1. Campbell NG, Zhu CB, Lindler KM, Yaspan BL, Kistner-Griffin E, Consortium NA, Hewlett WA, Tate CG, Blakely RD, Sutcliffe JS. {{Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome}}. {Mol Autism}. 2013; 4(1): 28.
BACKGROUND: Recent discoveries highlight rare genetic variation as an important class of autism spectrum disorder (ASD) risk factors, and that such variants can implicate biological networks for further investigation. Altered serotonin (5-HT) signaling has been implicated in ASD for over 50 years, and we and others have identified multiple, rare, ASD-associated variants in the 5-HT transporter (SERT, SLC6A4) gene that lead to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci encoding SERT regulatory proteins harbor genetic variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways leading to enhanced SERT surface expression and catalytic activity, respectively. METHODS: To test our SERT network hypothesis, we asked whether a relative increase of rare functional variants in the A3AR gene (ADORA3) was present in cases vs. controls. Discovery Sanger sequencing of ADORA3 exons and flanking DNA in a case-control sample, and subsequent analysis of a comparison sample using whole exome sequence data were conducted to test for increased functional variants in cases. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity. RESULTS: Sequencing discovery showed an overall increase in rare coding variants in cases vs. controls (P=0.013). While a comparison sample from exome sequence did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association of rare, functional variants in ASD (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90 A3AR revealed elevated basal cGMP levels compared with cells expressing the wildtype receptor. Additionally, the specific A3AR agonist N6-(3-iodobenzyl)-N-methyl-5′-carbamoyladenosine (IB-MECA) induced increased cGMP levels across the full time course studied in Val90 A3AR cells, as compared with the wildtype receptor expressing cells. In Val90 A3AR/SERT co-transfected cells, IB-MECA stimulation elevated SERT activity over that seen with the wildtype receptor, with a delayed recovery of 5-HT uptake activity to baseline levels. By comparison, the Ile171 A3AR variant was unable to support IB-MECA stimulation of SERT. Although both Val90 and Ile171 were present in greater numbers in these ASD cases, segregation analysis in carrier families showed incomplete penetrance, consistent with other documented rare ASD risk alleles. CONCLUSIONS: Our results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network as a site for additional functional variation that may impact ASD risk.
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2. Fisch GS. {{Autism and epistemology IV: Does autism need a theory of mind?}}. {Am J Med Genet A}. 2013.
In their article, « Does the autistic child have a ‘theory of mind’?, » Baron-Cohen et al. [1985] proposed a novel paradigm to explain social impairment in children diagnosed as autistic (AD). Much research has been undertaken since their article went to print. The purpose of this commentary is to gauge whether Theory of Mind (ToM)-or lack thereof-is a valid model for explaining abnormal social behavior in children with AD. ToM is defined as « the ability to impute mental states to oneself and to others » and « the ability to make inferences about what other people believe to be the case. » The source for their model was provided by an article published earlier by Premack and Woodruff, « Does the chimpanzee have a theory of mind? » Later research in chimpanzees did not support a ToM in primates. From the outset, ToM as a neurocognitive model of autism has had many shortcomings-methodological, logical, and empirical. Other ToM assumptions, for example, its universality in all children in all cultures and socioeconomic conditions, are not supported by data. The age at which a ToM emerges, or events that presage a ToM, are too often not corroborated. Recent studies of mirror neurons, their location and interconnections in brain, their relationship to social behavior and language, and the effect of lesions there on speech, language and social behavior, strongly suggests that a neurobiological as opposed to neurocognitive model of autism is a more parsimonious explanation for the social and behavioral phenotypes observed in autism. (c) 2013 Wiley Periodicals, Inc.
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3. Happe F. {{International society for autism research news}}. {Autism Res}. 2013; 6(4): 306.
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4. Hazen EP, McDougle CJ, Volkmar FR. {{Changes in the diagnostic criteria for autism in DSM-5: controversies and concerns}}. {J Clin Psychiatry}. 2013; 74(7): 739-40.
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5. Kamio Y, Moriwaki A, Takei R, Inada N, Inokuchi E, Takahashi H, Nakahachi T. {{[Psychiatric issues of children and adults with autism spectrum disorders who remain undiagnosed]}}. {Seishin Shinkeigaku Zasshi}. 2013; 115(6): 601-6.
