1. Bissonnette JM, Schaevitz LR, Knopp SJ, Zhou Z. {{Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X}}. {Neuroscience};2014 (Mar 10)
Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only approximately 10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2T158A/+) or a nonsense mutation R168X (Mecp2R168X/+). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2T158A/+ and Mecp2R168X/+ heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild type controls. Interestingly, the incidence of apnea was much greater in Mecp2R168X/+ heterozygotes, 189 per hour, than Mecp2T158A/+ heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.
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2. Das DK, Jadhav V, Ghattargi VC, Udani V. {{Novel mutation in Forkhead box G1 (FOXG1) gene in an Indian patient with Rett syndrome}}. {Gene};2014 (Mar 15);538(1):109-112.
Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome.
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3. de Theije CG, Wu J, Koelink PJ, Korte-Bouws GA, Borre Y, Kas MJ, Lopes da Silva S, Korte SM, Olivier B, Garssen J, Kraneveld AD. {{Autistic-like behavioural and neurochemical changes in a mouse model of food allergy}}. {Behav Brain Res};2014 (Mar 15);261:265-274.
Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow’s milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-Fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD.
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4. Dudova I, Kasparova M, Markova D, Zemankova J, Beranova S, Urbanek T, Hrdlicka M. {{Screening for autism in preterm children with extremely low and very low birth weight}}. {Neuropsychiatr Dis Treat};2014;10:277-282.
BACKGROUND: Studies of children with very low birth weight (VLBW, 1,000-1,500 g) and extremely low birth weight (ELBW, less than 1,000 g) indicate that this population seems to be at increased risk of autism spectrum disorder (ASD). METHODS: Parents of 101 VLBW and ELBW children (age 2 years, corrected for prematurity) agreed to participate in the study and signed informed consents; however, parents of only 75 children (44 boys, 31 girls) completed the screening questionnaires. The screening battery included the Modified Checklist for Autism in Toddlers (M-CHAT), Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist (CSBS-DP-ITC), and the Infant/Toddler Sensory Profile (ITSP). Children with disabilities were excluded. All children who screened positive on any of the screening tools were subsequently invited for a detailed assessment. RESULTS: Thirty-two children (42.7%) screened positive on at least one of the screening questionnaires. The screening tool with the most positive results was the CSBS-DP-ITC (26 positive screens), followed by the M-CHAT (19 positive screens) and the ITSP (11 positive screens). Of the 32 children who tested positive, 19 participated in the detailed follow-up assessment. A diagnosis of ASD was confirmed in eight of the 19 children. ASD prevalence, calculated from those 19 children and those with negative screening results (43 children), yielded a prevalence of 12.9% in the sample. The difference in frequency of positive screens between the tests was significant (P=0.011). In pair comparisons, ITSP was found to be significantly less positive than CSBS-DP-ITC (P=0.032). No significant differences were found between the M-CHAT and CSBS-DP-ITC or between the M-CHAT and ITSP. CONCLUSION: The results strongly support the hypothesis of an increased prevalence of autism in children with a birth weight less than 1,500 g.
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5. Kim SY, Tassone F, Simon TJ, Rivera SM. {{Altered neural activity in the ‘when’ pathway during temporal processing in fragile X premutation carriers}}. {Behav Brain Res};2014 (Mar 15);261:240-248.
Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Large expansions of the CGG repeat (>200 repeats) consequently result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 of CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA. Recent studies have shown that infants with FXS exhibit severely reduced resolution of temporal attention, whereas spatial resolution of attention is not impaired. Following from these findings in the full mutation, the current study used fMRI to examine whether premutation carriers would exhibit atypical temporal processing at behavioral and/or neural levels. Using spatial and temporal working memory (SWM and TWM) tasks, separately tagging spatial and temporal processing, we demonstrated that neurotypical adults showed greater activation in the ‘when pathway’ (i.e., the right temporoparietal junction: TPJ) during TWM retrieval than SWM retrieval. However, premutation carriers failed to show this increased involvement of the right TPJ during retrieval of temporal information. Further, multiple regression analyses on right TPJ activation and FMR1 gene expression (i.e., CGG repeat size and FMR1 mRNA) suggests that elevated FMR1 mRNA level is a powerful predictor accounting for reduced right TPJ activation associated with temporal processing in premutation carriers. In conclusion, the current study provides the first evidence on altered neural correlates of temporal processing in adults with the premutation, explained by their FMR1 gene expression.
