1. Baker SA, Chen L, Wilkins AD, Yu P, Lichtarge O, Zoghbi HY. {{An AT-Hook Domain in MeCP2 Determines the Clinical Course of Rett Syndrome and Related Disorders}}. {Cell};2013 (Feb 28);152(5):984-996.
Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2’s key functions is to alter chromatin structure.
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2. Baudouin SJ. {{[Mouse models of autism: a common basis for syndromic and non syndromic autisms ?]}}. {Med Sci (Paris)};2013 (Feb);29(2):121-123.
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3. Dickstein DP, Pescosolido MF, Reidy BL, Galvan T, Kim KL, Seymour KE, Laird AR, Di Martino A, Barrett RP. {{Developmental meta-analysis of the functional neural correlates of autism spectrum disorders}}. {J Am Acad Child Adolesc Psychiatry};2013 (Mar);52(3):279-289 e216.
OBJECTIVE: There is a pressing need to elucidate the brain-behavior interactions underlying autism spectrum disorders (ASD) given the marked rise in ASD diagnosis over the past decade. Functional magnetic resonance imaging (fMRI) has begun to address this need, but few fMRI studies have evaluated age-related changes in ASD. Therefore, we conducted a developmental analysis of activation likelihood estimation (ALE) meta-analysis to compare child versus adult ASD fMRI studies. We hypothesized that children and adolescents with ASD (<18 years old) would rely less on prefrontal cortex structures than adults (>/=18 years old). METHOD: PubMed and PsycInfo literature searches were conducted to identify task-dependent fMRI studies of children or adults with ASD. Then recent GingerALE software improvements were leveraged to perform direct comparisons of child (n = 18) versus adult (n = 24) studies. RESULTS: ALE meta-analyses of social tasks showed that children and adolescents with ASD versus adults had significantly greater hyperactivation in the left post-central gyrus, and greater hypoactivation in the right hippocampus and right superior temporal gyrus. ALE meta-analyses of nonsocial tasks showed that children with ASD versus adults had significantly greater hyperactivation in the right insula and left cingulate gyrus, and hypoactivation in the right middle frontal gyrus. CONCLUSION: Our data suggest that the neural alterations associated with ASD are not static, occurring only in early childhood. Instead, children with ASD have altered neural activity compared to adults during both social and nonsocial tasks, especially in fronto-temporal structures. Longitudinal neuroimaging studies are required to examine these changes prospectively, as potential targets for brain-based treatments for ASD.
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4. Frye RE, Delatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N, James SJ. {{Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study}}. {Transl Psychiatry};2013;3:e237.
Sapropterin, a synthetic form of tetrahydrobiopterin (BH), has been reported to improve symptoms in children with autism spectrum disorder (ASD). However, as BH is involved in multiple metabolic pathway that have been found to be dysregulated in ASD, including redox, pterin, monoamine neurotransmitter, nitric oxide (NO) and immune metabolism, the metabolic pathway by which sapropterin exerts its therapeutic effect in ASD effect remains unclear. This study investigated which metabolic pathways were associated with symptomatic improvement during sapropterin treatment. Ten participants (ages 2-6 years old) with current social and/or language delays, ASD and a central BH concentration </=30 nM l were treated with a daily morning 20 mg kg dose of sapropterin for 16 weeks in an open-label fashion. At baseline, 8 weeks and 16 weeks after starting the treatment, measures of language, social function and behavior and biomarkers of redox, pterin, monoamine neurotransmitter, NO and immune metabolism were obtained. Two participants discontinued the study, one from mild adverse effects and another due to noncompliance. Overall, improvements in subscales of the Preschool Language Scale (PLS), Vineland Adaptive Behavior Scale (VABS), Aberrant Behavior Checklist (ABC) and autism symptoms questionnaire (ASQ) were seen. Significant changes in biomarkers of pterin, redox and NO were found. Improvement on several subscales of the PLS, VABS, ABC and ASQ were moderated by baseline and changes in biomarkers of NO and pterin metabolism, particularly baseline NO metabolism. These data suggest that behavioral improvement associated with daily 20 mg kg sapropterin treatment may involve NO metabolism, particularly the status of pretreatment NO metabolism.
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5. Grant R, Nozyce M. {{Proposed Changes to the American Psychiatric Association Diagnostic Criteria for Autism Spectrum Disorder: Implications for Young Children and Their Families}}. {Matern Child Health J};2013 (Mar 2)
The American Psychiatric Association has revised the diagnostic criteria for their DSM-5 manual. Important changes have been made to the diagnosis of the current (DSM-IV) category of Pervasive Developmental Disorders. This category includes Autistic Disorder (autism), Asperger’s Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). The DSM-5 deletes Asperger’s Disorder and PDD-NOS as diagnostic entities. This change may have unintended consequences, including the possibility that the new diagnostic framework will adversely affect access to developmental interventions under Individuals with Disabilities Education Act (IDEA) programs, Early Intervention (for birth to 2 years olds) and preschool special education (for 3 and 4 years olds). Changing the current diagnosis of PDD-NOS to a « Social Communication Disorder » focused on language pragmatics in the DSM-5 may restrict eligibility for IDEA programs and limit the scope of services for affected children. Young children who meet current criteria for PDD-NOS require more intensive and multi-disciplinary services than would be available with a communication domain diagnosis and possible service authorization limited to speech-language therapy. Intensive behavioral interventions, inclusive group setting placements, and family support services are typically more available for children with an autism spectrum disorder than with diagnoses reflecting speech-language delay. The diagnostic distinction reflective of the higher language and social functioning between Asperger’s Disorder and autism is also undermined by eliminating the former as a categorical diagnosis and subsuming it under autism. This change may adversely affect treatment planning and misinform parents about prognosis for children who meet current criteria for Asperger’s Disorder.
