1. Babbs C, Lloyd D, Pagnamenta AT, Twigg SR, Green J, McGowan SJ, Mirza G, Naples R, Sharma VP, Volpi EV, Buckle VJ, Wall SA, Knight SJ, Parr JR, Wilkie AO. {{De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder}}. {J Med Genet};2014 (Sep 16)
BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of approximately 70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.
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2. Biancalana V, Glaeser D, McQuaid S, Steinbach P. {{EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders}}. {Eur J Hum Genet};2014 (Sep 17)
Different mutations occurring in the unstable CGG repeat in 5′ untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over approximately 200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation’ and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation’ is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation’ occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation’ is characterized by the presence of 55 to approximately 200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.185.
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3. Chi RP, Snyder AW. {{Treating autism by targeting the temporal lobes}}. {Med Hypotheses};2014 (Aug 11)
Compelling new findings suggest that an early core signature of autism is a deficient left anterior temporal lobe response to language and an atypical over-activation of the right anterior temporal lobe. Intriguingly, our recent results from an entirely different line of reasoning and experiments also show that applying cathodal stimulation (suppressing) at the left anterior temporal lobe together with anodal stimulation (facilitating) at the right anterior temporal lobe, by transcranial direct current stimulation (tDCS), can induce some autistic-like cognitive abilities in otherwise normal adults. If we could briefly induce autistic like cognitive abilities in healthy individuals, it follows that we might be able to mitigate some autistic traits by reversing the above stimulation protocol, in an attempt to restore the typical dominance of the left anterior temporal lobe. Accordingly, we hypothesize that at least some autistic traits can be mitigated, by applying anodal stimulation (facilitating) at the left anterior temporal lobe together with cathodal stimulation (suppressing) at the right anterior temporal lobe. Our hypothesis is supported by strong convergent evidence that autistic symptoms can emerge and later reverse due to the onset and subsequent recovery of various temporal lobe (predominantly the left) pathologies. It is also consistent with evidence that the temporal lobes (especially the left) are a conceptual hub, critical for extracting meaning from lower level sensory information to form a coherent representation, and that a deficit in the temporal lobes underlies autistic traits.
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4. Constantino JN. {{Recurrence rates in autism spectrum disorders}}. {JAMA};2014 (Sep 17);312(11):1154-1155.
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5. Lim L, Chantiluke K, Cubillo AI, Smith AB, Simmons A, Mehta MA, Rubia K. {{Disorder-specific grey matter deficits in attention deficit hyperactivity disorder relative to autism spectrum disorder}}. {Psychol Med};2014 (Sep 17):1-12.
Background. Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two common childhood disorders that exhibit genetic and behavioural overlap and have abnormalities in similar brain systems, in particular in frontal and cerebellar regions. This study compared the two neurodevelopmental disorders to investigate shared and disorder-specific structural brain abnormalities. Method. Forty-four predominantly medication-naive male adolescents with ADHD, 19 medication-naive male adolescents with ASD and 33 age-matched healthy male controls were scanned using high-resolution T1-weighted volumetric imaging in a 3-T magnetic resonance imaging (MRI) scanner. Voxel-based morphometry (VBM) was used to test for group-level differences in structural grey matter (GM) and white matter (WM) volumes. Results. There was a significant group difference in the GM of the right posterior cerebellum and left middle/superior temporal gyrus (MTG/STG). Post-hoc analyses revealed that this was due to ADHD boys having a significantly smaller right posterior cerebellar GM volume compared to healthy controls and ASD boys, who did not differ from each other. ASD boys had a larger left MTG/STG GM volume relative to healthy controls and at a more lenient threshold relative to ADHD boys. Conclusions. The study shows for the first time that the GM reduction in the cerebellum in ADHD is disorder specific relative to ASD whereas GM enlargement in the MTG/STG in ASD may be disorder specific relative to ADHD. This study is a first step towards elucidating disorder-specific structural biomarkers for these two related childhood disorders.
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6. Sandin S, Reichenberg A. {{Recurrence rates in autism spectrum disorders–reply}}. {JAMA};2014 (Sep 17);312(11):1155.
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7. Santos AR, Kanellopoulos AK, Bagni C. {{Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us}}. {Learn Mem};2014 (Oct);21(10):543-555.
The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.
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8. Tian M, Zeng Y, Hu Y, Yuan X, Liu S, Li J, Lu P, Sun Y, Gao L, Fu D, Li Y, Wang S, McClintock SM. {{7, 8-dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome}}. {Neuropharmacology};2014 (Sep 13)
Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB posporylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharamcotherapeutic strategy for FXS.
