1. Alfaro Arenas R, Rosell Andreo J, Heine Suner D. {{Fragile X syndrome screening in pregnant women and women planning pregnancy shows a remarkably high FMR1 premutation prevalence in the Balearic Islands}}. {Am J Med Genet B Neuropsychiatr Genet}. 2016.
There are no reported studies to determine incidence of Fragile X Syndrome (FXS) in women within the Spanish population. For this reason, together with the high incidence of FXS in the general population, the exclusively maternal expansion, the familial and social impact of the syndrome, and the ease of use and level of detection of current PCR-based techniques, we have conducted a population-based screening pilot program of which we present here the molecular results. We typed prospectively 3,413 pregnant and 318 non-pregnant women and found a prevalence of premutation (PM) carriers of 1 in 106, which is the highest described to date in any population. We also found 230 different alleles of which the most frequent are 10A9A9 (38.4%), 9A9A9 (15.1%), and 10A9 (10.5%). Furthermore, alleles with 0 AGG interruptions or with a pure (uninterrupted) CGG repeat run larger than 34 (presumably more unstable), were more frequent among PM alleles compared to normal alleles. Thea unexpected high frequency of expanded PM alleles in females in the general population makes a very compelling argument for the need for prenatal or preconceptional FXS screening in our community. Furthermore, we find FMR1 triplet primed PCR (TP-PCR) confidently and precisely determines sizes for both alleles of the CGG repeat in women and offers AGG information which greatly improves CGG expansion risk estimations for genetic counselling. Thus, TP-PCR is an informative, efficient and robust method for FXS screening in the female population. (c) 2016 Wiley Periodicals, Inc.
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2. Becker MM, Riesgo RS, Roesler R, Bosa C, Ohlweiler L, Backes B, Endres RG, Zanon RB, Marchezan J, Schwartsmann G. {{Improvement in Symptoms of Autism Spectrum Disorder in Children With the Use of Gastrin-Releasing Peptide: An Open Trial}}. {Clin Neuropharmacol}. 2016.
OBJECTIVES: The aim of this study was to determine the efficacy and tolerability of gastrin-releasing peptide (GRP) for core symptoms of autism spectrum disorder. METHODS: This is a prospective, open-label study with 160 pmol/kg of GRP tested in 10 children with autism. Outcome measures used were the Clinical Global Impressions-Improvement Scale, Aberrant Behavior Checklist (ABC), Childhood Autism Rating Scale, and Autism Diagnostic Interview-Revised. Positive response was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impressions-Improvement Scale and an improvement of 25% or greater on at least 1 subscale of ABC. RESULTS: Six (60%) of the 10 subjects responded to GRP. Improvements were observed on the ABC irritability and hyperactivity subscales in 80% of patients, and 70% exhibited improvement on the social withdrawal subscale. On the Childhood Autism Rating Scale, there was a mean reduction of 4 points (4.3 +/- 2.9). Analysis of the Autism Diagnostic Interview-Revised results detected significant improvements in the domain that assesses social interaction, with a mean reduction of 2.4 points (2.4 +/- 2.83). Adverse effects occurred in 3 patients. CONCLUSIONS: Gastrin-releasing peptide was safe and well tolerated by most subjects and may be effective for core symptoms of autism.
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3. Brown J. {{BILL AND VIRGINIA LEFFEN CENTER FOR AUTISM}}. {Behav Healthc}. 2016; 36(1): 44, 6-7.
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4. Campos LK, Fernandes FD. {{School profile and language and cognitive abilities of children and adolescents with autism spectrum disorders}}. {Codas}. 2016; 0: 0.
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5. Darville H, Poulet A, Rodet-Amsellem F, Chatrousse L, Pernelle J, Boissart C, Heron D, Nava C, Perrier A, Jarrige M, Coge F, Millan MJ, Bourgeron T, Peschanski M, Delorme R, Benchoua A. {{Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome}}. {EBioMedicine}. 2016.
Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments.
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6. Egilson ST, Jakobsdottir G, Olafsson K, Leosdottir T. {{Community participation and environment of children with and without autism spectrum disorder: parent perspectives}}. {Scand J Occup Ther}. 2016: 1-10.
