. {Hum Mol Genet}. 2013 Jun 10.
Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRalpha+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.
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2. Pequegnat B, Sagermann M, Valliani M, Toh M, Chow H, Allen-Vercoe E, Monteiro MA. {{A vaccine and diagnostic target for Clostridium bolteae, an autism-associated bacterium}}. {Vaccine}. 2013 Jun 10;31(26):2787-90.
Constipation and diarrhea are common in autistic patients. Treatment with antibiotics against bacteria appears to partially alleviate autistic-related symptoms. Clostridium bolteae is a bacterium that has been shown to be overabundant in the intestinal tract of autistic children suffering from gastric intestinal ailments, and as such is an organism that could potentially aggravate gastrointestinal symptoms. We set out to investigate the cell-wall polysaccharides of C. bolteae in order to evaluate their structure and immunogenicity. Our explorations revealed that C. bolteae produces a conserved specific capsular polysaccharide comprised of rhamnose and mannose units: [–>3)-alpha-D-Manp-(1–>4)-beta-d-Rhap-(1–>], which is immunogenic in rabbits. These findings are the first description of a C. bolteae immunogen and indicate the prospect of using this polysaccharide as a vaccine to reduce or prevent C. bolteae colonization of the intestinal tract in autistic patients, and as a diagnostic marker for the rapid detection of C. bolteae in a clinical setting.
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3. Wang JY, Hessl D, Schneider A, Tassone F, Hagerman RJ, Rivera SM. {{Fragile X-Associated Tremor/Ataxia Syndrome: Influence of the FMR1 Gene on Motor Fiber Tracts in Males With Normal and Premutation Alleles}}. {JAMA neurology}. 2013 Jun 10:1-8.
IMPORTANCE Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS. OBJECTIVE To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles. DESIGN AND SETTING A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene. PARTICIPANTS Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community. MAIN OUTCOMES AND MEASURES The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum. RESULTS All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P </= .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r2 = 0.23-0.33, P </= .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41-0.56, P </= .04). CONCLUSIONS AND RELEVANCE Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.