1. Banerjee-Basu S, Larsen E, Muend S. {{Common microRNAs Target Established ASD Genes}}. {Front Neurol};2014;5:205.
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2. Charzewska A, Rzonca S, Janeczko M, Nawara M, Smyk M, Bal J, Hoffman-Zacharska D. {{A duplication of the whole KIAA2022 gene validates the gene role in the pathogenesis of intellectual disability and autism}}. {Clin Genet};2014 (Nov 13)
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3. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Fu SC, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Crooks L, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Sean Hill R, Ionita-Laza I, Jimenez Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Wang LS, Weiss LA, Jeremy Willsey A, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barrett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD. {{Synaptic, transcriptional and chromatin genes disrupted in autism}}. {Nature};2014 (Nov 13);515(7526):209-215.
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
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4. Gadalla KK, Ross PD, Riddell JS, Bailey ME, Cobb SR. {{Gait analysis in a mecp2 knockout mouse model of rett syndrome reveals early-onset and progressive motor deficits}}. {PLoS One};2014;9(11):e112889.
Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the Mecp2 gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male Mecp2 knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.
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5. Gomez JC. {{Hand Leading and Hand Taking Gestures in Autism and Typically Developing Children}}. {J Autism Dev Disord};2014 (Nov 12)
Children with autism use hand taking and hand leading gestures to interact with others. This is traditionally considered to be an example of atypical behaviour illustrating the lack of intersubjective understanding in autism. However the assumption that these gestures are atypical is based upon scarce empirical evidence. In this paper I present detailed observations in children with autism and typically developing children, suggesting that hand-leading gestures may be an adaptive form of interaction in typically developing children neglected by mainstream developmental psychology. I conclude that, although there may be features differentiating how these gestures are used in autism and typical children, systematic research on them is needed to clarify their nature and significance for both typical and atypical development.
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6. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M. {{The contribution of de novo coding mutations to autism spectrum disorder}}. {Nature};2014 (Nov 13);515(7526):216-221.
Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
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7. Lugnegard T, Hallerback MU, Gillberg C. {{Asperger syndrome and schizophrenia: Overlap of self-reported autistic traits using the Autism-spectrum Quotient (AQ)}}. {Nord J Psychiatry};2014 (Nov 12):1-7.
Background: In clinical practice, the differential diagnosis of Asperger syndrome (AS) versus schizophrenia can be a challenge. Some self-report instruments-such as the Autism-spectrum Quotient (AQ)-have been portrayed as proxies for the diagnosis of AS. However, it has not been demonstrated to what extent autistic traits-as measured by the AQ-separate AS from schizophrenia. Aim: To examine the AS-schizophrenia discriminating ability of the AQ. Method: The AQ is a 50-item self-administered questionnaire (with score range 0-50) for measuring « autistic traits » in adults. Here, it was completed by 136 individuals: 36 with schizophrenic psychosis, 51 with AS and 49 non-clinical comparison cases. A receiver operating characteristic (ROC) analysis for the total AQ score was performed to examine the discriminating power of the instrument. Result: Both individuals with schizophrenia and individuals with AS scored significantly higher on AQ than the non-clinical group. The mean total AQ score (+/- standard deviation) of the AS group (26.7 +/- 8.9; range 9-44) was significantly higher than that of the schizophrenia group (22.7 +/- 6.2; range 10-35) (P = 0.041). However, when using the full Likert scale for scoring, the difference did not reach significance. In the ROC analysis of total AQ scores for AS versus schizophrenia, the area under the curve (AUC) was 0.65 (P = 0.02). Conclusion: Although mean AQ scores separated AS and schizophrenia at a group comparison level, significant overlap of AQ scores across the two diagnostic groups clearly reduces the discriminating power of the AQ in the separation of schizophrenia from AS.
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8. Misquiatti AR, Brito MC, Olivati AG, Santos TR, Fernandes FD. {{Sociocognitive performance in autism spectrum disorders and interference of the therapeutic environment}}. {Codas};2014 (Oct);26(5):402-406.