Individuals of normal intelligence with autism spectrum disorders (ASD) tend to be diagnosed with ASD late in childhood or sometimes in adulthood, despite a persistent symptomatology. When such patients visit psychiatric clinics for co-occurring psychiatric symptoms, the diagnostic procedure can be challenging due to a lack of accurate developmental information and a mixed clinical presentation. The same is true for those with subthreshold autistic symptoms. Although individuals with subthreshold ASD also have social adjustment difficulties of a similar degree to those with ASD, the relative clinical significance of this population is unclear. Here, data from a large national population sample of schoolchildren were examined to determine the psychiatric needs of children with threshold and subthreshold autistic symptoms. First, autistic symptoms or traits assessed by the Social Responsiveness Scale (SRS), a quantitative behavioral measure, showed a continuous distribution in the general child population (n = 22,529), indicating no evidence of a natural gap that could differentiate children diagnosed with ASD from subthreshold or unaffected children. Second, data from 25,075 children demonstrated that having threshold autistic symptoms predicted a high psychiatric risk, as indicated by higher scores on the Strengths and Difficulties Questionnaire (SDQ; odds ratio [OR] 200.52, 95% confidence interval [CI]: 152.12-264.33), and that having subthreshold autistic symptoms indicated the same (OR 12.78, 95% CI: 11.52-14.18). Having threshold autistic symptoms predicted emotional problems (OR 20.19, 95% CI: 17.00-24.00), as did having subthreshold autistic symptoms (OR 5.90, 95% CI: 5.29-6.58). Third, among 2,250 children at a high psychiatric risk, most had threshold or subthreshold autistic symptoms (21 and 44%, respectively). These findings have important implications for the comprehensive psychiatric and developmental evaluation and treatment of this patient population, whose diagnosis and treatment are often delayed, and a further in-depth study is warranted.
6. Levin-Decanini T, Maltman N, Francis SM, Guter S, Anderson GM, Cook EH, Jacob S. {{Parental Broader Autism Subphenotypes in ASD Affected Families: Relationship to Gender, Child’s Symptoms, SSRI Treatment, and Platelet Serotonin}}. {Autism Res}. 2013.
Relationships between parental broader autism phenotype (BAP) scores, gender, selective serotonin reuptake inhibitor (SSRI) treatment, serotonin (5HT) levels, and the child’s symptoms were investigated in a family study of autism spectrum disorder (ASD). The Broader Autism Phenotype Questionnaire (BAPQ) was used to measure the BAP of 275 parents. Fathers not taking SSRIs (F-SSRI; n = 115) scored significantly higher on BAP Total and Aloof subscales compared to mothers not receiving treatment (M-SSRI; n = 136.) However, mothers taking SSRIs (M + SSRI; n = 19) scored higher than those not taking medication on BAP Total and Rigid subscales, and they were more likely to be BAPQ Total, Aloof, and Rigid positive. Significant correlations were noted between proband autism symptoms and parental BAPQ scores such that Total, Aloof, and Rigid subscale scores of F-SSRI correlated with proband restricted repetitive behavior (RRB) measures on the ADOS, CRI, and RBS-R. However, only the Aloof subscale score of M + SSRI correlated with proband RRB on the ADOS. The correlation between the BAPQ scores of mothers taking SSRIs and child scores, as well as the increase in BAPQ scores of this group of mothers, requires careful interpretation and further study because correlations would not withstand multiple corrections. As expected by previous research, significant parent-child correlations were observed for 5HT levels. However, 5HT levels were not correlated with behavioral measures. Study results suggest that the expression of the BAP varies not only across parental gender, but also across individuals using psychotropic medication and those who do not. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Lin PI, Kuo PH, Chen CH, Wu JY, Gau SS, Wu YY, Liu SK. {{Runs of homozygosity associated with speech delay in autism in a taiwanese han population: evidence for the recessive model}}. {PLoS One}. 2013; 8(8): e72056.
Runs of homozygosity (ROH) may play a role in complex diseases. In the current study, we aimed to test if ROHs are linked to the risk of autism and related language impairment. We analyzed 546,080 SNPs in 315 Han Chinese affected with autism and 1,115 controls. ROH was defined as an extended homozygous haplotype spanning at least 500 kb. Relative extended haplotype homozygosity (REHH) for the trait-associated ROH region was calculated to search for the signature of selection sweeps. Totally, we identified 676 ROH regions. An ROH region on 11q22.3 was significantly associated with speech delay (corrected p = 1.73×10(-8)). This region contains the NPAT and ATM genes associated with ataxia telangiectasia characterized by language impairment; the CUL5 (culin 5) gene in the same region may modulate the neuronal migration process related to language functions. These three genes are highly expressed in the cerebellum. No evidence for recent positive selection was detected on the core haplotypes in this region. The same ROH region was also nominally significantly associated with speech delay in another independent sample (p = 0.037; combinatorial analysis Stouffer’s z trend = 0.0005). Taken together, our findings suggest that extended recessive loci on 11q22.3 may play a role in language impairment in autism. More research is warranted to investigate if these genes influence speech pathology by perturbing cerebellar functions.
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8. Saito Y, Suga M, Tochigi M, Abe O, Yahata N, Kawakubo Y, Liu X, Kawamura Y, Sasaki T, Kasai K, Yamasue H. {{Neural correlate of autistic-like traits and a common allele in the oxytocin receptor gene}}. {Soc Cogn Affect Neurosci}. 2013.