AIM: This study explored parent perspectives of participation patterns and environmental supports and barriers for high-functioning children with autism spectrum disorder (ASD) within their communities compared with a group of children without ASD. METHOD: The Participation and Environment Measure for Children and Youth was used to gather online data from parents of 99 children with ASD and 241 children without ASD. Mann-Whitney U test and chi-square tests were used to explore differences between groups and partial eta squared was calculated to examine effect sizes. RESULTS: Significant differences between children with and without ASD were observed for all participation and environment summary scores. Children with ASD participated less frequently, were less involved, and their parents were less satisfied with their child’s participation in community-based activities. Parents of children with ASD also identified fewer supports for their child’s participation and more environmental barriers than other parents. CONCLUSION: Children with ASD participated less in community-related activities than children without ASD as perceived by their parents. Barriers limiting community participation included features of the social and physical environment and limited resources. SIGNIFICANCE: Occupational therapists should focus on decreasing environmental challenges in their efforts to facilitate participation of children with ASD in the community.
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7. Folmsbee SS, Wilcox DR, Tyberghein K, De Bleser P, Tourtellotte WG, van Hengel J, van Roy F, Gottardi CJ. {{alphaT-catenin in restricted brain cell types and its potential connection to autism}}. {J Mol Psychiatry}. 2016; 4: 2.
BACKGROUND: Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (alphaT-cat, CTNNA3) with the development of autism. Where alphaT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown. METHODS: We used the alphaT-cat knockout mouse to examine the localization of alphaT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss. RESULTS: We found that alphaT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of alphaE-cat expression. Notably, alphaT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While alphaT-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although alphaT-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with alphaT-cat loss, such as GABA-A receptor activation. CONCLUSIONS: These findings raise the possibility that the genetic associations between alphaT-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder.
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8. Frye RE, Rossignol DA. {{Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes}}. {Clin Med Insights Pediatr}. 2016; 10: 43-56.
Despite the fact that the prevalence of autism spectrum disorder (ASD) continues to rise, no effective medical treatments have become standard of care. In this paper we review some of the pathophysiological abnormalities associated with ASD and their potential associated treatments. Overall, there is evidence for some children with ASD being affected by seizure and epilepsy, neurotransmitter dysfunction, sleep disorders, metabolic abnormalities, including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and gastrointestinal disorders. Although evidence for an association between these pathophysiological abnormalities and ASD exists, the exact relationship to the etiology of ASD and its associated symptoms remains to be further defined in many cases. Despite these limitations, treatments targeting some of these pathophysiological abnormalities have been studied in some cases with high-quality studies, whereas treatments for other pathophysiological abnormalities have not been well studied in many cases. There are some areas of more promising treatments specific for ASD including neurotransmitter abnormalities, particularly imbalances in glutamate and acetylcholine, sleep onset disorder (with behavioral therapy and melatonin), and metabolic abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, and redox pathways. There is some evidence for treatments of epilepsy and seizures, mitochondrial and immune disorders, and gastrointestinal abnormalities, particularly imbalances in the enteric microbiome, but further clinical studies are needed in these areas to better define treatments specific to children with ASD. Clearly, there are some promising areas of ASD research that could lead to novel treatments that could become standard of care in the future, but more research is needed to better define subgroups of children with ASD who are affected by specific pathophysiological abnormalities and the optimal treatments for these abnormalities.
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9. Hartley SL, Papp LM, Blumenstock SM, Floyd F, Goetz GL. {{The Effect of Daily Challenges in Children With Autism on Parents’ Couple Problem-Solving Interactions}}. {J Fam Psychol}. 2016.
