1. {{Neurodevelopmental disorders: Paternal obesity raises risk of autism spectrum disorders}}. {Nat Rev Neurol};2014 (Apr 22)
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2. Breitenkamp AF, Matthes J, Nass RD, Sinzig J, Lehmkuhl G, Nurnberg P, Herzig S. {{Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function}}. {PLoS One};2014;9(4):e95579.
Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVbeta2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.
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3. Chang K, Shin JI. {{Association of gestational maternal hypothyroxinemia and increased autism risk: The role of BDNF ?}}. {Ann Neurol};2014 (Mar 19)
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4. Ecker C, Shahidiani A, Feng Y, Daly E, Murphy C, D’Almeida V, Deoni S, Williams SC, Gillan N, Gudbrandsen M, Wichers R, Andrews D, Van Hemert L, Murphy DG. {{The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder}}. {J Neural Transm};2014 (Apr 22)
Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group x age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall.
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5. El Khatib AA, El Tekeya MM, El Tantawi MA, Omar T. {{Oral health status and behaviours of children with Autism Spectrum Disorder: a case-control study}}. {Int J Paediatr Dent};2013 (Sep 24)
BACKGROUND: Autism Spectrum Disorder (ASD) is a lifelong neuro-developmental disorder characterized by abnormalities in social interactions and communication and by stereotyped, repetitive activities. PURPOSE: Assess the oral health status and behaviours of children with ASD. METHODS: The study included 100 children with ASD and 100 healthy children from Alexandria, Egypt. Data were collected using a questionnaire and clinical examination. Questionnaire assessed socio-demographics, medical history, dental history, oral hygiene, dietary habits, and presence of self-injurious behaviours. Clinical examination assessed behaviour during examination, gingival condition, plaque accumulation, caries, and other oral conditions. RESULTS: Children with ASD had significantly poorer oral hygiene and gingival condition than healthy children (P < 0.001 for both). No significant differences were found in caries prevalence or experience in primary or permanent dentition. More children with ASD behaved ‘negatively’ or ‘definitely negatively’ (37% and 11%) than did healthy controls (11% and 2%) (P < 0.0001). Self-injurious behaviour and bruxism were more practised by children with ASD (32% of children with ASD and 2% of healthy children, P < 0.001). More children with ASD had difficulty in accessing dental care (P = 0.002). CONCLUSIONS: The oral condition of children with ASD might increase the risk of developing dental diseases. Their behaviour and life factors may complicate provision of services and limit access to dental care. Therefore, individualized oral health education programmes should be implemented for those children.
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6. Goldman SE, Adkins KW, Calcutt MW, Carter MD, Goodpaster RL, Wang L, Shi Y, Burgess HJ, Hachey DL, Malow BA. {{Melatonin in Children with Autism Spectrum Disorders: Endogenous and Pharmacokinetic Profiles in Relation to Sleep}}. {J Autism Dev Disord};2014 (Apr 22)
Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C max) and time to peak concentration (T max) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin.
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7. Guy L, Souders M, Bradstreet L, Delussey C, Herrington JD. {{Brief Report: Emotion Regulation and Respiratory Sinus Arrhythmia in Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Apr 22)
Emotion regulation (ER) may be an important transdiagnostic factor for understanding mental and behavioral health given its association with several psychiatric disorders, including autism spectrum disorder (ASD). However, there is limited research on ER in ASD, particularly using biomarkers such as respiratory sinus arrhythmia (RSA). The aim of the current study was to examine RSA among school-aged children with ASD in relation to symptoms of anxiety, executive functioning, and adaptive socialization skills. Results showed decreased RSA in children with ASD (relative to typically developing controls), reflecting decreased parasympathetic nervous system activity. In addition, decreased RSA was associated with increased symptoms of anxiety and lower socialization skills. These findings emphasize the need for interventions targeting emotional and arousal regulation in ASD.
