Pubmed du 09/11/19

samedi 9 novembre 2019

1. Bankaitis VA, Xie Z. The neural stem cell/carnitine malnutrition hypothesis : New prospects for effective reduction of autism risk ?. J Biol Chem ;2019 (Nov 7)

Autism spectrum disorders (ASDs) are developmental neuropsychiatric disorders with heterogeneous etiologies. As the incidence of these disorders is rising, such disorders represent a major human health problem with escalating social cost. While recent years witnessed advances in our understanding of the genetic basis of some dysmorphic ASDs, little progress has been made in translating the improved understanding into effective strategies for ASD management or minimization of general ASD risk. Herein, we explore the idea, described in terms of the NSC/carnitine malnutrition hypothesis, that an unappreciated risk factor for ASD is diminished capacity for carnitine-dependent long-chain fatty acid beta-oxidation (FAO) in neural stem cells (NSCs) of the developing mammalian brain. The basic premise is that fetal carnitine status is a significant metabolic component in determining NSC vulnerability to derangements in their self-renewal program, and therefore to fetal ASD risk. As fetal carnitine status exhibits a genetic component that relates to de novo carnitine biosynthesis, and is sensitive to environmental and behavioral factors that affect maternal circulating carnitine levels to which the fetus is exposed, we propose reduced carnitine availability during gestation is a common risk factor that lurks beneath the genetically complex ASD horizon. One major prediction of the NSC/carnitine malnutrition hypothesis is that a significant component of ASD risk might be effectively managed from a public policy perspective by implementing a carnitine surveillance and dietary supplementation strategy for women planning pregnancies, and for women in their first trimester of pregnancy. We argue this prediction is deserving of serious clinical interrogation.

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2. Cascio L, Chen CF, Pauly R, Srikanth S, Jones K, Skinner CD, Stevenson RE, Schwartz CE, Boccuto L. Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder. Mol Genet Genomic Med ;2019 (Nov 7):e1036.

BACKGROUND : Autism spectrum disorder (ASD) is a common neurodevelopmental disorder whose molecular mechanisms are largely unknown. Several studies have shown an association between ASD and abnormalities in the metabolism of amino acids, specifically tryptophan and branched-chain amino acids (BCAAs). METHODS : Ninety-seven patients with ASD were screened by Sanger sequencing the genes encoding the heavy (SLC3A2) and light subunits (SLC7A5 and SLC7A8) of the large amino acid transporters (LAT) 1 and 2. LAT1 and 2 are responsible for the transportation of tryptophan and BCAA across the blood-brain barrier and are expressed both in blood and brain. Functional studies were performed employing the Biolog Phenotype Microarray Mammalian (PM-M) technology to investigate the metabolic profiling in lymphoblastoid cell lines from 43 patients with ASD and 50 controls with particular focus on the amino acid substrates of LATs. RESULTS : We detected nine likely pathogenic variants in 11 of 97 patients (11.3%) : three in SLC3A2, three in SLC7A5, and three in SLC7A8. Six variants of unknown significance were detected in eight patients, two of which also carrying a likely pathogenic variant. The functional studies showed a consistently reduced utilization of tryptophan, accompanied by evidence of reduced utilization of other large aromatic amino acids (LAAs), either alone or as part of a dipeptide. CONCLUSION : Coding variants in the LAT genes were detected in 17 of 97 patients with ASD (17.5%). Metabolic assays indicate that such abnormalities affect the utilization of certain amino acids, particularly tryptophan and other LAAs, with potential consequences on their transport across the blood barrier and their availability during brain development. Therefore, abnormalities in the LAT1 and two transporters are likely associated with an increased risk of developing ASD.

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3. Chandrasekhar T. Supporting the needs of college students with autism spectrum disorder. J Am Coll Health ;2019 (Nov 8):1-4.