The vulnerability-stress-adaptation model guided this examination of the impact of daily fluctuations in the symptoms and co-occurring behavior problems of children with autism spectrum disorder (ASD) on parents’ couple problem-solving interactions in natural settings and as these interactions spontaneously occur. A 14-day daily diary was completed by mothers and fathers in 176 families who had a child with ASD. On each day of the diary, parents separately reported on the child with ASD’s daily level of symptoms and co-occurring behavior problems and the topic and level of negative affect in their most meaningful or important daily couple problem-solving interaction. Multilevel modeling was used to account for the within-person, within-couple nested structure of the data. Results indicated that many parents are resilient to experiencing a day with a high level of child ASD symptoms and co-occurring behavior problems and do not report more negative couple problem-solving interactions. However, household income, level of parental broader autism phenotype, and presence of multiple children with special care needs served as vulnerability factors in that they were related to a higher overall rating of negative affect in couple interactions and moderated the impact of reporting a day with a high level of child ASD symptoms and co-occurring behavior problems on next-day ratings of negative couple problem-solving interactions. The magnitude of these effects was small. Understanding mechanisms that support adaptive couple interactions in parents of children with ASD is critical for promoting best outcomes. (PsycINFO Database Record
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10. Lieb-Lundell CC. {{Three Faces of Fragile X}}. {Phys Ther}. 2016.
Fragile X syndrome (FXS) is the first of three syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other two conditions are Fragile X-associated primary ovarian insufficiency syndrome (FXPOI) and Fragile X-associated tremor/ataxia syndrome (FXTAS) which together are referred to as Fragile X-associated disorders (FXD). Collectively, this group comprises the three faces of Fragile X. Even though the three conditions share a common genetic defect each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains; and, for FXTAS, a late onset neurodegeneration. Although each FXD condition may benefit from physical therapy intervention, available evidence as to the efficacy of intervention appropriate to FXD is, as yet, lacking. This perspective will discuss the genetic basis of FMR1 gene dysfunction and describes health conditions related to this mutation which have a range of expressions within a family. Physical therapy concerns and possible assessment and intervention strategies will be introduced. Understanding the inter-generational effect of the FMR1 mutation with potential life span expression is a key component to identifying and treating the health conditions related to this specific genetic condition.
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11. Mazahery H, Conlon C, Beck KL, Kruger MC, Stonehouse W, Camargo CA, Jr., Meyer BJ, Tsang B, Mugridge O, von Hurst PR. {{Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial}}. {Trials}. 2016; 17(1): 295.
BACKGROUND: There is strong mechanistic evidence to suggest that vitamin D and omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs), specifically docosahexaenoic acid (DHA), have the potential to significantly improve the symptoms of autism spectrum disorder (ASD). However, there are no trials that have measured the effect of both vitamin D and n-3 LCPUFA supplementation on autism severity symptoms. The objective of this 2 x 2 factorial trial is to investigate the effect of vitamin D, n-3 LCPUFAs or a combination of both on core symptoms of ASD. METHODS/DESIGN: Children with ASD living in New Zealand (n = 168 children) will be randomised to one of four treatments daily: vitamin D (2000 IU), n-3 LCPUFAs (722 mg DHA), vitamin D (2000 IU) + n-3 LCPUFAs (722 mg DHA) or placebo for 12 months. All researchers, participants and their caregivers will be blinded until the data analysis is completed, and randomisation of the active/placebo capsules and allocation will be fully concealed from all mentioned parties. The primary outcome measures are the change in social-communicative functioning, sensory processing issues and problem behaviours between baseline and 12 months. A secondary outcome measure is the effect on gastrointestinal symptoms. Baseline data will be used to assess and correct basic nutritional deficiencies prior to treatment allocation. For safety measures, serum 25-hydroxyvitamin D 25(OH)D and calcium will be monitored at baseline, 6 and 12 months, and weekly compliance and gastrointestinal symptom diaries will be completed by caregivers throughout the study period. DISCUSSION: To our knowledge there are no randomised controlled trials assessing the effects of both vitamin D and DHA supplementation on core symptoms of ASD. If it is shown that either vitamin D, DHA or both are effective, the trial would reveal a non-invasive approach to managing ASD symptoms. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12615000144516 . Registered on 16 February 2015.
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12. Ozsivadjian A, Hollocks MJ, Southcott J, Absoud M, Holmes E. {{Anxious Imagery in Children With and Without Autism Spectrum Disorder: An Investigation into Occurrence, Content, Features and Implications for Therapy}}. {J Autism Dev Disord}. 2016.
