1. Bal VH, Kim SH, Cheong D, Lord C. {{Daily living skills in individuals with autism spectrum disorder from 2 to 21 years of age}}. {Autism};2015 (Apr 28)
Daily living skills (DLS), such as personal hygiene, meal preparation, and money management, are important to independent living. Research suggests that many individuals with autism spectrum disorder exhibit impairments in daily living skills relative to their cognitive skills. This study examined predictors of daily living skills attainment and trajectories of daily living skills in a longitudinal sample referred for possible autism spectrum disorder and followed from 2 to 21 years of age. Consistent with previous studies, participants with autism spectrum disorder and nonspectrum diagnoses showed continual development of daily living skills throughout childhood and adolescence. Early childhood nonverbal mental age was the strongest predictor of daily living skills attainment for both diagnostic groups. Group-based modeling suggested two distinct trajectories of daily living skills development for participants with autism spectrum disorder. Skill levels for both groups of young adults with autism spectrum disorder remained considerably below age level expectations. Whereas the « High-DLS » group gained approximately 12 years in daily living skills from T2 to T21, the « Low-DLS » group’s daily living skills improved 3-4 years over the 16- to 19-year study period. Nonverbal mental age, receptive language, and social-communication impairment at 2 years predicted High- versus Low-DLS group membership. Receiving greater than 20 h of parent-implemented intervention before age 3 was also associated with daily living skills trajectory. Results suggest that daily living skills should be a focus of treatment plans for individuals with autism spectrum disorder, particularly adolescents transitioning to young adulthood.
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2. Basuta K, Schneider A, Gane L, Polussa J, Woodruff B, Pretto D, Hagerman R, Tassone F. {{High functioning male with fragile X syndrome and fragile x-associated tremor/ataxia syndrome}}. {Am J Med Genet A};2015 (Apr 29)
Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. (c) 2015 Wiley Periodicals, Inc.
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3. Choucair N, Ghoch JA, Corbani S, Cacciagli P, Mignon-Ravix C, Salem N, Jalkh N, El Sabbagh S, Fawaz A, Ibrahim T, Villard L, Megarbane A, Chouery E. {{Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients}}. {Mol Cytogenet};2015;8:26.
BACKGROUND: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. RESULTS: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient’s unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. CONCLUSION: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs.
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4. Fiske KE, Isenhower RW, Bamond MJ, Delmolino L, Sloman KN, LaRue RH. {{Assessing the value of token reinforcement for individuals with autism}}. {J Appl Behav Anal};2015 (Apr 30)
The use of token systems has been supported across a variety of populations, but little research has evaluated the reinforcing value of token systems for individuals with autism. We used progressive-ratio schedules to compare the reinforcing value of an established token system, primary reinforcement, and tokens unpaired with reinforcement. Token systems were variably reinforcing for 2 students with autism and more so than primary reinforcement for 1 student. Results support formal assessment of the effectiveness of token systems.
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5. Gharib A, Mier D, Adolphs R, Shimojo S. {{Eyetracking of Social Preference Choices Reveals Normal but Faster Processing in Autism}}. {Neuropsychologia};2015 (Apr 25)
People with autism spectrum disorder (ASD) have been reported to show atypical attention and evaluative processing, in particular for social stimuli such as faces. The usual measure in these studies is an explicit, subjective judgment, which is the culmination of complex-temporally extended processes that are not typically dissected in detail. Here we addressed a neglected aspect of social decision-making in order to gain further insight into the underlying mechanisms: the temporal evolution of the choice. We investigated this issue by quantifying the alternating patterns of gaze onto faces, as well as nonsocial stimuli, while subjects had to decide which of the two stimuli they preferred. Surprisingly, the temporal profile of fixations relating to choice (the so-called « gaze cascade ») was entirely normal in ASD, as were the eventual preference choices. Despite these similarities, we found two key abnormalities: People with ASD made choices more rapidly than did control subjects across the board, and their reaction times for social preference judgments were insensitive to choice difficulty. We suggest that ASD features an altered decision-making process when basing choice on social preferences. One hypothesis motivated by these data is that a choice criterion is reached in ASD regardless of the discriminability of the options.
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6. Gross C, Chang CW, Kelly SM, Bhattacharya A, McBride SM, Danielson SW, Jiang MQ, Chan CB, Ye K, Gibson JR, Klann E, Jongens TA, Moberg KH, Huber KM, Bassell GJ. {{Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome}}. {Cell Rep};2015 (Apr 21)
The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.
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7. Gross C, Raj N, Molinaro G, Allen AG, Whyte AJ, Gibson JR, Huber KM, Gourley SL, Bassell GJ. {{Selective Role of the Catalytic PI3K Subunit p110beta in Impaired Higher Order Cognition in Fragile X Syndrome}}. {Cell Rep};2015 (Apr 22)
Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110beta plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110beta, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110beta in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110beta knockdown. Our results suggest that FMRP-mediated control of p110beta is crucial for neuronal protein synthesis and cognition.