Objective : Young adults with autism spectrum disorder (ASD) are enrolling in colleges at increasing rates. This case highlights the need for college mental health clinicians to be aware of features of ASD in emerging adults. Participants : A case of a young woman with dysphoria and anxiety who also met ASD criteria during a diagnostic evaluation. Methods : The author describes diagnostic criteria for ASD, common psychiatric co-morbidities, and commonly used campus services. Results : The student in this case was diagnosed with ASD during the course of treatment for dysphoria and anxiety. Knowledge of this diagnosis led to better self-understanding and discovery of new supports. Conclusions : College mental health clinicians will increasingly encounter students with ASD whose social and communication challenges impact their success in post-secondary educational environments. Clinicians should be knowledgeable of ASD features, common mental health challenges, and how best to support students.

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4. D’Antoni S, de Bari L, Valenti D, Borro M, Bonaccorso CM, Simmaco M, Vacca RA, Catania MV. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome. Biol Chem ;2019 (Nov 8)

Impaired energy metabolism may play a role in the pathogenesis of neurodevelopmental disorders including fragile X syndrome (FXS). We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS. We found that, despite a hyperactivation of MRC complexes, adenosine triphosphate (ATP) production via mitochondrial oxidative phosphorylation (OXPHOS) is compromised, resulting in brain energy impairment in juvenile and late-adult Fmr1 KO mice. Thus, an altered mitochondrial energy metabolism may contribute to neurological impairment in FXS.

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5. Kim JW, Kim HW, Moon DS, Lim YS, McDougle CJ, Howe YJ. Comparison of Services for Autism Spectrum Disorder in Massachusetts with Those in Seoul. J Korean Med Sci ;2019 (Nov 11) ;34(43):e288.

BACKGROUND : This article intended to identify and describe areas in need of services and interventions for individuals with autism spectrum disorder (ASD) and their families in Seoul, Korea. METHODS : A descriptive comparison was made between available services and interventions in Seoul, Korea and Massachusetts, USA. Relevant information was obtained through sending phone/email inquiries to the governments and organizations, visiting their official websites, and searching for published articles or reports. RESULTS : In a few areas such as level of education, economy, and general quality of healthcare, Seoul was found to be similar to Massachusetts. However, in terms of services and interventions for individuals with ASD and their families, especially early identification and intervention, special education, care coordination, school-based programs, and transition to adulthood, Massachusetts was shown to have far more availability. CONCLUSION : The limited availability of services and interventions for individuals with ASD and their families in Seoul in comparison to Massachusetts, underlines target areas for further investment and development.

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6. Malaia EA, Ahn S, Rubchinsky LL. Dysregulation of Temporal Dynamics of Synchronous Neural Activity in Adolescents on Autism Spectrum. Autism Res ;2019 (Nov 8)

Autism spectrum disorder is increasingly understood to be based on atypical signal transfer among multiple interconnected networks in the brain. Relative temporal patterns of neural activity have been shown to underlie both the altered neurophysiology and the altered behaviors in a variety of neurogenic disorders. We assessed brain network dynamics variability in autism spectrum disorders (ASD) using measures of synchronization (phase-locking) strength, and timing of synchronization and desynchronization of neural activity (desynchronization ratio) across frequency bands of resting-state electroencephalography (EEG). Our analysis indicated that frontoparietal synchronization is higher in ASD but with more short periods of desynchronization. It also indicates that the relationship between the properties of neural synchronization and behavior is different in ASD and typically developing populations. Recent theoretical studies suggest that neural networks with a high desynchronization ratio have increased sensitivity to inputs. Our results point to the potential significance of this phenomenon to the autistic brain. This sensitivity may disrupt the production of an appropriate neural and behavioral responses to external stimuli. Cognitive processes dependent on the integration of activity from multiple networks maybe, as a result, particularly vulnerable to disruption. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Parts of the brain can work together by synchronizing the activity of the neurons. We recorded the electrical activity of the brain in adolescents with autism spectrum disorder and then compared the recording to that of their peers without the diagnosis. We found that in participants with autism, there were a lot of very short time periods of non-synchronized activity between frontal and parietal parts of the brain. Mathematical models show that the brain system with this kind of activity is very sensitive to external events.

