1. Chevreul K, Berg Brigham K, Brunn M, des Portes V. {{Fragile X syndrome: economic burden and health-related quality of life of patients and caregivers in France}}. {J Intellect Disabil Res};2015 (Sep 15)
BACKGROUND: Fragile X syndrome (FXS) is the main hereditary cause of intellectual disability. Although the associated burden appears to be considerable, to date no study has comprehensively assessed the cost incurred because of FXS, including its specific impact on health-related quality of life and the burden on caregivers using standardised quantitative tools. The aim of this article is to provide data in order to increase awareness of the repercussions of FXS on patients and caregivers as well as on the health and social care systems in France. METHODS: A retrospective cross-sectional study was carried out on 145 patients recruited through Le Goeland X-Fragile and Mosaiques, the French FXS patient associations. Data on their demographic characteristics and resource use were obtained from an online questionnaire, and costs were estimated by a bottom-up approach. The EQ-5D health questionnaire was used to measure patients’ and caregivers’ health-related quality of life. Perceived burden of care was measured using the Zarit Caregiver Burden Interview. The Barthel index, a non-utility-based assessment, was used to measure patients’ level of dependence. RESULTS: The annual total direct cost of FXS was estimated at euro25 800 per patient. The main contributors were informal care provided by the main caregiver (euro10 500) and social services (euro8400). Healthcare costs, estimated at euro2700, represented only a minor share. Mean EQ-5D utility scores were 0.49 for patients and 0.75 for caregivers. The mean burden for caregivers as measured by the Zarit Caregiver Burden Interview was 39.9. CONCLUSIONS: Fragile X syndrome requires significant resources that are mainly of a non-medical nature and are higher for children than for adults. Compared with related diseases, it constitutes a particularly high burden for caregivers. Using a bottom-up approach and a wide range of standardised measures, this study underscores the need for greater awareness of the burden of FXS as well as an assessment of new and existing interventions to address it.
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2. Cianfaglione R, Clarke A, Kerr M, Hastings RP, Oliver C, Felce D. {{Ageing in Rett syndrome}}. {J Intellect Disabil Res};2015 (Sep 16)
BACKGROUND: The aim was to gain a UK national sample of people with Rett syndrome across the age range and (1) conduct a cross-sectional comparison of age groups and (2) undertake a longitudinal follow-up. METHODS: From 308 potential participants approached to take part, a sample of 91 girls and women was achieved (29.5%). Their ages ranged from 4 to 47 years, and 71 were known to have a mutation in the methyl-CpG binding protein-2 (MECP2) gene. Seventy-two of the initial sample were followed up 16 months later, and 50 returned completed assessments (69.4%). Their ages ranged from 7 to 48 years, and 42 were MECP2 positive. Parental questionnaire measures of Rett syndrome specific characteristics, impulsivity, overactivity, mood, interest and pleasure, repetitive behaviour and self-injury were administered. RESULTS: Adaptive behaviour and behavioural characteristics of Rett syndrome were similar across age groups and, where assessed, stable over time, as were repetitive behaviours generally and self-injury. There was some suggestion of deterioration in health arising with ageing, principally contributed to by deteriorations in dental and gastro-intestinal problems both with moderate effect sizes. Indicators of mood, interest and pleasure differed significantly across age groups. The total scale score significantly deteriorated over time, with a moderate effect size. CONCLUSIONS: This study provides further evidence for the post-regression stability that characterises Rett syndrome. Emergent low mood in Rett syndrome requires further research.