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8. Hara M, Ohba C, Yamashita Y, Saitsu H, Matsumoto N, Matsuishi T. {{De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient}}. {Am J Med Genet A};2015 (Apr 30)
Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability. (c) 2015 Wiley Periodicals, Inc.
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9. Hull MM, Madhavan D, Zaroff CM. {{Autistic spectrum disorder, epilepsy, and vagus nerve stimulation}}. {Childs Nerv Syst};2015 (Apr 29)
PURPOSE: In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizure control and a positive behavioral side effect profile. We aimed to examine the behavioral side effect profile using longitudinal and quantitative data and review the potential mechanisms behind behavioral changes. METHODS: We present a case report of a 10-year-old boy with autistic spectrum disorder and epilepsy, who underwent vagus nerve stimulation subsequent to unsuccessful treatment with antiepileptic medication. RESULTS: Following vagus nerve stimulation implantation, initial, if temporary, improvement was observed in seizure control. Modest improvements were also observed in behavior and development, improvements which were observed independent of seizure control. CONCLUSIONS: Vagus nerve stimulation in autistic spectrum disorder is associated with modest behavioral improvement, with unidentified etiology, although several candidates for this improvement are evident.
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10. Kindregan D, Gallagher L, Gormley J. {{Gait deviations in children with autism spectrum disorders: a review}}. {Autism Res Treat};2015;2015:741480.
In recent years, it has become clear that children with autism spectrum disorders (ASDs) have difficulty with gross motor function and coordination, factors which influence gait. Knowledge of gait abnormalities may be useful for assessment and treatment planning. This paper reviews the literature assessing gait deviations in children with ASD. Five online databases were searched using keywords « gait » and « autism, » and 11 studies were found which examined gait in childhood ASD. Children with ASD tend to augment their walking stability with a reduced stride length, increased step width and therefore wider base of support, and increased time in the stance phase. Children with ASD have reduced range of motion at the ankle and knee during gait, with increased hip flexion. Decreased peak hip flexor and ankle plantar flexor moments in children with ASD may imply weakness around these joints, which is further exhibited by a reduction in ground reaction forces at toe-off in children with ASD. Children with ASD have altered gait patterns to healthy controls, widened base of support, and reduced range of motion. Several studies refer to cerebellar and basal ganglia involvement as the patterns described suggest alterations in those areas of the brain. Further research should compare children with ASD to other clinical groups to improve assessment and treatment planning.
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11. Liu J, Yang A, Zhang Q, Yang G, Yang W, Lei H, Quan J, Qu F, Wang M, Zhang Z, Yu K. {{Association between genetic variants in SLC25A12 and risk of autism spectrum disorders: An integrated meta-analysis}}. {Am J Med Genet B Neuropsychiatr Genet};2015 (Apr 29)
The solute carrier family 25 (aspartate/glutamate carrier), member 12 gene (SLC25A12) has been strongly posed as a candidate gene for autism spectrum disorder (ASD) given its important role in mitochondrial function and adenosine triphosphate (ATP) synthesis. Evidence is mounting for the association between SLC25A12 variants (rs2056202 and rs2292813) and ASD risk, but the results are inconsistent. To clarify the effect of these two variants on ASD, a meta-analysis integrating case-control and transmission disequilibrium test (TDT) studies was performed. The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature (CBM), Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies published up to May 2014. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to assess the strength of association. A total of 775 cases, 922 controls, and 1289 families available from 8 studies concerning rs2056202, and 465 cases, 450 controls, and 1516 families available from 7 studies concerning rs2292813 were finally included. In the overall meta-analysis, the rs2056202 T allele and rs2292813 T allele were both significantly associated with a decreased risk of ASD (rs2056202: OR = 0.809, P = 0.001, 95%CI: 0.713-0.917, I2 = 0.0%, and Pheterogeneity = 0.526; rs2292813: OR = 0.752, P < 0.001, 95%CI: 0.649-0.871, I2 = 0.0%, Pheterogeneity = 0.486). Besides, subjects with T-T haplotype of rs2056202-rs2292813 had a significantly reduced risk of ASD (OR = 0.672, P < 0.001, 95%CI: 0.564-0.801, I2 = 0.0%, Pheterogeneity = 0.631). Sensitivity analysis, cumulative meta-analysis, and publication bias diagnostics confirmed the reliability and stability of our results. Our meta-analysis suggests that rs2056202 and rs2292813 in SLC25A12 may contribute significantly to ASD risk. (c) 2015 Wiley Periodicals, Inc.