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8. Hobson JA, Hobson RP, Cheung Y, Calo S. {{Symbolizing as Interpersonally Grounded Shifts in Meaning: Social Play in Children With and Without Autism}}. {J Autism Dev Disord};2014 (Apr 22)
The aim of this study was to examine the relation between symbolic play and communicative engagement among children with and without autism. Our predictions were firstly, that in moment-by-moment interactions during semi-structured interactive play with an adult, children with and without autism would tend to show shifts in meanings in symbolic play when engaged in coordinated states of joint engagement (events involving ‘sharing-of-meaning’); secondly, that across atypically developing participants, sharing-of-meaning would (a) correlate with scores on a standardized test of pretend play, and (b) be inversely correlated with scores on the Autism Diagnostic Observation Schedule; and finally, that participants with autism would contrast with matched developmentally delayed participants in manifesting lower levels of joint engagement, lower levels of symbolic play, and fewer shifts in symbolic meaning. Each of these predictions was borne out. The intimate developmental relation between social engagement and symbolic play appears to be important for explaining the developmental psychopathology of autism.
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9. Kang V, Wagner GC, Ming X. {{Gastrointestinal Dysfunction in Children With Autism Spectrum Disorders}}. {Autism Res};2014 (Apr 21)
Gastrointestinal (GI) dysfunctions are frequently reported by parents of children with autism spectrum disorders (ASD) and have been recently recognized as a comorbid condition. However, the clinical significance of these GI dysfunctions remains to be delineated. This study describes the clinical characteristics, associated comorbid disorders, and endoscopic and colonoscopic evaluation of GI dysfunction in a cohort of 164 children with ASD evaluated at a pediatric neurology practice. Symptoms of GI dysfunction were prevalent: 49% of the children reported one or more chronic GI complaints, 22% exhibited diarrhea, 26% suffered from constipation. Furthermore 13% of the parents reported their children to suffer from bloating and/or being gassy and while 10% of the parents reported vomiting or gastroesophageal reflux problems. Similar rates of GI symptoms were reported among pre-school and school-aged children. Inflammation of the gut was found in 6 of the 12 subjects who underwent endoscopic and colonoscopic evaluations, however clinical symptoms did not predict the results of the evaluation. GI dysfunction was significantly associated with sleep disorders and food intolerance, but not with irritability or aggressiveness. In summary, GI dysfunction was prevalent in this cohort of children with ASD, observations consistent with the reports of parents and other clinicians. We conclude that the GI dysfunction in ASD requires proper evaluation and treatment. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Malhi P, Singhi P. {{A retrospective study of toddlers with autism spectrum disorder: Clinical and developmental profile}}. {Ann Indian Acad Neurol};2014 (Jan);17(1):25-29.
OBJECTIVE: To retrospectively examine the developmental and clinical characteristics of children with autism spectrum disorders (ASD) in the first 2 years of life in order to narrow the interval between parental concern and getting a reliable diagnosis of autism. MATERIALS AND METHODS: The case records of 21 children in whom a diagnosis of ASD was made in the first 2 years of life and confirmed 6 months to 1 year later were examined. The inclusion criterion was absence of neurological, metabolic, or genetic disorders and sensory or motor impairments. These case records were maintained in the Pediatric Psychology Clinic at the Department of Pediatrics of a tertiary care teaching hospital in North India. RESULTS: The average age at presentation to the clinic was 21.23 months (SD = 2.18). The clinical characteristics that were found in two-thirds or more children included lack of speech, inability to follow verbal commands, lack of pretend play, no index finger pointing, difficulty in playing with toys in a constructive manner, lack of joint attention, and motor stereotypies. The mean IQ was 66.62 (SD = 15.11) and the mean SQ as measured by the Vineland Social Maturity Scale was 80.43 (SD = 17.45). CONCLUSIONS: Given the validity of early diagnosis over time, clinicians should be encouraged not only to make an early diagnosis but also to initiate early interventions in children with ASD.