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3. Daroles L, Gribaudo S, Doulazmi M, Scotto-Lomassese S, Dubacq C, Mandairon N, Greer CA, Didier A, Trembleau A, Caille I. {{Fragile X Mental Retardation Protein and Dendritic Local Translation of the Alpha Subunit of the Calcium/Calmodulin-Dependent Kinase II Messenger RNA Are Required for the Structural Plasticity Underlying Olfactory Learning}}. {Biol Psychiatry};2015 (Aug 7)
BACKGROUND: In the adult brain, structural plasticity allowing gain or loss of synapses remodels circuits to support learning. In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) leads to defects in plasticity and learning deficits. FMRP is a master regulator of local translation but its implication in learning-induced structural plasticity is unknown. METHODS: Using an olfactory learning task requiring adult-born olfactory bulb neurons and cell-specific ablation of FMRP, we investigated whether learning shapes adult-born neuron morphology during their synaptic integration and its dependence on FMRP. We used alpha subunit of the calcium/calmodulin-dependent kinase II (alphaCaMKII) mutant mice with altered dendritic localization of alphaCaMKII messenger RNA, as well as a reporter of alphaCaMKII local translation to investigate the role of this FMRP messenger RNA target in learning-dependent structural plasticity. RESULTS: Learning induces profound changes in dendritic architecture and spine morphology of adult-born neurons that are prevented by ablation of FMRP in adult-born neurons and rescued by an metabotropic glutamate receptor 5 antagonist. Moreover, dendritically translated alphaCaMKII is necessary for learning and associated structural modifications and learning triggers an FMRP-dependent increase of alphaCaMKII dendritic translation in adult-born neurons. CONCLUSIONS: Our results strongly suggest that FMRP mediates structural plasticity of olfactory bulb adult-born neurons to support olfactory learning through alphaCaMKII local translation. This reveals a new role for FMRP-regulated dendritic local translation in learning-induced structural plasticity. This might be of clinical relevance for the understanding of critical periods disruption in autism spectrum disorder patients, among which fragile X syndrome is the primary monogenic cause.
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4. Fox-Edmiston E, Van de Water J. {{Maternal Anti-Fetal Brain IgG Autoantibodies and Autism Spectrum Disorder: Current Knowledge and its Implications for Potential Therapeutics}}. {CNS Drugs};2015 (Sep 14)
Several studies have found a correlation between the presence of circulating maternal autoantibodies and neuronal dysfunction in the neonate. Specifically, maternal anti-brain autoantibodies, which may access the fetal compartment during gestation, have been identified as one risk factor for developing autism spectrum disorder (ASD). Studies by our laboratory elucidated seven neurodevelopmental proteins recognized by maternal autoantibodies whose presence is associated with a diagnosis of maternal autoantibody-related (MAR) autism in the child. While the specific process of anti-brain autoantibody generation is unclear and the detailed pathogenic mechanisms are currently unknown, identification of the maternal autoantibody targets increases the therapeutic possibilities. The potential therapies discussed in this review provide a framework for possible future medical interventions.
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5. Lageix F, Nicaise-Roland P, Houlier M, Zylberberg P, Dubrel M, Heulin M, Fain O, Lachassinne E, Heron B, Chollet-Martin S, Mekinian A, de Pontual L. {{[Association between the presence of antiphospholipid antibodies and the occurrence of autism spectrum disorder in childhood]}}. {Arch Pediatr};2015 (Sep 16)
OBJECTIVES: To evaluate the association between the presence of antiphospholipid (APL) antibodies and the occurrence of autism spectrum disorder (ASD) in childhood. METHODS: A prospective, monocentric case-control study from February 2012 to August 2014 comparing the APL antibodies of children with ASD (group 1) and children without ASD (group 2). RESULTS: Group 1 consisted of 44 children with ASD defined by clinical, genetic, metabolic, and morphological criteria. Group 2 consisted of 26 control children without ASD. One of children with ASD (2.3 %) had persistent anticardiolipin (ACL) antibodies, five of them (11.4 %) had persistent APL antibodies, one of them (2.3 %) had antiannexin V (AAV) antibodies, and two of them (4.5 %) had antiphosphatidylethanolamine (APE) antibodies. Two of the control children (7.7 %) had persistent APL antibodies. None of them had persistent ACL, AAV, or APE antibodies. Comparing group 1 and 2 children, no significant difference was found between the presence and the titers of conventional and non conventional antibodies (P<0.05). Furthermore, one mother of an autistic child (3 %) had persistent APL antibodies. CONCLUSION: ASD had no significant relation with the presence of APL antibodies.