Sub-clinical autistic-like traits (ALTs) are continuously distributed in the general population and genetically linked to autism. Although identifying the neurogenetic backgrounds of ALTs might enhance our ability to identify those of autism, they are largely unstudied. Here, we have examined the neuroanatomical basis of ALTs and their association with the oxytocin receptor gene (OXTR) rs2254298A, a known risk allele for autism in Asian populations which has also been implicated in limbic-paralimbic brain structures. First, we extracted a four-factor structure of ALTs, as measured using the Autism-Spectrum Quotient, including « Prosociality », « Communication », « Details/patterns » and « Imagination » in 135 neurotypical adults (79 men, 56 women) to reduce the genetic heterogeneity of ALTs. Then, in the same population, voxel-based morphometry revealed that lower « Prosociality », which indicates strong ALTs, was significantly correlated with smaller regional gray matter volume in the right insula in males. Males with lower « Prosociality » also had less interregional structural coupling between the right insula and the ventral anterior cingulate cortex. Furthermore, males with OXTR rs2254298A had significantly smaller gray matter volume in the right insula. These results show that decreased volume of the insula is a neuroanatomical correlate of ALTs and a potential intermediate phenotype linking ALTs with OXTR in male subjects.
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9. Sowden H, Clegg J, Perkins M. {{The development of co-speech gesture in the communication of children with autism spectrum disorders}}. {Clin Linguist Phon}. 2013.
Abstract Co-speech gestures have a close semantic relationship to speech in adult conversation. In typically developing children co-speech gestures which give additional information to speech facilitate the emergence of multi-word speech. A difficulty with integrating audio-visual information is known to exist for individuals with Autism Spectrum Disorder (ASD), which may affect development of the speech-gesture system. A longitudinal observational study was conducted with four children with ASD, aged 2;4 to 3;5 years. Participants were video-recorded for 20 min every 2 weeks during their attendance on an intervention programme. Recording continued for up to 8 months, thus affording a rich analysis of gestural practices from pre-verbal to multi-word speech across the group. All participants combined gesture with either speech or vocalisations. Co-speech gestures providing additional information to speech were observed to be either absent or rare. Findings suggest that children with ASD do not make use of the facilitating communicative effects of gesture in the same way as typically developing children.
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10. Uchiyama T. {{[Case study of 10 subjects diagnosed with autism spectrum disorders in adulthood and currently under long-term follow-up]}}. {Seishin Shinkeigaku Zasshi}. 2013; 115(6): 607-15.
This study involved 10 adults with autism spectrum disorders (ASD) who were referred to a specialized developmental disability clinic and were being treated for periods extending to years. Checks included past diagnoses, the chief complaint at the first examination, psychiatric symptoms, medication, employment, and whether a diagnosis of ASD would have been possible during their formative years. Their age at referral was 21-30 and, at the time of this study, they were aged 25-40. There were eight males and two females, and their treatment periods were between four and 16 years. Using DSM-IV-TR criteria, six were diagnosed with autistic disorders and four with PDDNOS. Wing and Gould criteria showed nine with Asperger syndrome and one with autism. Their IQ ranged from 88 to 121, with the mean score being 103 (SD = 10.0). Eight of the 10 had previously been examined in psychiatric clinics, which identified two as having depression, two with schizophrenia, one with Obsessive-Compulsive Disorder, and one with autism/Asperger syndrome, and there was no diagnosis for the other two. For these eight cases, the PDD-Autism Society Japan Rating Scale (PARS) was used. The PARS early childhood peak score ranged from 9 to 41, so all reached the cutoff point of 9. At the time of this study, the following psychiatric symptoms were noted: three cases of depression, two of anxiety, one with auditory hallucinations, and one who displayed odd behavior and facial expressions that became apparent during the follow-up. In two cases there seemed to be no apparent psychiatric co-morbidity. The current PARS scores of 8 cases were between 12 and 38, and four cases exceeded the cutoff point of 20. One was taking anti-psychotic drugs for auditory hallucinations, four were using SSRI for anxiety and depression, and one was occasionally prescribed medication for anxiety. Four were not on medication. When diagnosing ASD in adulthood, interviewing using such instruments as PARS seemed useful. We should keep in mind that families tend not to recognize co-morbid psychotic symptoms.
11. Yoshida Y. {{[Disclosure of the autism spectrum]}}. {Seishin Shinkeigaku Zasshi}. 2013; 115(6): 616-22.
Since the concept of Asperger syndrome was advocated by the child psychiatrist Lorna Wing (1981), atypical cases not accompanied by intellectual disability have been considered for support. In clinical settings in the 1990s, children began asking the names of their diagnoses. In a field study by the authors, an increasing number of children at the age of 8 years realize the name of their diagnosis, and many children know their diagnosis at the ages of 12 years. Although explaining the diagnosis to the child plays an important role in the treatment of autism and Asperger syndrome in a clinical setting, very few studies have examined such explanations as part of the treatment technique. This paper presents the authors’ efforts in psycho-medical education, by disclosing the diagnosis to the children. Further, the study examines the effects and side effects of diagnosis disclosure as a counselling technique. For the symposium’s theme of ‘re-examining the clinical significance of diagnostic thresholds’, in this manuscript, the author discusses her views on explaining the diagnoses to the children.