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11. Micheau J, Vimeney A, Normand E, Mulle C, Riedel G. {{Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice}}. {Hippocampus};2014 (Apr 17)
Autism is a complex neurodevelopmental disorder with high heritability. grik2 (which encodes the GluK2 subunit of kainate receptors) has been identified as a susceptibility gene in Autism Spectrum Disorders (ASD), but its role in the core- and associated-symptoms of ASD still remains elusive.We used mice lacking GluK2 (GluK2 KO) to examine their endophenotype with a view to modeling aspects of autism, including social deficits, stereotyped and repetitive behaviour and decreased cognitive abilities. Anxiety was recorded in the elevated plus maze, social behaviour in a 3-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task. In addition, GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behaviour and showed no memory. However, GluK2 KO mice were impaired in spatial reversal learning. These behavioural data together with previously published electrophysiology showing severe anomalies in CA3 network activity, suggest a computational shift in this network for enhanced propensity of pattern completion that would explain the loss of behavioural flexibility in GluK2 KO mice. Although a single mutation cannot recapitulate the entire core symptoms of ASD, our data provide evidence for glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD. (c) 2014 Wiley Periodicals, Inc.
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12. Napoli E, Wong S, Hertz-Picciotto I, Giulivi C. {{Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism}}. {Pediatrics};2014 (Apr 21)
Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of >/=7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing >/=1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children’s mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.
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13. Rojas DC. {{The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment}}. {J Neural Transm};2014 (Apr 22)
Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.
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14. Smith AL, Romski M, Sevcik RA, Adamson LB, Barker RM. {{Parent Stress and Perceptions of Language Development: Comparing Down Syndrome and Other Developmental Disabilities}}. {Fam Relat};2014 (Feb);63(1):71-84.
This study extended research on the Down syndrome advantage by examining differences in parent stress and parent perceptions of language development between 29 parents of young children with Down syndrome and 82 parents of children with other developmental disabilities. Parents of children with Down syndrome reported lower levels of total stress, child-related stress, and stress surrounding the parent-child interaction. Parents of children in both groups reported that they felt successful in their ability to impact their children’s communication development but did differ on perceptions of difficulty such that parents of children with Down syndrome perceived their children’s communication difficulties as less severe despite the children exhibiting similar language skills. Finally, after accounting for potential explanatory confounding variables, child diagnosis remained a significant predictor of parent stress and perceptions of language development. Results highlight the importance of considering etiology when assisting families raising a child with a disability.
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15. Smith RM, Banks W, Hansen E, Sadee W, Herman GE. {{Family-Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder}}. {Autism Res};2014 (Apr 17)
The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor « A » allele of rs6311 to offspring with ASD (permuted P = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5′ untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5’UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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16. Zhao PW, He XL, Lin J, Wu GF, Yue X, Bi B, Hu JS, Liu ZS. {{[Clinical features and MECP2 mutations in children with Rett syndrome]}}. {Zhongguo Dang Dai Er Ke Za Zhi};2014 (Apr);16(4):393-396.
OBJECTIVE: To study the clinical features and mutations in methyl-CpG-binding protein 2 (MECP2) gene among children with classical Rett syndrome in China. METHODS: PCR and direct sequencing were employed to analyze the three exons of MECP2 gene in 9 children recently diagnosed with Rett syndrome and their parents. RESULTS: Heterozygous mutations were identified in 5 out of 9 patients, with a mutation rate of over 50%; there was one case of insert mutation (c.913insT) and 4 cases of missense mutation (exon 3: c.316C>T (R106W); exon 4: c.502C>T (R168X), c.808C>T (R270X), and c.1126C>T (P376S). A new mutation (c.913insT) was found. No mutations were detected in their parents. Two patients had MECP2 mutations in the transcriptional repression domain (TRD). They had almost lost language functions and were found to have significantly delayed development compared with other patients. CONCLUSIONS: Mutations in MECP2 gene were detected in 5 confirmed cases of Rett syndrome, and most of them were on exon 4. Mutations in the TRD of MECP2 protein may affect the language ability and development in children with Rett syndrome.