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6. Ling TT, Sorrentino S. {{Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability}}. {Am J Med Genet A};2015 (Sep 16)
Alazami syndrome is an autosomal recessive disease characterized by primordial dwarfism, distinct dysmorphic features, and severe intellectual disability. Since it was first identified in a large consanguineous Arabic family in 2012, additional cases have not been published in the literature. We present a 2-year-old Northern European/Caucasian female with short stature, failure to thrive, and developmental delay. Whole exome sequencing (WES) identified two novel pathogenic variants in LARP7 (c.213_214dup and c.651_655del), indicating a diagnosis of Alazami syndrome. The case report describes a novel genotypic and phenotypic presentation of Alazami syndrome, contributing to the current knowledge of the condition as well as the expansion of differential diagnoses for growth restriction and intellectual disability. (c) 2015 Wiley Periodicals, Inc.
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7. Miodovnik A, Harstad E, Sideridis G, Huntington N. {{Timing of the Diagnosis of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder}}. {Pediatrics};2015 (Sep 14)
BACKGROUND AND OBJECTIVE: Symptoms of inattention, hyperactivity, and impulsivity are core features of attention-deficit/hyperactivity disorder (ADHD). However, children with autism spectrum disorder (ASD) often present with similar symptoms and may receive a diagnosis of ADHD first. We investigated the relationship between the timing of ADHD diagnosis in children with ASD and the age at ASD diagnosis. METHODS: Data were drawn from the 2011-2012 National Survey of Children’s Health, which asked parents to provide the age(s) at which their child received a diagnosis of ADHD and/or ASD. Using weighted prevalence estimates, we examined the association between a previous diagnosis of ADHD and the age at ASD diagnosis, while controlling for factors known to influence the timing of ASD diagnosis. RESULTS: Our study consisted of 1496 children with a current diagnosis of ASD as reported by parents of children ages 2 to 17 years. Approximately 20% of these children had initially been diagnosed with ADHD. Children diagnosed with ADHD before ASD were diagnosed with ASD approximately 3 years (95% confidence interval 2.3-3.5) after children in whom ADHD was diagnosed at the same time or after ASD. The children with ADHD diagnosed first were nearly 30 times more likely to receive their ASD diagnosis after age 6 (95% confidence interval 11.2-77.8). The delay in ASD diagnosis was consistent across childhood and independent of ASD severity. CONCLUSION: To avoid potential delays in ASD diagnosis, clinicians should consider ASD in young children presenting with ADHD symptoms.
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8. Pilorge M, Fassier C, Le Corronc H, Potey A, Bai J, De Gois S, Delaby E, Assouline B, Guinchat V, Devillard F, Delorme R, Nygren G, Rastam M, Meier JC, Otani S, Cheval H, James VM, Topf M, Dear TN, Gillberg C, Leboyer M, Giros B, Gautron S, Hazan J, Harvey RJ, Legendre P, Betancur C. {{Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism}}. {Mol Psychiatry};2015 (Sep 15)
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the alpha2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR alpha2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2Deltaex8-9). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2Deltaex8-9 protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2Deltaex8-9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.Molecular Psychiatry advance online publication, 15 September 2015; doi:10.1038/mp.2015.139.
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9. Robinson EB, Neale BM, Hyman SE. {{Genetic research in autism spectrum disorders}}. {Curr Opin Pediatr};2015 (Sep 18)
PURPOSE OF REVIEW: The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder’s underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research. RECENT FINDINGS: Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology. SUMMARY: Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.
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10. Sokhadze EM, Tasman A, Sokhadze GE, El-Baz AS, Casanova MF. {{Behavioral, Cognitive, and Motor Preparation Deficits in a Visual Cued Spatial Attention Task in Autism Spectrum Disorder}}. {Appl Psychophysiol Biofeedback};2015 (Sep 16)
Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display « motor dyspraxia » or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more refined specifics of dyspraxia symptoms to investigate functional connectivity abnormalities underlying motor skills deficits in autism.