Mental imagery has been implicated in anxiety disorders in adults, but has not been investigated in child and adolescent populations. Anxiety is highly prevalent in autism spectrum disorder (ASD), and as people with ASD are often thought of as ‘visual thinkers’, the potential role of distressing imagery in children with ASD merits exploration. Participants aged 8-16 years were grouped as follows: ASD/high anxiety, ASD/low anxiety, non-ASD/high anxiety and non-ASD/low anxiety. Imagery and associated features were assessed using an interview. Group differences were found in number and frequency of images experienced. There were few differences between the groups in the characteristics of the spontaneous images, which included emotional valence, vividness, controllability and realism. Implications for treatment are discussed.
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13. Patriquin MA, DeRamus T, Libero LE, Laird A, Kana RK. {{Neuroanatomical and neurofunctional markers of social cognition in autism spectrum disorder}}. {Hum Brain Mapp}. 2016.
Social impairments in autism spectrum disorder (ASD), a hallmark feature of its diagnosis, may underlie specific neural signatures that can aid in differentiating between those with and without ASD. To assess common and consistent patterns of differences in brain responses underlying social cognition in ASD, this study applied an activation likelihood estimation (ALE) meta-analysis to results from 50 neuroimaging studies of social cognition in children and adults with ASD. In addition, the group ALE clusters of activation obtained from this was used as a social brain mask to perform surface-based cortical morphometry (SBM) in an empirical structural MRI dataset collected from 55 ASD and 60 typically developing (TD) control participants. Overall, the ALE meta-analysis revealed consistent differences in activation in the posterior superior temporal sulcus at the temporoparietal junction, middle frontal gyrus, fusiform face area (FFA), inferior frontal gyrus (IFG), amygdala, insula, and cingulate cortex between ASD and TD individuals. SBM analysis showed alterations in the thickness, volume, and surface area in individuals with ASD in STS, insula, and FFA. Increased cortical thickness was found in individuals with ASD, the IFG. The results of this study provide functional and anatomical bases of social cognition abnormalities in ASD by identifying common signatures from a large pool of neuroimaging studies. These findings provide new insights into the quest for a neuroimaging-based marker for ASD. Hum Brain Mapp, 2016. (c) 2016 Wiley Periodicals, Inc.
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14. Patterson KC, Hawkins VE, Arps KM, Mulkey DK, Olsen ML. {{MeCP2 Deficiency Results in Robust Rett-like Behavioral and Motor Deficits in Male and Female Rats}}. {Hum Mol Genet}. 2016.
Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioral function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2 ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2 ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2 ZFN/y and Mecp2 ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2 ZFN/y rats, whereas Mecp2 ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.
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15. Pruett JR, Jr., Povinelli DJ. {{Commentary – Autism Spectrum Disorder: Spectrum or Cluster?}}. {Autism Res}. 2016.
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16. Ruzich E, Allison C, Smith P, Ring H, Auyeung B, Baron-Cohen S. {{The Autism-Spectrum Quotient in Siblings of People With Autism}}. {Autism Res}. 2016.
This study measures the distribution of autistic traits, using the autism-spectrum quotient (AQ), in siblings of individuals with autism spectrum conditions (ASC). Total AQ scores, along with AQ subscales, were collected from child, adolescent and adult controls, siblings, and volunteers with ASC using one of the three age-appropriate versions of the instrument: the AQ (adult self-report), the AQ-adolescent and AQ-child (both parent-reports). We examined the effect of Group (case, sibling and control) and AQ version (adult, adolescent and adult) on total and subscale scores. In addition, we tested for sex differences in all groups and on all versions. We found that in male and female adults, AQ scores in siblings fell between cases and controls (cases > siblings > controls). In children and adolescents, female siblings also scored higher than control females (female cases > female siblings > female controls), but there was no difference between male siblings and controls (male cases > male siblings = male controls). An investigation of subscale scores revealed that male siblings only differed from controls on the « Communication » subscale (male cases > male siblings > male controls), while female siblings differed from controls on all subscales except « Imagination » (female cases > female siblings > female controls). This study confirms the broader autism phenotype in siblings, and reveals this is modulated by sex and AQ version. Autism Res 2016. (c) 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