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7. Moodliar S, Naguy A, Elsori DH, AlKhadhari S. Paliperidone-Associated Priapism in an Autistic Child. Am J Ther ;2019 (Nov 4)

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8. Naveed S, Waqas A, Amray AN, Memon RI, Javed N, Tahir MA, Ghozy S, Jahan N, Khan AS, Rahman A. Implementation and effectiveness of non-specialist mediated interventions for children with Autism Spectrum Disorder : A systematic review and meta-analysis. PLoS One ;2019 ;14(11):e0224362.

INTRODUCTION : In recent years, several non-specialist mediated interventions have been developed and tested to address problematic symptoms associated with autism. These can be implemented with a fraction of cost required for specialist delivered interventions. This review represents a robust evidence of clinical effectiveness of these interventions in improving the social, motor and communication deficits among children with autism. METHODS : An electronic search was conducted in eight academic databases from their inception to 31st December 2018. A total of 31 randomized controlled trials were published post-2010 while only 2 were published prior to it. Outcomes pertaining to communication, social skills and caregiver-child relationship were meta-analyzed when reported in > 2 studies. RESULTS : A significant improvement was noted in child distress (SMD = 0.55), communication (SMD = 0.23), expressive language (SMD = 0.47), joint engagement (SMD = 0.63), motor skills (SMD = 0.25), parental distress (SMD = 0.33) parental self-efficacy (SMD = 0.42) parent-child relationship (SMD = 0.67) repetitive behaviors (SMD = 0.33), self-regulation (SMD = 0.54), social skills (SMD = 0.53) symptom severity (SMD = 0.44) and visual reception (SMD = 0.29). CONCLUSION : Non-specialist mediated interventions for autism spectrum disorder demonstrate effectiveness across a range of outcomes for children with autism and their caregivers.

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9. Nicholas DB, Mitchell W, Zulla R, Solomatin E, Qi S. A Review of CommunityWorks Canada((R)) : Toward Employability Among High School-Age Youth With Autism Spectrum Disorder. Glob Pediatr Health ;2019 ;6:2333794x19885542.

CommunityWorks Canada((R)) is a 12-week (30-hour) program that provides social, communication, and job skill-building activities as well as peer mentorship to youth with autism spectrum disorder. Administration of a pre- and postprogram employment readiness measure (n = 76 participants) demonstrated positive changes as reflected by the participants’ decreased concerns about their responsibility, flexibility, job skills, communication, self-view, and health and safety. Postprogram qualitative interviews and survey data collected from a range of program stakeholders (participants, parents, peer mentors, and community partners/employers) corroborated identified gains in personal development, employment exposure, work proficiency, and comfort in work settings. For community partners/employers and peer mentors, greater understanding about autism spectrum disorder and commitment to inclusive hiring reportedly resulted from program engagement. Implications and recommendations are offered.

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10. Singh J, Lanzarini E, Santosh P. Autonomic dysfunction and sudden death in patients with Rett syndrome : a systematic review. J Psychiatry Neurosci ;2019 (Nov 8) ;45(1):190033.