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11. Windham GC, Lyall K, Anderson M, Kharrazi M. {{Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California}}. {J Autism Dev Disord};2015 (Sep 14)
We examined prenatal screening markers and offspring autism spectrum disorder (ASD) using California statewide data on singleton births in 1996 and 2002. Second trimester levels of unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and maternal serum alpha-fetoprotein (MSAFP) were compared between mothers of children with ASD (n = 2586) and of non-cases (n = 600,103). Adjusted odds ratios (AOR) were calculated by logistic regression. Lower uE3 (AOR for < 10th percentile vs. 25th-74th percentiles = 1.21, 95 % CI 1.06-1.37), and higher MSAFP (AOR = 1.21, 95 % CI 1.07-1.37 for > 90th percentile) were significantly associated with ASD. A U-shaped relationship was seen for hCG (AOR = 1.16, 95 % CI 1.02-1.32 for < 10th percentile; AOR = 1.19, 95 % CI 1.05-1.36 for > 90th percentile). Our results further support prenatal hormone involvement in ASD risk.
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12. Xu L, Ma X, Zhao W, Luo L, Yao S, Kendrick KM. {{Oxytocin enhances attentional bias for neutral and positive expression faces in individuals with higher autistic traits}}. {Psychoneuroendocrinology};2015 (Sep 5);62:352-358.
There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in altering attentional bias towards emotional social stimuli in psychiatric disorders. However, it is still unclear whether oxytocin primarily influences attention towards positive or negative valence social stimuli. Here in a double-blind, placebo controlled, between subject design experiment in 60 healthy male subjects we have used the highly sensitive dual-target rapid serial visual presentation (RSVP) paradigm to investigate whether intranasal oxytocin (40IU) treatment alters attentional bias for emotional faces. Results show that oxytocin improved recognition accuracy of neutral and happy expression faces presented in the second target position (T2) during the period of reduced attentional capacity following prior presentation of a first neutral face target (T1), but had no effect on recognition of negative expression faces (angry, fearful, sad). Oxytocin also had no effect on recognition of non-social stimuli (digits) in this task. Recognition accuracy for neutral faces at T2 was negatively associated with autism spectrum quotient (ASQ) scores in the placebo group, and oxytocin’s facilitatory effects were restricted to a sub-group of subjects with higher ASQ scores. Our results therefore indicate that oxytocin primarily enhances the allocation of attentional resources towards faces expressing neutral or positive emotion and does not influence that towards negative emotion ones or non-social stimuli. This effect of oxytocin is strongest in healthy individuals with higher autistic trait scores, thereby providing further support for its potential therapeutic use in autism spectrum disorder.
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13. Zerbo O, Yoshida C, Gunderson EP, Dorward K, Croen LA. {{Interpregnancy Interval and Risk of Autism Spectrum Disorders}}. {Pediatrics};2015 (Sep 14)
OBJECTIVE: To determine whether subsequent births after short and long interpregnancy intervals (IPIs) are associated with risk of autism spectrum disorder (ASD). METHOD: We assessed the association between IPI and ASD risk in a cohort of 45 261 children born at Kaiser Permanente Northern California (KPNC) between 2000 and 2009. Children with ASD were identified from International Classification of Diseases, Revision 9 diagnostic codes 299.0, 299.8, and 299.9 recorded in KPNC electronic medical records. IPI was defined as the time from the birth of the first child to the conception of the second child. Survival analysis and logistic regression models were used to evaluate the association between IPI and risk of ASD in second-born children. RESULTS: Children born after an IPI of <12 months or >/=72 months had a 2- to 3-fold increased ASD risk compared with children born after an interval of 36 to 47 months. Respective adjusted hazard ratios (95% confidence intervals) were as follows: <6 months, 3.0 (1.9-4.7); 6 to 8 months, 2.1 (1.4-3.3); 9 to 11 months, 1.9 (1.3-2.1); 12 to 23 months, 1.5 (1.1-2.1); and >/=72 months, 2.4 (1.5-3.7). The results are not explained by maternal BMI or change in BMI between pregnancies or by parental age, maternal antidepressant medication use, or unfavorable events occurring during the first or second pregnancy. CONCLUSIONS: Children born after interpregnancy intervals <2 years or >6 years may be at increased risk of ASD. The mechanism explaining this association is unknown, and more research is needed.
