1. Barua S, Kuizon S, Ted Brown W, Junaid MA. {{High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring}}. {J Mol Neurosci};2015 (Nov 7)
Maternal nutrients play critical roles in modulating epigenetic events and exert long-term influences on the progeny’s health. Folic acid (FA) supplementation during pregnancy has decreased the incidence of neural tube defects in newborns, but the influence of high doses of maternal FA supplementation on infants’ brain development is unclear. The present study was aimed at investigating the effects of a high dose of gestational FA on the expression of genes in the cerebral hemispheres (CHs) of 1-day-old pups. One week prior to mating and throughout the entire period of gestation, female C57BL/6J mice were fed a diet, containing FA at either 2 mg/kg (control diet (CD)) or 20 mg/kg (high maternal folic acid (HMFA)). At postnatal day 1, pups from different dams were sacrificed and CH tissues were collected. Quantitative RT-PCR and Western blot analysis confirmed sex-specific alterations in the expression of several genes that modulate various cellular functions (P < 0.05) in pups from the HMFA group. Genomic DNA methylation analysis showed no difference in the level of overall methylation in pups from the HMFA group. These findings demonstrate that HMFA supplementation alters offsprings' CH gene expression in a sex-specific manner. These changes may influence infants' brain development.
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2. Carmeli E, Bachar A, Rom O, Aizenbud D. {{Oxidative Stress and Nitric Oxide in Sedentary Older Adults with Intellectual and Developmental Disabilities}}. {Adv Exp Med Biol};2015 (Nov 6)
Individuals with moderate-to-profound intellectual and developmental disabilities (IDD) are characterized by significant cognitive deficits, abnormal muscle tone, poor posture and balance, and inactive lifestyle. Increased oxidative stress (OS) has been implicated in a variety of chronic diseases, inflammatory conditions, aging, and even following intense physical exercise. Nitric oxide (NO) is a highly reactive mediator that has been shown to play different roles in a variety of different biological process and in aging. The aim of the study was to investigate the serum levels of global OS and NO metabolites (NOx) in sedentary and non-sedentary older adults with IDD. Global OS was measured by CR 3000 instrument, FORM system, and NOx were measured by determination of serum nitrite levels. OS and NOx levels were significantly higher in sedentary IDD comparing non-sedentary controls. The increased of OS and NOx levels suggest their possible involvement in the phenomenon of ‘accelerated aging’ in IDD. Our findings can provide another aspect indicating both OS and NOx as possible biochemical markers and their potential application in minimizing their negative influence through future therapeutic strategies.
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3. Cummings JR, Lynch FL, Rust KC, Coleman KJ, Madden JM, Owen-Smith AA, Yau VM, Qian Y, Pearson KA, Crawford PM, Massolo ML, Quinn VP, Croen LA. {{Health Services Utilization Among Children With and Without Autism Spectrum Disorders}}. {J Autism Dev Disord};2015 (Nov 7)
Using data from multiple health systems (2009-2010) and the largest sample to date, this study compares health services use among youth with and without an autism spectrum disorder (ASD)-including preventive services not previously studied. To examine these differences, we estimated logistic and count data models, controlling for demographic characteristics, comorbid physical health, and mental health conditions. Results indicated that youth with an ASD had greater health care use in many categories, but were less likely to receive important preventive services including flu shots and other vaccinations. An improved understanding of the overall patterns of health care use among this population could enable health systems to facilitate the receipt of appropriate and effective health care.
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4. Drasgow E, Martin CA, Chezan LC, Wolfe K, Halle JW. {{Mand Training: An Examination of Response-Class Structure in Three Children With Autism and Severe Language Delays}}. {Behav Modif};2015 (Nov 5)
Our primary purpose in this study was to examine the structure of a response class when new members are acquired through mand training. To do this, we replaced existing mands (e.g., reaching) in three children with autism with two new functionally equivalent mands. Next, we examined their responding under immediate- and delayed-reinforcement conditions. Then, we assessed generalization to novel social partners. We employed a reversal design to examine the effectiveness of mand training and to assess responding under both immediate- and delayed-reinforcement conditions. Our results suggest that all children acquired the new mands and that two of the children emitted these responses as replacements when the social partner did not provide access to the reinforcer contingent on the child’s first mand. Generalization data indicate that all three children emitted the new mands and two of the children alternated between the new mands with novel social partners. We discuss the clinical implications and the conceptual significance of teaching multiple replacement mands to children with autism and severe language delays.