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6. Messinger D, Young GS, Ozonoff S, Dobkins K, Carter A, Zwaigenbaum L, Landa RJ, Charman T, Stone WL, Constantino JN, Hutman T, Carver LJ, Bryson S, Iverson JM, Strauss MS, Rogers SJ, Sigman M. {{Beyond autism: a baby siblings research consortium study of high-risk children at three years of age}}. {J Am Acad Child Adolesc Psychiatry};2013 (Mar);52(3):300-308 e301.
OBJECTIVE: First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD. METHOD: Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ). RESULTS: At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings. CONCLUSIONS: Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children.
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7. Stavropoulos KK, Carver LJ. {{Research Review: Social motivation and oxytocin in autism – implications for joint attention development and intervention}}. {J Child Psychol Psychiatry};2013 (Mar 2)
BACKGROUND AND SCOPE: The social motivation hypothesis (SMH) suggests that individuals with autism spectrum disorders (ASD) are less intrinsically rewarded by social stimuli than their neurotypical peers. This difference in social motivation has been posited as a factor contributing to social deficits in ASD. Social motivation is thought to involve the neuropeptide oxytocin. Here, we review the evidence for oxytocin effects in ASD, and discuss its potential role in one important social cognitive behavior. METHODS: Systematic searches were conducted using the PsychINFO and MEDLINE databases and the search terms ‘oxytocin’ and ‘autism’; the same databases were used for separate searches for ‘joint attention’, ‘intervention’, and ‘autism’, using the same inclusion criteria as an earlier 2011 review but updating it for the period 2010 to October 2012. FINDINGS: Several studies suggest that giving oxytocin to both individuals with ASD and neurotypical individuals can enhance performance on social cognitive tasks. Studies that have attempted to intervene in joint attention in ASD suggest that social motivation may be a particular obstacle to lasting effects. CONCLUSIONS: The review of the evidence for the SMH suggests a potential role for oxytocin in social motivation deficits in ASD. Because of its importance for later communicative and social development, the focus here is on implications of oxytocin and social motivation in the development of and interventions in joint attention. Joint attention is a central impairment in ASD, and as a result is the focus of several behavioral interventions. In describing this previous research on joint attention interventions in ASD, we pay particular attention to problems encountered in such studies, and propose ways that oxytocin may facilitate behavioral intervention in this area. For future research, integrating behavioral and pharmacological interventions (oxytocin administration) would be a worthwhile experimental direction to improve understanding of the role of oxytocin in ASD and help optimize outcomes for children with ASD.
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8. Szalavitz M. {{Aging out of autism. A new study suggest symptoms can fade with time}}. {Time};2013 (Feb 4);181(4):16.
9. Usui D, Shimada S, Shimojima K, Sugawara M, Kawasaki H, Shigematu H, Takahashi Y, Inoue Y, Imai K, Yamamoto T. {{Interstitial duplication of 2q32.1-q33.3 in a patient with epilepsy, developmental delay, and autistic behavior}}. {Am J Med Genet A};2013 (Mar 5)
Duplications of the 2q33 region are rare; to date, only 13 patients have been reported to have this chromosomal abnormality. The reported duplications are of varying size, and the patients shared developmental delay and minor dysmorphic findings. In this study, we identified a duplication of 2q32.1-q33.3 in a patient with psychomotor developmental delay, epilepsy, and autistic behavior. The duplicated region of this patient was reciprocal to the 2q32-q33 deletion syndrome. Chromosomal microarray testing confirmed the 19.5 Mb of duplication that includes over 100 genes, some of which could have functional relevance to the neurological features of this patient. The SATB homeobox 2 gene (SATB2)-the primary gene responsible for the 2q32-q33 deletion syndrome-may be one of them, because of its expression in the cortical projection neurons of the developing brain. The duplication of the potassium channel tetramerisation domain-containing 18 gene (KCTD18) and the ADAM metallopeptidase domain 23 gene (ADAM23) may also contribute to the phenotype. FISH analysis confirmed a tandem configuration of the duplicated segments. This result is in agreement with our previous study, in which we observed that duplicated segments as interstitial duplications are generally inserted in the tandem configuration. (c) 2013 Wiley Periodicals, Inc.
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10. Zeidan-Chulia F, Rybarczyk-Filho JL, Salmina AB, de Oliveira BH, Noda M, Moreira JC. {{Exploring the Multifactorial Nature of Autism Through Computational Systems Biology: Calcium and the Rho GTPase RAC1 Under the Spotlight}}. {Neuromolecular Med};2013 (Mar 2)
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca2+) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism.