PURPOSE: To analyze the sociocognitive performance of children and adolescents with autism spectrum disorders in two environments of language therapy, which differ as to the physical structure. METHODS: Ten children and adolescents with ages between 4 and 13 years, of both genders, diagnosed with autism spectrum disorders took part in the study. For data collection, eight filming sessions were performed during individual language therapy lasting 30 minutes, being four in a room with conventional environmental organization (common room) and four in a room with specific ambiance [children’s interaction core (CIC) room], interspersed during a month. For the analysis of filmed situations, the Sociocognitive Performance Protocol was used and obtained data were subjected to statistical analysis. RESULTS: No statistical significance was found in sociocognitive performance of 10 subjects in the common and CIC rooms, although specific differences were observed in some cases. CONCLUSION: The creation of preestablished physical environments or specific materials is not and should not be considered essential for language therapy. It is noteworthy, however, that the absence of a large volume of statistically significant data does not indicate that the results are not expressive, reiterating the need for further research in the area.
9. Papini AM, Nuti F, Real-Fernandez F, Rossi G, Tiberi C, Sabatino G, Pandey S, Leoncini S, Signorini C, Pecorelli A, Guerranti R, Lavielle S, Ciccoli L, Rovero P, De Felice C, Hayek J. {{Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction}}. {J Immunol Res};2014;2014:260973.
Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n = 53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n = 82) and healthy age-matched controls (n = 29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a synthetic N-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P = 0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.
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10. Plasschaert E, Descheemaeker MJ, Van Eylen L, Noens I, Steyaert J, Legius E. {{Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1}}. {Am J Med Genet B Neuropsychiatr Genet};2014 (Nov 12)
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition. While considerable work has focused on cognitive functioning, several research groups also observed difficulties in social functioning as a prominent feature of NF1. These problems and the possible link between NF1 and Autism Spectrum Disorder (ASD) have become increasingly important in recent NF1 literature. The aim of the current study was to assess ASD characteristics in a hospital-based NF1 pediatric population (n = 82) using the standardized Children Social Behavior Questionnaire (CSBQ) and Social Responsiveness Scale (SRS) to account for the prevalence, severity, and nature of social problems. In a parallel study, comprehensive ASD assessment was performed in a subgroup of NF1 children with a strong suspicion of ASD (n = 31). Results indicate that NF1 children have more social problems than typical controls, more frequently reported above 8 years. The SRS shows that 63% is at risk of ASD symptoms. According to item analyses, most problems were observed on items measuring orientation in, understanding of and being tuned onto a social situation (CSBQ) and social cognition and communication (SRS). In the parallel study, 27 NF1 children were diagnosed with ASD. These children have a distinct phenotype compared to a heterogeneous ASD group, with pronounced social-communicative impairments and fewer restrictive/repetitive behaviors. This study provides a better understanding of social problems in NF1 and the phenotypical overlap with ASD symptomatology. Despite their willingness to engage with others, NF1 children with or without ASD encounter various difficulties in their social-communicative life. (c) 2014 Wiley Periodicals, Inc.
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11. Ram S, Devapriya IA, Fenton G, McVay L, Nguyen DV, Tassone F, Maselli RA, Hagerman RJ. {{Axonal neuropathy in female carriers of the fragile X premutation with fragile X-associated tremor ataxia syndrome}}. {Muscle Nerve};2014 (Nov 11)
Introduction: We examined whether females with the fragile X-associated tremor ataxia syndrome (FXTAS) and non-FXTAS premutation carriers have electrophysiological signs of underlying peripheral neuropathy. Methods: Nerve conduction studies (NCS) were performed on 19 women with FXTAS, 20 non- FXTAS carriers, and 26 age-matched controls. The results were compared to existing data on corresponding male carriers. Results: Women with FXTAS and non-FXTAS carriers had reduced sensory nerve action potential amplitudes. Also, there was a strong trend for reduced compound muscle action potential amplitudes observed in women with FXTAS, but not in non-FXTAS carriers. No significant slowing of nerve conduction velocities, prolongation of F-wave latencies, or associations with molecular measures was observed. Discussion: This study suggests an underlying axonal neuropathy in women with FXTAS. However, in comparison to men with FXTAS, the NCS abnormalities in women were less severe, possibly due to the effect of a normal X-chromosome. (c) 2014 Wiley Periodicals, Inc.