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6. Paul JD. {{The Vacuum of the Mind: A Self-Report on the Phenomenology of Autistic, Obsessive-Compulsive, and Depressive Comorbidity}}. {Schizophr Bull};2014 (Mar 13)
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7. Rzhetsky A, Bagley SC, Wang K, Lyttle CS, Cook EH, Jr., Altman RB, Gibbons RD. {{Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability}}. {PLoS Comput Biol};2014 (Mar);10(3):e1003518.
Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10-5). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10-5), and 43% ID rate increase (CI: [23%, 67%], p<6×10-5). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10-16).
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8. Schuwerk T, Vuori M, Sodian B. {{Implicit and explicit Theory of Mind reasoning in autism spectrum disorders: The impact of experience}}. {Autism};2014 (Mar 13)
This study aimed to investigate the relationship between explicit and implicit forms of Theory of Mind reasoning and to test the influence of experience on implicit Theory of Mind reasoning in individuals with autism spectrum disorders and in neurotypical adults. Results from two standard explicit Theory of Mind tasks are mixed: Individuals with autism spectrum disorders did not differ from neurotypical adults in their performance in the Strange Stories Test, but scored significantly lower on the Reading the Mind in the Eyes Test. Furthermore, in an implicit false-belief task, individuals with autism spectrum disorders differed from neurotypical adults in false belief-congruent anticipatory looking. However, this group difference disappeared by (1) providing participants with the outcome of a false belief-based action and (2) subsequently repeating this test trial. Although the tendency to fixate the false belief-congruent location significantly increased from the first to the second test trial in individuals with autism spectrum disorders, it differed in neither test trial from chance. These findings support the notion of an implicit Theory of Mind deficit in autism spectrum disorders, but give rise to the idea that anticipatory looking behaviors in autism spectrum disorders may be affected by experience. Additionally, the pattern of results from implicit and explicit Theory of Mind measures supports the theory of two independent Theory of Mind reasoning systems.
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9. Zhu L, Wang X, Li XL, Towers A, Cao X, Wang P, Bowman R, Yang H, Goldstein J, Li YJ, Jiang YH. {{Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders}}. {Hum Mol Genet};2014 (Mar 15);23(6):1563-1578.
The molecular basis for the majority of cases of autism spectrum disorders (ASD) remains unknown. We tested the hypothesis that ASD have an epigenetic cause by performing DNA methylation profiling of five CpG islands (CGI-1 to CGI-5) in the SHANK3 gene in postmortem brain tissues from 54 ASD patients and 43 controls. We found significantly increased overall DNA methylation (epimutation) in three intragenic CGIs (CGI-2, CGI-3 and CGI-4). The increased methylation was clustered in the CGI-2 and CGI-4 in approximately 15% of ASD brain tissues. SHANK3 has an extensive array of mRNA splice variants resulting from combinations of five intragenic promoters and alternative splicing of coding exons. Altered expression and alternative splicing of SHANK3 isoforms were observed in brain tissues with increased methylation of SHANK3 CGIs in ASD brain tissues. A DNA methylation inhibitor modified the methylation of CGIs and altered the isoform-specific expression of SHANK3 in cultured cells. This study is the first to find altered methylation patterns in SHANK3 in ASD brain samples. Our finding provides evidence to support an alternative approach to investigating the molecular basis of ASD. The ability to alter the epigenetic modification and expression of SHANK3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.
