1. Bemben MA, Nguyen QA, Wang T, Li Y, Nicoll RA, Roche KW. {{Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses}}. {Proc Natl Acad Sci U S A};2015 (Feb 9)
Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.
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2. Freeman SF, Gulsrud A, Kasari C. {{Brief Report: Linking Early Joint Attention and Play Abilities to Later Reports of Friendships for Children with ASD}}. {J Autism Dev Disord};2015 (Feb 13)
This study examined the influence of early joint attention and play in children with autism on child- and parent-reported friendship quality 5 years later. Initially, children participated in developmental, joint attention, and play measures. At follow-up (age 8-9), parents and children completed the Friendship Qualities Scale (Bukowski et al. in J Soc Personal Relatsh 11:471-484, 1994) rating the child’s friendship on companionship, help, security, closeness, and conflict. Parents and children described their children’s friendships similarly except children’s ratings were significantly higher than their parents on companionship. Children with better joint attention at age three reported their friendships to have higher closeness and lower conflict. Children with better initial play reported greater helpfulness. This study provides preliminary evidence linking early core abilities to later friendship qualities.
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3. Gordon RG, Watson LR. {{Brief Report: Gestures in Children at Risk for Autism Spectrum Disorders}}. {J Autism Dev Disord};2015 (Feb 13)
Retrospective video analyses indicate that disruptions in gesture use occur as early as 9-12 months of age in infants later diagnosed with autism spectrum disorders (ASD). We report a prospective study of gesture use in 42 children identified as at-risk for ASD using a general population screening. At age 13-15 months, gesture were more disrupted in infants who, at 20-24 months, met cutoffs for « autism » on the ADOS than for those who met cutoffs for « autism spectrum » or those who did not meet cutoffs for either, whereas these latter two groups displayed similar patterns of gesture use. Total gestures predicted later receptive and expressive language outcomes; therefore, gesture use may help identify infants who can benefit from early communication interventions.
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4. Hidding E, Swaab H, Vorstman JA, van Engeland H, Sijmens-Morcus ME, Klaassen PW, Duijff SN, de Sonneville LM. {{Intellectual functioning in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 deletion syndrome}}. {J Intellect Disabil Res};2015 (Feb 13)
BACKGROUND: The 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial syndrome) is associated with an increased risk of various disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). With this study, we aimed to investigate the relation between intellectual functioning and severity of ASD and ADHD symptomatology in 22q11DS. METHOD: A sample of 102 individuals (62 females) with 22q11DS aged 9 to 18.5 years were assessed using age appropriate Wechsler scales of intelligence as well as psychological and psychiatric assessment to evaluate the presence of ASD and ADHD symptomatology. RESULTS: Intelligence profiles were characterised by lower scores on the factor perceptual organisation and higher scores on the factor processing speed, with on subtest level higher scores on digit span and lower scores on arithmetic and vocabulary as compared with the mean factor or subtest score respectively. No differences in intelligence profiles were found between subgroups with and without ASD and/or ADHD. Low scores on coding were associated with higher severity of ASD symptomatology, while lower scores on block design were associated with more severe ADHD symptomatology. CONCLUSIONS: On several sub-domains of intelligence, poorer performance was associated with higher severity of ASD and ADHD symptomatology. The impact of developmental disorders in 22q11DS can be traced in specific domains of intellectual functioning as well as in severity of symptomatology.
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5. Johnston SB, Raines RT. {{Conformational Stability and Catalytic Activity of PTEN Variants Linked to Cancers and Autism Spectrum Disorders}}. {Biochemistry};2015 (Feb 13)
Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have activity higher than the activity of those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has conformational stability greater than that of the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism and suggest that PTEN-L is a repository for a critical catalytic activity.
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6. Malhi P, Singhi P. {{Adaptive Behavior Functioning in Children with Autism}}. {Indian J Pediatr};2015 (Feb 13)
OBJECTIVE: To investigate the relationship between intellectual functioning, symptom severity, and adaptive behavior functioning of children with autism spectrum disorders (ASD). METHODS: Retrospective case records (1999 to 2013) of 523 children [Mean age 4.79y (SD 2.37)] maintained by the Pediatric Psychology Unit at the Department of Pediatrics of a tertiary care teaching hospital in North India were examined. The adaptive behavior functioning was measured by the Indian adaptation of the Vineland Social Maturity Scale. Symptom severity was assessed using the Childhood Autism Rating Scale (CARS). RESULTS: The mean Social Quotient (SQ) of the sample was 62.40 (SD = 20.41). Nearly two-third (63.3%) of the ASD had SQs less than 70 and only 15% of the ASD children had SQs above 85. Adaptive behavior scores in the lower functioning ASD children were significantly higher than their Intelligence Quotient (IQ) scores while for the high functioning ASD group, the SQs were significantly lower than their IQs. Multiple regression analysis revealed that IQ, age of the child, CARS score, and education of the mother accounted for 62.5% of the variance in the SQ of children with ASD (F = 198.01, P 0.000). CONCLUSIONS: Adaptive behavior measures must constitute a crucial component of not only diagnostic assessment of ASD children but also as an important goal of treatment.