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12. Liu Y, Zhang Y, Zhao D, Dong R, Yang X, Tammimies K, Uddin M, Scherer SW, Gai Z. {{Rare de novo deletion of metabotropic glutamate receptor 7 (GRM7) gene in a patient with autism spectrum disorder}}. {Am J Med Genet B Neuropsychiatr Genet};2015 (Apr 29)
GRM7, the gene encoding metabotropic glutamate receptor 7 (mGluR7), have been implicated in multiple neuropsychiatric disorders and shown to mediate excitatory synaptic neurotransmitter signaling and plasticity in the mammalian brain. Here we report a 303 kb de novo deletion at band 3q26.1, disrupting five coding exons of GRM7 in a proband with autism spectrum disorder, and hyperactivity. Our exon transcriptome-mutation contingency index method shows that three of the exons within the breakpoint boundaries are under purifying selection and highly expressed in prenatal brain regions. Based on our results and a thorough review of the literature, we propose that haploinsufficiency of the GRM7 product (mGluR7) contributes to autism spectrum disorders and hyperactivity phenotype as seen in the patient described here. (c) 2015 Wiley Periodicals, Inc.
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13. May T, Cornish K, Rinehart NJ. {{Parent-Child Agreement Using the Spence Children’s Anxiety Scale and a Thermometer in Children with Autism Spectrum Disorder}}. {Autism Res Treat};2015;2015:315495.
Children with Autism Spectrum Disorder (ASD) experience high anxiety which often prompts clinical referral and requires intervention. This study aimed to compare parent and child reports on the Spence Children’s Anxiety Scale (SCAS) and a child-reported « worry thermometer » in 88 children aged 8-13 years, 44 with ASD and 44 age, gender, and perceptual IQ matched typically developing children. There were no gender differences in child report on the SCAS and worry thermometers. Results indicated generally good correlations between parent and child self-reported SCAS symptoms for typically developing children but poor agreement in parent-child ASD dyads. The worry thermometer child-report did not reflect child or parent reports on the SCAS. Findings suggest 8-13-year-old children with ASD may have difficulties accurately reporting their anxiety levels. The clinical implications were discussed.
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14. Ozonoff S, Young GS, Landa RJ, Brian J, Bryson S, Charman T, Chawarska K, Macari SL, Messinger D, Stone WL, Zwaigenbaum L, Iosif AM. {{Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study}}. {J Child Psychol Psychiatry};2015 (Apr 29)
BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.
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15. Solomon O. {{« But-He’ll Fall! »: Children with Autism, Interspecies Intersubjectivity, and the Problem of ‘Being Social’}}. {Cult Med Psychiatry};2015 (Apr 30)
‘Being autistic’ or ‘having Autism Spectrum Disorder’ implies a limited range of ‘being social,’ but the in situ organization of interaction, what Maynard and Marlaire (Qual Soc 15(2):177-202, 1992) call the ‘interactional substrate,’ within which this delimitation enfolds is usually hidden from sight. Analysis of processes constituting different ‘interactional substrates’ provides a view of how one comes to be known by and to self and others as a certain kind of being who is available (or not) for acting and feeling in certain ways. People diagnosed with Autism Spectrum Disorder (American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013) are often described as ‘being’ impaired in intersubjective understanding of others. But the story of ASD as an impairment of sociality and intersubjectivity becomes more complicated when animals enter into the picture. I consider two interactional substrates: a psychological interview in a mental health clinic, and an animal-assisted activity in a child’s neighborhood. I aim to elucidate the practical problems of ‘being social’ encountered by two children with ASD, both nine-year-old girls, within these two very differently organized interactional substrates. I consider ways in which ‘being with’ therapy animals provides a way of ‘being social’ through « sensory modalities of knowing » (Haraway, When species meet, 2008:371).
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16. Urbano M, Okwara L, Manser P, Hartmann K, Deutsch SI. {{A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders}}. {J Neuropsychiatry Clin Neurosci};2015 (Spring);27(2):133-138.
Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d-Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d-Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration.
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17. Van Naarden Braun K, Christensen D, Doernberg N, Schieve L, Rice C, Wiggins L, Schendel D, Yeargin-Allsopp M. {{Trends in the prevalence of autism spectrum disorder, cerebral palsy, hearing loss, intellectual disability, and vision impairment, metropolitan atlanta, 1991-2010}}. {PLoS One};2015;10(4):e0124120.
This study examined the prevalence and characteristics of autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss (HL), intellectual disability (ID), and vision impairment (VI) over a 15-20 year time period, with specific focus on concurrent changes in ASD and ID prevalence. We used data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta. From 1991-2010, prevalence estimates of ID and HL were stable with slight increases in VI prevalence. CP prevalence was constant from 1993-2010. The average annual increase in ASD prevalence was 9.3% per year from 1996-2010, with a 269% increase from 4.2 per 1,000 in 1996 to 15.5 per 1,000 in 2010. From 2000-2010, the prevalence of ID without ASD was stable; during the same time, the prevalence of ASD with and without co-occurring ID increased by an average of 6.6% and 9.6% per year, respectively. ASD prevalence increases were found among both males and females, and among nearly all racial/ethnic subgroups and levels of intellectual ability. Average annual prevalence estimates from 1991-2010 underscore the significant community resources needed to provide early intervention and ongoing supports for children with ID (13.0 per 1,000), CP, (3.5 per 1,000), HL (1.4 per 1,000) and VI (1.3 in 1,000), with a growing urgency for children with ASD.