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12. Song DK, Sawada M, Yokota S, Kuroda K, Uenishi H, Kanazawa T, Ogata H, Ihara H, Nagai T, Shimoda K. {{Comparative analysis of autistic traits and behavioral disorders in Prader-Willi syndrome and Asperger disorder}}. {Am J Med Genet A};2014 (Nov 11)
Prader-Willi syndrome (PWS) is a neuro-genetic disorder caused by the absence/loss of expression of one or more paternally expressed genes on chromosome 15 (q11-13). In this study, a comparative analysis of intelligence level and autistic traits was conducted between children with PWS (n = 30; 18 males, 12 females; age = 10.6 +/- 2.8 years) and those with Asperger disorder (AD; n = 31; 24 males, 7 females; age = 10.5 +/- 3.1 years). The children were compared by age group: lower elementary school age (6-8 years), upper elementary school age (9-12 years), and middle school age (13-15 years). As results, the intelligence levels of children with PWS were significantly lower than those with AD across all age groups. Autistic traits, assessed using the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), revealed that among elementary school age children, those with PWS had less prominent autistic traits than those with AD, however, among middle school age children, those with PWS and AD showed similar prominence. An analysis of the PARS subscale scores by age group showed that while the profiles of autistic traits for children with PWS differed from those of children with AD at elementary school age, the profiles showed no significant differences between the groups at middle school age. The findings suggest that autistic traits in PWS become gradually more prominent with increasing of age and that these autistic traits differ in their fundamental nature from those observed in AD. (c) 2014 Wiley Periodicals, Inc.
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13. Suresh AP, Benjamin TE, Crasta JE, Alwinesh MT, Kanniappan G, Padankatti SM, Nair MK, Russell PS. {{Comparison of Burden Among Primary Care-givers of Children with Autism and Intellectual Disability Against Children with Intellectual Disability Only in a Hospital Population in India}}. {Indian J Pediatr};2014 (Nov 13)
OBJECTIVE: To compare the burden among the primary caregivers (PCG) of children with autism and intellectual disability (ASD + ID) against intellectual disability (ID) only, and identify the factors that predict high caregiver burden. METHODS: Children with either ASD + ID (N = 41) or ID (N = 56) and their PCG were recruited and assessed using the Family Burden Interview Schedule, Binet Kamat Scale of Intelligence or Gesell’s Developmental Schedule and Vineland Social Maturity Scale, Childhood Autism Rating Scale, Sensory Profile and Brief Autism Mealtime Behavior Inventory after collecting the socio-demographic details. Appropriate bivariate and multivariate statistical test were used. RESULTS: The total burden and level of burden was similar among PCG of children with ASD + ID and ID (P = 0.8). However, financial burden (P = 0.03) and burden due to the effects on the physical health of other family members (P = 0.03) was more among the ID group. The burden due to the effects on family interaction was more (P = 0.009) in the ASD + ID group. The socio-economic status (OR = 3.60; P = 0.03) and the kinship of the primary care-giver (OR = 0.37; P = 0.008) were significantly associated with high level of burden. In addition, the diagnosis, and gender of the child contributed to the prediction model for high level of burden. CONCLUSIONS: The interventions for children with ASD + ID and ID should have modules to address burden among PCG. Disability specific burden alleviating strategies should be used among PCG who are at risk of having high burden.
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14. Xing J, Wang C, Kimura H, Takasaki Y, Kunimoto S, Yoshimi A, Nakamura Y, Koide T, Banno M, Kushima I, Uno Y, Okada T, Aleksic B, Ikeda M, Iwata N, Ozaki N. {{Resequencing and Association Analysis of PTPRA, a Possible Susceptibility Gene for Schizophrenia and Autism Spectrum Disorders}}. {PLoS One};2014;9(11):e112531.
BACKGROUND: The PTPRA gene, which encodes the protein RPTP-alpha, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. METHODS: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3’UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. RESULTS: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3’UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. MAJOR CONCLUSIONS: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.