Background : Rett syndrome (RTT), a debilitating neuropsychiatric disorder that begins in early childhood, is characterized by impairments in the autonomic nervous system that can lead to sudden unexpected death. This study explores the mechanisms of autonomic dysfunction to identify potential risk factors for sudden death in patients with RTT. Methods : Following the Reporting Items for Systematic Review and Meta-Analyses (PRISMA) criteria, we undertook comprehensive systematic reviews using the PubMed, Scopus, Cochrane, PsycINFO, Embase and Web of Science databases. Results : We identified and critically appraised 39 articles for autonomic dysfunction and 5 for sudden death that satisfied the eligibility criteria. Following thematic analysis, we identified 7 themes : breathing irregularities, abnormal spontaneous brainstem activations, heart rate variability metrics, QTc changes, vagal imbalance, fluctuation in peptides and serotonergic neurotransmission. We grouped these 7 themes into 3 final themes : (A) brainstem modulation of breathing, (B) electrical instability of the cardiovascular system and (C) neurochemical changes contributing to autonomic decline. We described key evidence relating to each theme and identified important areas that could improve the clinical management of patients with RTT. Limitations : The heterogeneity of the methods used to assess autonomic function increased the difficulty of making inferences from the different studies. Conclusion : This study identified the important mediators of autonomic dysfunction and sudden death in patients with RTT. We proposed brainstem mechanisms and emphasized risk factors that increase brainstem vulnerability. We discussed clinical management to reduce sudden death and future directions for this vulnerable population.

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11. Song J, Yang X, Zhou Y, Chen L, Zhang X, Liu Z, Niu W, Zhan N, Fan X, Khan AA, Kuang Y, Song L, He G, Li W. Dysregulation of neuron differentiation in an autistic savant with exceptional memory. Mol Brain ;2019 (Nov 7) ;12(1):91.

Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders without a unique or definite underlying pathogenesis. Although savant syndrome is common in ASD, few models are available for studying the molecular and cellular mechanisms of this syndrome. In this study, we generated urinary induced pluripotent stem cells (UiPSCs) from a 13-year-old male autistic savant with exceptional memory. The UiPSC-derived neurons of the autistic savant exhibited upregulated expression levels of ASD genes/learning difficulty-related genes, namely PAX6, TBR1 and FOXP2, accompanied by hypertrophic neural somas, enlarged spines, reduced spine density, and an increased frequency of spontaneous excitatory postsynaptic currents. Although this study involved only a single patient and a single control because of the rarity of such cases, it provides the first autistic savant UiPSC model that elucidates the potential cellular mechanisms underlying the condition.

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12. Zhou J, Hu Q, Wang X, Cheng W, Pan C, Xing X. Development and validation of a novel and robust blood small nuclear RNA signature in diagnosing autism spectrum disorder. Medicine (Baltimore) ;2019 (Nov) ;98(45):e17858.

Reliable molecular signatures are needed to improve the early and accurate diagnosis of autism spectrum disorder (ASD), and indicate physicians to provide timely intervention. This study aimed to identify a robust blood small nuclear RNA (snRNA) signature in diagnosing ASD. 186 blood samples in the microarray dataset were randomly divided into the training set (n = 112) and validation set (n = 72). Then, the microarray probe expression profiles were re-annotated into the expression profiles of 1253 snRNAs though probe sequence mapping. In the training set, least absolute shrinkage and selection operator (LASSO) penalized generalized linear model was adopted to identify the 9-snRNA signature (RNU1-16P, RNU6-1031P, RNU6-258P, RNU6-335P, RNU6-485P, RNU6-549P, RNU6-98P, RNU6ATAC26P, and RNVU1-15), and a diagnostic score was calculated for each sample according to the snRNA expression levels and the model coefficients. The score demonstrated a good diagnostic ability for ASD in the training set (area under receiver operating characteristic curve (AUC) = 0.90), validation set (AUC = 0.87), and the overall (AUC = 0.88). Moreover, the blood samples of 23 ASD patients and 23 age- and gender-matched controls were collected as the external validation set, in which the signature also showed a good diagnostic ability for ASD (AUC = 0.88). In subgroup analysis, the signature was robust when considering the confounders of gender, age, and disease subtypes, and displayed a significantly better performance among the female and younger cases (P = .039 ; P = .002). In comparison with a 55-gene signature deriving from the same dataset, the snRNA signature showed a better diagnostic ability (AUC : 0.88 vs 0.80, P = .049). In conclusion, this study identified a novel and robust blood snRNA signature in diagnosing ASD, which might help improve the diagnostic accuracy for ASD in clinical practice. Nevertheless, a large-scale prospective study was needed to validate our results.

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