1. DeSoto MC. {{Speculations on vitamin K, VKORC1 genotype and autism}}. {Med Hypotheses};2016 (Nov);96:30-33.
Humans vary in the gene that encodes for Vitamin K epoxide reductase complex (VKORC1). Recent research has documented the protective effect of Vitamin K on neural cells and its role in maintaining normal neural development. Of interest, specific neural effects of Vitamin K overlap with key brain development aberrations, including those associated with autism. Furthermore, Vitamin K protects against oxidative stress associated with toxic exposure. Research on the neural effects is reviewed, and a small sample of severely autistic children of Somali descent residing in the Minneapolis/St. Paul area of Minnesota were genotyped and found to have a higher than expected genetic substitution that results in reduction in the efficiency of the Vitamin K cycle. The possibility that this genetic difference could play an etiological role in the development of autism is considered.
Lien vers le texte intégral (Open Access ou abonnement)
2. Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, Buie TM, Kelly DL, Cascella N, Fasano A. {{Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders}}. {Mol Autism};2016;7:49.
BACKGROUND: Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene-environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. METHODS: Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. RESULTS: Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls. CONCLUSIONS: In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.
Lien vers le texte intégral (Open Access ou abonnement)
3. Fluegge K. {{Adipic acid and autism spectrum disorders: A confounding role for environmental exposure to nitrous oxide}}. {Psychiatry Res};2016 (Dec 02);247:330-331.
Lien vers le texte intégral (Open Access ou abonnement)
4. Inga Jacome MC, Morales Chacon LM, Vera Cuesta H, Maragoto Rizo C, Whilby Santiesteban M, Ramos Hernandez L, Noris Garcia E, Gonzalez Fraguela ME, Fernandez Verdecia CI, Vegas Hurtado Y, Siniscalco D, Goncalves CA, Robinson-Agramonte ML. {{Peripheral Inflammatory Markers Contributing to Comorbidities in Autism}}. {Behav Sci (Basel)};2016 (Dec 14);6(4)
This study evaluates the contribution of peripheral biomarkers to comorbidities and clinical findings in autism. Seventeen autistic children and age-matched typically developing (AMTD), between three to nine years old were evaluated. The diagnostic followed the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DMS-IV) and the Childhood Autism Rating Scale (CARS) was applied to classify the severity. Cytokine profile was evaluated in plasma using a sandwich type ELISA. Paraclinical events included electroencephalography (EEG) record. Statistical analysis was done to explore significant differences in cytokine profile between autism and AMTD groups and respect clinical and paraclinical parameters. Significant differences were found to IL-1beta, IL-6, IL-17, IL-12p40, and IL-12p70 cytokines in individuals with autism compared with AMTD (p < 0.05). All autistic patients showed interictalepileptiform activity at EEG, however, only 37.5% suffered epilepsy. There was not a regional focalization of the abnormalities that were detectable with EEG in autistic patients with history of epilepsy. A higher IL-6 level was observed in patients without history of epilepsy with interictalepileptiform activity in the frontal brain region, p < 0.05. In conclusion, peripheral inflammatory markers might be useful as potential biomarkers to predict comorbidities in autism as well as reinforce and aid informed decision-making related to EEG findings in children with Autism spectrum disorders (ASD). Lien vers le texte intégral (Open Access ou abonnement)
5. Ji X, Kember RL, Brown CD, Bucan M. {{Increased burden of deleterious variants in essential genes in autism spectrum disorder}}. {Proc Natl Acad Sci U S A};2016 (Dec 12)
Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.
Lien vers le texte intégral (Open Access ou abonnement)
6. Karakoc Demirkaya S, Tutkunkardas MD, Mukaddes NM. {{Assessment of suicidality in children and adolescents with diagnosis of high functioning autism spectrum disorder in a Turkish clinical sample}}. {Neuropsychiatr Dis Treat};2016;12:2921-2926.
OBJECTIVES: Considering that suicide is one of the most common reasons of adolescent death worldwide, there is a lack of clinical awareness on suicidal behaviors of children and adolescents with autism spectrum disorder (ASD). The present study aims to assess the rate of suicidality (suicidal ideation, behaviors and attempts) and associated risk factors for suicidality in high functioning ASD. METHODS: Medical records of 55 adolescents (six girls, 49 boys), aged between 7-20 years, with diagnosis of ASD were reviewed. The participants were all able to speak fluently and had no significant limitations in intellectual functioning. Clinical assessment of participants was carried out on the basis of Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision criteria and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Eskin’s Suicide Screening Questionnaire and sociodemographic data form including detailed history of suicidal behaviors were used. The study group was also divided into suicidal and non-suicidal groups for the purpose of comparing the results. RESULTS: The rate of suicidal behaviors was 29% and suicide attempt was 12.7%. Types of suicidality were behaviors (43.7%), thoughts (37.5%), and verbal declarations (18.7%). A number of bizarre acts were recorded. Rates of comorbid psychiatric disorders such as mood disorders, anxiety disorders and disruptive behaviors were 23.6%, 43.6% and 65.4% respectively. Groups with the psychotic features, positive family history for suicidal behaviors and completed suicide showed more suicidality than the non-suicidal group. CONCLUSION: Consistent with the previous findings, rate of suicidality is higher in individuals with ASD. The type of suicidal behaviors showed some differences compared to typically developing individuals. The presence of psychotic features and positive family history for suicidality may be risk factors for suicidality in children and adolescents with ASD. To prevent suicide and implement protective health care systems, identifying the population at risk is crucial.
