1. Bar-Nur O, Caspi I, Benvenisty N. {{Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives}}. {J Mol Cell Biol};2012 (Apr 19)
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2. Chahrour MH, Yu TW, Lim ET, Ataman B, Coulter ME, Hill RS, Stevens CR, Schubert CR, Greenberg ME, Gabriel SB, Walsh CA. {{Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism}}. {PLoS Genet};2012 (Apr);8(4):e1002635.
Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
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3. Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. {{Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors}}. {Autism Res};2012 (Apr);5(2):101-108.
The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. One hundred twenty-one children were recruited into three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their child’s behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% confidence interval 2.54-56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by health-care providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.
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4. Kohane IS, McMurry A, Weber G, Macfadden D, Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, Churchill S. {{The co-morbidity burden of children and young adults with autism spectrum disorders}}. {PLoS One};2012;7(4):e33224.
OBJECTIVES: Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults. STUDY DESIGN: A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18-34 years) individuals with ASD was compared. RESULTS: 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72-6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41-10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26-0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79-1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI -0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0-17 vs 18-34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly. CONCLUSIONS: The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.
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5. Lin PI, Chien YL, Wu YY, Chen CH, Gau SS, Huang YS, Liu SK, Tsai WC, Chiu YN. {{The WNT2 gene polymorphism associated with speech delay inherent to autism}}. {Res Dev Disabil};2012 (Apr 19);33(5):1533-1540.
Previous evidence suggests that language function is modulated by genetic variants on chromosome 7q31-36. However, it is unclear whether this region harbors loci that contribute to speech delay in autism. We previously reported that the WNT2 gene located on 7q31 was associated with the risk of autism. Additionally, two other genes on 7q31-36, FOXP2 and the EN2 genes are also found to play a role in language impairment. Therefore, we hypothesize that the WNT2 gene, FOXP2 gene, and EN2 gene, may act in concert to influence language development in the same population. A total of 373 individuals diagnosed with autistic disorder were recruited in the current study. We selected 6 tag single nucleotide polymorphisms (SNPs) within the WNT2 gene, 3 tag SNPs in the FOXP2, and 3 tag SNPs in the EN2 genes, to study the effect of these genes on language development. Age of first phrase was treated as a quantitative trait. We used general linear model to assess the association between speech delay and these variants. The results show that rs2896218 in the WNT2 gene was moderately significantly associated with age of first phrase (permutation p=0.0045). A three-locus haplotype in the WNT2 gene was significantly associated with age of first phrase (permutation p=2×10(-4)). Furthermore, we detected an interaction effect on age of first phrase between a SNP rs2228946 in the WNT2 gene and another SNP rs6460013 in the EN2 gene (p=0.0012). Therefore, the WNT2 gene may play a suggestive role in language development in autistic disorder. Additionally, the WNT2 gene and EN2 gene may act in concert to influence the language development in autism.
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6. Rumpf AL, Kamp-Becker I, Becker K, Kauschke C. {{Narrative competence and internal state language of children with Asperger Syndrome and ADHD}}. {Res Dev Disabil};2012 (Apr 19);33(5):1395-1407.
The central question of the present study was whether there are differences between children with Asperger Syndrome (AS), children with attention deficit hyperactivity disorder (ADHD) and healthy controls (HC) with respect to the organization of narratives and their verbalization of internal states. Oral narrations of a wordless picture book produced by 31 children (11 with AS, 9 with ADHD, 11 HC, aged 8-12) were analyzed regarding the following linguistic variables: story length, sentence structure and sentence complexity, coherence and cohesion of the stories, verbalization of the narrator’s perspective, as well as internal state language (verbal reference to mental states). Considerable similarities were noted between the two clinical groups, which deviate from HC children. Narratives of the children with AS and ADHD were shorter than the narratives produced by the HC children. The children of both clinical groups failed to point out the main aspects of the story. In particular, children with AS did not refer to cognitive states as often as the other groups. With respect to narrative coherence, they produced fewer pronominal references than HC children and children with ADHD. In conclusion, the two clinical groups differed from the HC group on a number of features, and a less frequent reference to cognitive states was identified for the children with AS.
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7. Tager-Flusberg H. {{International society for autism research news}}. {Autism Res};2012 (Apr);5(2):152.
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8. Tanne JH. {{Maternal obesity and diabetes are linked to children’s autism and similar disorders}}. {BMJ};2012;344:e2768.
9. Taylor MA, Schreck KA, Mulick JA. {{Sleep disruption as a correlate to cognitive and adaptive behavior problems in autism spectrum disorders}}. {Res Dev Disabil};2012 (Apr 19);33(5):1408-1417.
Sleep problems associated with autism spectrum disorders (ASD) have been well documented, but less is known about the effects of sleep problems on day-time cognitive and adaptive performance in this population. Children diagnosed with autism or pervasive developmental disorder-not otherwise specified (PDD-NOS) (N=335) from 1 to 10 years of age (M=5.5 years) were evaluated for the relationships of Behavioral Evaluation of Disorders of Sleep (BEDS; Schreck, 1998) scores to measures of intelligence and adaptive behavior. Results suggested that children who slept fewer hours per night had lower overall intelligence, verbal skills, overall adaptive functioning, daily living skills, socialization skills, and motor development. Children who slept fewer hours at night with waking during the night had more communication problems. Breathing related sleep problems and fewer hours of sleep related most often to problems with perceptual tasks. The results indicate that quality of sleep – especially sleep duration – may be related to problems with day-time cognitive and adaptive functioning in children with autism and PDD-NOS. However, future research must be conducted to further understand these relationships.
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10. Xinyuanhe C, Portera-Cailliau C. {{The trouble with spines in fragile X syndrome: density, maturity and plasticity}}. {Neuroscience};2012 (Apr 19)
Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the troublewith spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levelsthat could helpsolve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder.