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5. Hirvikoski T, Mittendorfer-Rutz E, Boman M, Larsson H, Lichtenstein P, Bolte S. {{Premature mortality in autism spectrum disorder}}. {Br J Psychiatry};2015 (Nov 5)
BackgroundMortality has been suggested to be increased in autism spectrum disorder (ASD).AimsTo examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability.MethodOdds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185).ResultsDuring the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38-2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability.ConclusionsPremature mortality was markedly increased in ASD owing to a multitude of medical conditions.
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6. House SA, Goodman DC, Weinstein SJ, Chang CH, Wasserman JR, Morden NE. {{Prescription Use among Children with Autism Spectrum Disorders in Northern New England: Intensity and Small Area Variation}}. {J Pediatr};2015 (Nov 7)
OBJECTIVE: To measure prescription use intensity and regional variation of psychotropic and 2 important nonpsychotropic drug groups among children with autism spectrum disorders (ASDs) compared with children in the general population. STUDY DESIGN: Cross-sectional study of ambulatory prescription fills from Maine, Vermont, and New Hampshire all-payer administrative data, 2007-2010. RESULTS: Overall there were 13 100 children diagnosed with ASD (34 584 person years [PYs]) and 936 721 (1.7 million PYs) without ASD diagnosis. The overall prescription fill rate was 16.6 per PY in children with ASD and 4.1 per PY in the general population. Psychotropic use among children with ASDs was 9-fold the general population rate (7.80 vs 0.85 fills per PY); these children comprised 2.0% of the pediatric population but received 15.6% of psychotropics. Nonpsychotropic drug use was also higher in the population with ASD, particularly the youngest: among those under age 3 years, antibiotic use was 2-fold and antacid use nearly 5-fold the general population rate (3.2 vs 1.4 and 1.0 vs 0.2 per PY, respectively). Among children with ASDs, prescription use varied substantially across hospital service areas, as much as 3-fold for antacids and alpha agonists, more than 4-fold for benzodiazepines (5th to 95th percentile). CONCLUSIONS: The overall psychotropic and nonpsychotropic prescription intensity among children with ASDs is characterized by broad regional variation, suggesting diverse provider responses to pharmacotherapeutic uncertainty. This variation highlights a need for more research, practice-based learning, and shared decision making with caregivers surrounding therapy for children with ASDs.
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7. Johnco C, Storch EA. {{Anxiety in youth with autism spectrum disorders: implications for treatment}}. {Expert Rev Neurother};2015 (Nov);15(11):1343-1352.
Anxiety disorders are one of the most common psychiatric comorbidities among children and adolescents with autism spectrum disorders (ASD). There has been a recent proliferation of research examining the prevalence, phenomenology, assessment and treatment of anxiety disorders among youth with ASD. While there is currently very limited support for the use of pharmacological agents to treat anxiety among youth with ASD and comorbid anxiety, there has been overwhelming support across numerous modestly sized controlled studies for the efficacy of cognitive behavioral therapy. This review discusses advances in the treatment literature for anxiety in youth with ASD, and discusses the current evidence base for whether standard treatment needs to be adapted for this population.
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8. Kripke C. {{Capsule Commentary on Fortuna et al., Health Conditions and Functional Status in Adults with Autism: A Cross Sectional Evaluation}}. {J Gen Intern Med};2015 (Nov 5)
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9. Lai MC, Baron-Cohen S. {{Identifying the lost generation of adults with autism spectrum conditions}}. {Lancet Psychiatry};2015 (Nov);2(11):1013-1027.
Autism spectrum conditions comprise a set of early-onset neurodevelopmental syndromes with a prevalence of 1% across all ages. First diagnosis in adulthood has finally become recognised as an important clinical issue due to the increasing awareness of autism, broadening of diagnostic criteria, and the introduction of the spectrum concept. Thus, the idea of a lost generation of people who were previously excluded from a diagnosis of classic autism has arisen. Making a first diagnosis of autism spectrum conditions in adults can be challenging for practical reasons (eg, no person to provide a developmental history), developmental reasons (eg, the acquisition of learnt or camouflaging strategies), and clinical reasons (eg, high frequency of co-occurring disorders). The diagnostic process includes referral, screening, interviews with informants and patients, and functional assessments. In delineating differential diagnoses, true comorbidities, and overlapping behaviour with other psychiatric diagnoses, particular attention should be paid to anxiety, depression, obsessive-compulsive disorder, psychosis, personality disorders, and other neurodevelopmental disorders. Possible misdiagnosis, especially in women, should be explored. The creation of supportive, accepting, and autism-friendly social and physical environments is important and requires a coordinated effort across agencies and needs support from government policies.