Lien vers le texte intégral (Open Access ou abonnement)
7. Naaijen J, Zwiers MP, Amiri H, Williams SC, Durston S, Oranje B, Brandeis D, Boecker-Schlier R, Ruf M, Wolf I, Banaschewski T, Glennon JC, Franke B, Buitelaar JK, Lythgoe DJ. {{Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder}}. {Neuropsychopharmacology};2016 (Dec 14)
Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8-13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.Neuropsychopharmacology advance online publication, 14 December 2016; doi:10.1038/npp.2016.260.
Lien vers le texte intégral (Open Access ou abonnement)
8. Ogawa S, Lee YA, Yamaguchi Y, Shibata Y, Goto Y. {{Associations of Acute and Chronic Stress Hormones with Cognitive Functions in Autism Spectrum Disorder}}. {Neuroscience};2016 (Dec 09)
Extensive studies have reported cognitive abnormalities in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Another line of evidence suggests that stress also affects cognitive functions. In this study, we investigated whether there were associations between stress hormones and cognitive functions in ASD and typically developing (TD) children. Cognitive functions in ASD and typically developing (TD) children were evaluated with a battery of psychological tests for working memory, behavioral flexibility, and social cognition for emotional assessments of others. ASD children exhibited higher hair and salivary cortisol, which reflects chronic and acute stress hormone levels of subjects, respectively, than TD children. Autism-spectrum quotient (AQ) scores were positively correlated with hair cortisol and the scores of Spence Children’s Anxiety Scale in ASD children. In addition, a negative correlation was present between spatial working memory performance and hair cortisol in ASD, but not in TD, children. These results suggest that chronic stress hormone elevation may have relationships with some aspects of cognitive dysfunction in ASD subjects.
Lien vers le texte intégral (Open Access ou abonnement)
9. Packer A. {{Enrichment of factors regulating canonical Wnt signaling among autism risk genes}}. {Mol Psychiatry};2016 (Dec 13)
Lien vers le texte intégral (Open Access ou abonnement)
10. Rubinstein M, Patowary A, Stanaway IB, McCord E, Nesbitt RR, Archer M, Scheuer T, Nickerson D, Raskind WH, Wijsman EM, Bernier R, Catterall WA, Brkanac Z. {{Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism}}. {Mol Psychiatry};2016 (Dec 13)
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.Molecular Psychiatry advance online publication, 13 December 2016; doi:10.1038/mp.2016.222.
Lien vers le texte intégral (Open Access ou abonnement)
11. Shelton AL, Cornish KM, Kolbe S, Clough M, Slater HR, Li X, Kraan CM, Bui QM, Godler DE, Fielding J. {{Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females}}. {Transl Psychiatry};2016 (Dec 13);6(12):e984.
DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism. Lien vers le texte intégral (Open Access ou abonnement)
12. Shire SY, Chang YC, Shih W, Bracaglia S, Kodjoe M, Kasari C. {{Hybrid implementation model of community-partnered early intervention for toddlers with autism: a randomized trial}}. {J Child Psychol Psychiatry};2016 (Dec 14)
BACKGROUND: Interventions found to be effective in research settings are often not as effective when implemented in community settings. Considering children with autism, studies have rarely examined the efficacy of laboratory-tested interventions on child outcomes in community settings using randomized controlled designs. METHODS: One hundred and thirteen children with autism enrolled in public early intervention classrooms in low resource neighborhoods were randomized to Joint Attention, Symbolic Play, Engagement, and Regulation (JASPER) intervention or treatment as usual waitlist for 10 weeks with 1-month follow-up. RESULTS: Teaching assistants delivered JASPER at adequate fidelity. Children randomized to JASPER demonstrated significant gains over treatment as usual in core developmental outcomes of joint engagement, joint attention, and play skills that were maintained at follow-up. CONCLUSIONS: Supervised teaching assistants delivered JASPER intervention with a range of toddlers with autism leading to significant gains in developmental outcomes.
Lien vers le texte intégral (Open Access ou abonnement)
13. Wadsworth HM, Maximo JO, Lemelman AR, Clayton K, Sivaraman S, Deshpande HD, Ver Hoef L, Kana RK. {{The Action Imitation Network and Motor Imitation in Children and Adolescents with Autism}}. {Neuroscience};2016 (Dec 09)
While deficits in imitation had been reported in children with autism spectrum disorder (ASD), its exact nature remains unclear. A dysfunction in mirroring mechanisms (through action imitation) has been proposed by some studies to explain this, although some recent evidence points against this hypothesis. The current study used behavior and functional MRI to examine the integrated functioning of the regions that are considered part of the Action Imitation network (AIN) in children and adolescents with ASD during a motor imitation task. Fourteen ASD and 15 age-and-IQ-matched typically developing (TD) children were asked to imitate a series of hand gestures in the MRI scanner. Intact performance on imitation (accurate imitation of hand gestures outside the scanner) in both ASD and TD groups was accompanied by significantly lower activity in ASD participants, relative to TD, in right angular gyrus, precentral gyrus, and left middle cingulate. In addition, autism traits were found to be significantly correlated with activation in the right angular gyrus. Overall, the findings of this study support the role of AIN in imitation and a potential difference in the recruitment of this network in ASD children.
