1. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG. {{Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey}}. {Transl Psychiatry};2013;3:e278.
Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes.
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2. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, Hertz-Picciotto I, Pessah IN, Van de Water J. {{Autism-specific maternal autoantibodies recognize critical proteins in developing brain}}. {Transl Psychiatry};2013;3:e277.
Autism spectrum disorders (ASDs) are neurodevelopmental in origin, affecting an estimated 1 in 88 children in the United States. We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens. Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls; P<0.0002; odds ratios of 24.2 (95% confidence interval: 1.45-405)) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies. We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism.
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3. Faucher MA. {{FOLIC ACID SUPPLEMENTATION BEFORE AND IN EARLY PREGNANCY MAY DECREASE RISK FOR AUTISM}}. {J Midwifery Womens Health};2013 (Jul 9)
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4. Gamsiz ED, Viscidi EW, Frederick AM, Nagpal S, Sanders SJ, Murtha MT, Schmidt M, Triche EW, Geschwind DH, State MW, Istrail S, Cook EH, Jr., Devlin B, Morrow EM. {{Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism}}. {Am J Hum Genet};2013 (Jul 2)
Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ </= 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.
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5. Harstad E, Huntington N, Bacic J, Barbaresi W. {{Disparity of care for children with parent-reported autism spectrum disorders}}. {Acad Pediatr};2013 (Jul-Aug);13(4):334-339.
OBJECTIVE: Although children with autism spectrum disorders (ASDs) are eligible to receive special education services via an individualized education program (IEP), approximately 12% to 20% do not. Our objective was to determine which clinical and demographic characteristics are associated with IEP receipt among a nationally representative sample of children with ASD. METHODS: Using data from the 2007 National Survey of Children’s Health, we determined which clinical and demographic covariates are associated with IEP receipt for children ages 6 to 17 years with a current, parent-reported ASD diagnosis (n = 759). Logistic regression models were used to assess the association of covariates with IEP receipt. Application of weighting techniques made the findings representative of the noninstitutionalized population of US children 6 to 17 years old. RESULTS: In the weighted model, 90% of children with ASD receive an IEP. Maternal education level above high school (adjusted odds ratio [aOR] 4.08, P = .01) and presence of perceived need for coordination of care (aOR 3.62, P = .02) were associated with IEP receipt, while Hispanic children were less likely to receive an IEP compared with white children (aOR 0.12, P = .001). The following factors were not associated with IEP receipt: severity of ASD, speech, and behavior problems. CONCLUSIONS: For children with ASD in the United States, socioeconomic factors, not disability severity, are associated with IEP receipt. Future research should address methods to overcome this disparity in care. Health care providers may help to advocate for appropriate educational services for patients with ASD.
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6. Horder J, Lavender T, Mendez MA, O’Gorman R, Daly E, Craig MC, Lythgoe DJ, Barker GJ, Murphy DG. {{Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study}}. {Transl Psychiatry};2013;3:e279.
Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the ‘narrowly’ defined criteria for typical autism, whereas 13 met the ‘broader phenotype’. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD-the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex-as well as in a parietal cortex ‘control’ region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the ‘narrow’ and ‘broader’ phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development.
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7. Lemaire M, Thomazeau B, Bonnet-Brilhault F. {{Gender Identity Disorder and Autism Spectrum Disorder in a 23-Year-Old Female}}. {Arch Sex Behav};2013 (Jul 9)
We describe the case of a 23-year-old woman with Gender Identity Disorder (GID) asking for a cross-sex hormonal treatment with sex reassignment surgery and who was recently diagnosed with Autism Spectrum Disorder (ASD). Gender identity clinics are now reporting an overrepresentation of individuals with ASD among GID patients. The prevalence of ASD is 10-fold higher among GID patients than in general population. However, few case reports or studies have explored the co-occurrence of ASD and GID. This co-occurrence is relevant for diagnostic and clinical management and also raises important theoretical issues.
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8. Liu T. {{Sensory processing and motor skill performance in elementary school children with autism spectrum disorder}}. {Percept Mot Skills};2013 (Feb);116(1):197-209.
Research to examine both sensory processing and motor skill performance in children with autism spectrum disorder (ASD) is limited. This study assessed whether children with ASD would show sensory and motor delays compared to typically developing children and examined the relationship between sensory processing and motor performance. 32 children diagnosed with ASD were assessed using the Short Sensory Profile (SSP) and the Movement ABC-2 (MABC-2). The SSP measures children’s sensory processing in daily life and the MABC-2 measures children’s fine and gross motor skill performance. Overall, the samples’ scores on the SSP indicated atypical sensory processing and scores on the MABC-2 showed poorer fine and gross motor performance as compared to age-matched norms. Furthermore, the samples’ scores for sensory processing were positively correlated with their motor performance. The results suggest that fine and gross motor difficulties of children with ASD may be related to their delayed sensory processing to visual, auditory, tactile, and movement stimuli, and that this hypothesis needs to be tested in future research.
9. Shen MD, Nordahl CW, Young GS, Wootton-Gorges SL, Lee A, Liston SE, Harrington KR, Ozonoff S, Amaral DG. {{Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder}}. {Brain};2013 (Jul 9)
Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
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10. Singh SK, Eroglu C. {{Neuroligins provide molecular links between syndromic and nonsyndromic autism}}. {Sci Signal};2013;6(283):re4.
Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism.
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11. Theoharides TC, Asadi S, Panagiotidou S, Weng Z. {{The « missing link » in autoimmunity and autism: Extracellular mitochondrial components secreted from activated live mast cells}}. {Autoimmun Rev};2013 (Jul 3)
Autoimmune diseases continue to increase, but the reason(s) remain obscure and infections have not proven to be major contributors. Mast cells are tissue immune cells responsible for allergies, but have been increasingly shown to be involved in innate and acquired immunity, as well as inflammation. This involvement is possible because of their ability to release multiple mediators in response to a great variety of triggers. We recently published that activation of mast cells is accompanied by mitochondrial fission and translocation to the cell surface from where they secrete at least ATP and DNA outside the cell without cell damage. These extracellular mitochondrial components are misconstrued by the body as « innate pathogens » leading to powerful autocrine and paracrine auto-immune/auto-inflammatory responses. We also showed that mitochondrial DNA is increased in the serum of young children with autism spectrum disorders (ASD), a condition that could involve « focal brain allergy/encephalitits. » Blocking the secretion of extracellular mitochondrial components could present unique possibilities for therapy of ASD and other autoimmune diseases. Unique formulation of the flavonoid luteolin offers unique advantages.