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10. Luo SY, Wu LQ, Duan RH. {{Molecular medicine of fragile X syndrome: based on known molecular mechanisms}}. {World J Pediatr};2015 (Nov 7)
BACKGROUND: Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. DATA SOURCES: Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included « fragile X syndrome », « FXS and medication », « FXS and therapeutics » and « FXS and treatment ». Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. RESULTS: The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. CONCLUSIONS: Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.
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11. Mansour L, El Sobky E, Mohamed SM, Marzouk H, Tarek LA. {{Genotype-phenotype relationship among Egyptian children with Rett syndrome}}. {J Egypt Public Health Assoc};2015 (Sep);90(3):133-137.
BACKGROUND: Rett syndrome (RTT) is an X-linked dominant neurodegenerative disorder with various MECP2 mutations. RTT is one of the most common causes of severe intellectual and complex disability in girls. Therefore, the aims of the study were as follows: to highlight the clinical manifestations of RTT; to present the genotype-phenotype relationship; and to assess the possible relation between severity score, clinical manifestations, and MECP2 gene mutations. PATIENTS AND METHODS: The present cross-sectional study included 15 girls with typical RTT, diagnosed according to the international criteria of RTT. All included patients were followed up at the pediatric neurology clinic, Cairo University Specialized Pediatric Hospital. They were subjected to screening of the entire coding region of the MECP2 gene (MECP2A and MECP2B) using denaturing high-performance liquid chromatography. The clinical severity was assessed among RTT cases using the International Scoring System. RESULTS: Stereotypic hand movements were present in all cases, acquired microcephaly was present in 73.3% of cases, autistic features in 66.7% of cases, recurrent seizures in 53.3% of cases, delayed language development in 46.6% of cases, deterioration of speech in 53.3% of cases, and growth retardation and peripheral vasomotor changes in 46.6% of cases. Positive mutations were detected in 10 cases (66.66%): heterozygous for p.R270X mutation (three cases), heterozygous for p.R255X mutation (three cases), and heterozygous for p.R168X nonsense mutation (four cases). Microcephaly, seizures, growth retardation, and autistic features were more frequent in patients with a mutated gene; it was also observed that walking ability was more frequent in patients without a mutation.; thus, genotype-phenotype relationship was confirmed. The relationship between severity score and MECP2 mutation was detected in three cases with severe RTT, but there was no relationship between the severity score and specific MECP2 mutation. There was a relationship between the severity score and the clinical manifestations of RTT. CONCLUSION: Mutations of MECP2 analysis were detected in 66.7% of RTT cases. There were relationships between the severity score, clinical manifestations, and MECP2 gene mutations. However, there was no relationship between the severity score and specific MECP2 gene mutation.
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12. Nebel MB, Eloyan A, Nettles CA, Sweeney KL, Ament K, Ward RE, Choe AS, Barber AD, Pekar JJ, Mostofsky SH. {{Intrinsic Visual-Motor Synchrony Correlates With Social Deficits in Autism}}. {Biol Psychiatry};2015 (Sep 3)
BACKGROUND: Imitation, which is impaired in children with autism spectrum disorder (ASD) and critically depends on the integration of visual input with motor output, likely impacts both motor and social skill acquisition in children with ASD; however, it is unclear what brain mechanisms contribute to this impairment. Children with ASD also exhibit what appears to be an ASD-specific bias against using visual feedback during motor learning. Does the temporal congruity of intrinsic activity, or functional connectivity, between motor and visual brain regions contribute to ASD-associated deficits in imitation, motor, and social skills? METHODS: We acquired resting state functional magnetic resonance imaging scans from 100 8- to 12-year-old children (50 ASD). Group independent component analysis was used to estimate functional connectivity between visual and motor systems. Brain-behavior relationships were assessed by regressing functional connectivity measures with social deficit severity, imitation, and gesture performance scores. RESULTS: We observed increased intrinsic asynchrony between visual and motor systems in children with ASD and replicated this finding in an independent sample from the Autism Brain Imaging Data Exchange. Moreover, children with more out-of-sync intrinsic visual-motor activity displayed more severe autistic traits, while children with greater intrinsic visual-motor synchrony were better imitators. CONCLUSIONS: Our twice replicated findings confirm that visual-motor functional connectivity is disrupted in ASD. Furthermore, the observed temporal incongruity between visual and motor systems, which may reflect diminished integration of visual consequences with motor output, was predictive of the severity of social deficits and may contribute to impaired social-communicative skill development in children with ASD.