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7. Russo AJ. {{Decreased plasma myeloperoxidase associated with probiotic therapy in autistic children}}. {Clin Med Insights Pediatr};2015;9:13-17.
AIM: To assess plasma myeloperoxidase (MPO) levels in autistic children and to test the hypothesis that there is an association between decreased MPO concentration and probiotic therapy. SUBJECTS AND METHODS: Plasma from 49 autistic children (39 males; mean age 11.4 years) (17 with diagnosed gastrointestinal (GI) disease – chronic diarrhea and/or constipation (10 of these GI patients were taking probiotics) and 26 receiving probiotic therapy) and 36 neurotypical controls (29 males; mean age 10.2 years; controls were not assessed for GI disease) were tested for MPO plasma concentration using Enzyme Linked Immunosorbent Assays (ELISAs). Plasma concentration of MPO in autistic individuals was compared to plasma concentration of copper and zinc. RESULTS: We found that individuals with autism, receiving no therapy, did not have significantly lower plasma MPO levels when compared to controls. In the autistic group, MPO levels were significantly lower in individuals taking probiotic therapy. In addition, plasma copper levels were significantly lower in autistic individuals taking probiotics compared to those not taking probiotics, but plasma zinc levels were not different in the probiotic group. DISCUSSION: These results suggest a relationship between low MPO levels found in a group of autistic individuals and probiotic therapy. By possibly changing gut bacterial flora and thereby changing absorption properties in the gut, probiotic therapy was also associated with lower copper levels.
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8. Jin X, Chen L. {{Fragile X syndrome as a rare disease in China – Therapeutic challenges and opportunities}}. {Intractable Rare Dis Res};2015 (Feb);4(1):39-48.
Recognized as the most common inherited from of intellectual disability (ID) and the most common known monogenic cause of autism spectrum disorders (ASD), Fragile X syndrome (FXS) is identified as an unmet medical need for the development of personalized medicine and targeted therapeutics for neurodevelopment disorders as a result of improved understanding of the genetic and cellular mechanisms. Consequently promising pharmacological targets have emerged from basic and translational research, are now being pursued by global pharmaceutical and biotech companies in early proof-of-concept clinical trials. With the world’s largest rare disease population, China potentially has a large number of FXS patients, many of whom are under-diagnosed or even misdiagnosed, barely with any treatment. In spite of improved awareness of FXS in recent years, big gaps still exist between China and developed countries in multiple aspects. With increased public awareness, strong government support and investment, coupled with an increasingly large number of Western-trained experienced researchers engaging in new drug discovery and development, China has the potential to become an important player in the discovery of effective diagnostics and treatments for a rare disease like FXS.
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9. Weiss JA. {{Transdiagnostic Case Conceptualization of Emotional Problems in Youth with ASD: An Emotion Regulation Approach}}. {Clin Psychol (New York)};2014 (Dec);21(4):331-350.
Youth with autism spectrum disorder often struggle to cope with co-occurring anxiety, depression, or anger, and having both internalizing and externalizing symptoms is a common clinical presentation. A number of authors have designed cognitive-behavioral interventions to address transdiagnostic factors related to multiple emotional problems, although none have applied this focus to youth with ASD. The current review article describes how a transdiagnostic emotion regulation framework may inform cognitive-behavioral interventions for youth with ASD, which until now have focused almost exclusively on anxiety. Research is needed to empirically test how a transdiagnostic intervention can address the processes of emotion regulation and assist youth with ASD to cope with their emotional disorders.
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10. Jin LW, Horiuchi M, Wulff H, Liu XB, Cortopassi GA, Erickson JD, Maezawa I. {{Dysregulation of Glutamine Transporter SNAT1 in Rett Syndrome Microglia: A Mechanism for Mitochondrial Dysfunction and Neurotoxicity}}. {J Neurosci};2015 (Feb 11);35(6):2516-2529.
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT.