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13. Sellinger VJ, Elder JH. {{Parent Training Intervention to Manage Externalizing Behaviors in Children With Autism}}. {J Pediatr Health Care};2015 (Nov 7)
Children with autism spectrum disorder (ASD) are more likely than their typically developing peers to exhibit externalizing behaviors; however, the etiology in children with ASD may be different and related to the core deficits of the disorder. Although parent training interventions have been effective in decreasing externalizing behaviors in typically developing children, the effectiveness in children with ASD has not been established. An in-depth analysis of the child’s behavior may provide the foundation upon which to develop an individualized parent training approach. This case study illustrates how a functional assessment interview was used to obtain in-depth information about externalizing behaviors exhibited by a child with ASD who is high functioning and how this information was used to develop an individualized parent training intervention.
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14. Stutzman D, Dopheide J. {{Acetylcysteine for treatment of autism spectrum disorder symptoms}}. {Am J Health Syst Pharm};2015 (Nov 15);72(22):1956-1959.
PURPOSE: Successful use of acetylcysteine to control irritability and aggressive behaviors in a hospitalized adolescent patient with autism spectrum disorder (ASD) is described. SUMMARY: A 17-year-old Hispanic male with ASD and intellectual disability was hospitalized for inpatient psychiatric treatment due to impulsive and violent behavior. Despite receiving various medications in the initial weeks of hospitalization, including intramuscular lorazepam and diphenhydramine injections (four days a week on average), the patient continued to exhibit aggressive and unpredictable behaviors. Treatment with 20% acetylcysteine oral solution was initiated at a dosage of 600 mg twice daily as an adjunct to quetiapine therapy. Over the next six weeks, reductions in the patient’s aggressive behavior, tantrums, and irritability were noted. The use of as-needed medications to control aggression was decreased, and the dosage of quetiapine was lowered from 700 to 400 mg daily over the course of the hospitalization. Acetylcysteine was well tolerated, with no observed or reported adverse effects. Unlike clonidine or guanfacine (other medications used for ASD-related behavioral symptoms), acetylcysteine is not sedating; moreover, it lacks the metabolic, extrapyramidal, and endocrine adverse effects of atypical antipsychotics. Published data from small controlled trials and case reports suggest that acetylcysteine use is associated with improvements in irritability and aggression in prepubertal children with ASD; these therapeutic benefits may be associated with acetylcysteine’s glutamatergic, dopaminergic, antioxidant, and anti-inflammatory properties. CONCLUSION: Treatment with acetylcysteine improved ASD symptoms, including irritability and aggression, in a teenage patient.
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15. Tirado MJ, Saldana D. {{Readers with Autism Can Produce Inferences, but they Cannot Answer Inferential Questions}}. {J Autism Dev Disord};2015 (Nov 7)
Readers with autism (ASD), poor comprehension (PC), and typical development (TD) took part in three reading experiments requiring the production of inferences. In Experiments 1 and 2 reading times for target phrases-placed immediately after text implicitly indicating the emotion of a protagonist or after a number of filler sentences, respectively-were used as measures of inferencing. In Experiment 3, participants were explicitly asked to identify the protagonist’s emotion. There were no significant differences among groups in Experiment 1. Compared to TD readers, the PC group performed poorly in Experiments 2 and 3. ASD readers performed worse than PC participants only in the explicit-question task. Although ASD readers can produce inferences, they respond to questions about them with difficulty.
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16. Westwood H, Eisler I, Mandy W, Leppanen J, Treasure J, Tchanturia K. {{Using the Autism-Spectrum Quotient to Measure Autistic Traits in Anorexia Nervosa: A Systematic Review and Meta-Analysis}}. {J Autism Dev Disord};2015 (Nov 5)
Interest in the link between Autism Spectrum Disorder (ASD) and Anorexia Nervosa (AN) has led to estimates of the prevalence of autistic traits in AN. This systematic review and meta-analysis assessed the use of the Autism-Spectrum Quotient (AQ) or abbreviated version (AQ-10) to examine whether patients with AN have elevated levels of autistic traits. Seven studies were identified and subsequent meta-analysis indicated that those with AN appear to have significant difficulties of a manner characteristic of ASD, relative to controls. Whilst this analysis supports previous indications of higher prevalence of ASD in AN, the aetiology of these traits remains unclear. Studies using more robust clinical measures of ASD within AN are needed to confirm what self-report measures appear to show.
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17. Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, Wu Y, Wang J, Gao F, Wu X, Jiang Y. {{Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities}}. {PLoS One};2015;10(11):e0141782.
OBJECTIVE: Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD. METHODS: We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene. RESULTS: We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24). SIGNIFICANCE: We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort.
