1. Allou L, Lambert L, Amsallem D, Bieth E, Edery P, Destree A, Rivier F, Amor D, Thompson E, Nicholl J, Harbord M, Nemos C, Saunier A, Moustaine A, Vigouroux A, Jonveaux P, Philippe C. {{14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements}}. {Eur J Hum Genet}. 2012.
The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.European Journal of Human Genetics advance online publication, 27 June 2012; doi:10.1038/ejhg.2012.127.
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2. Burnett HG, Jellema T. {{(Re-)conceptualisation in Asperger’s Syndrome and Typical Individuals with Varying Degrees of Autistic-like Traits}}. {J Autism Dev Disord}. 2012.
The abilities to form new concepts from scratch (conceptualisation), and to flexibly switch from one concept to another (re-conceptualisation), were investigated in adults with Asperger’s Syndrome and in typically-developed adults with low and high autism spectrum quotients. In consecutively presented morphs, containing increasing percentages of animate or inanimate objects, the emerging objects had to be identified. The abilities to conceptualise and reconceptualise became increasingly impaired with increasing autistic(-like) traits. Across both tasks, all groups recognised animate objects quicker than inanimate objects. However, this ‘animate advantage’ was differently affected by the two tasks. In the Reconceptualisation task, the ‘animate advantage’ gradually disappeared with increasing autistic(-like) traits, whereas in the Conceptualisation task it remained present.
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3. Chaste P, Betancur C, Gerard-Blanluet M, Bargiacchi A, Kuzbari S, Drunat S, Leboyer M, Bourgeron T, Delorme R. {{High-functioning autism spectrum disorder and fragile X syndrome: report of two affected sisters}}. {Mol Autism}. 2012; 3(1): 5.
ABSTRACT: BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID), as well as the most frequent monogenic cause of autism spectrum disorder (ASD). Men with FXS exhibit ID, often associated with autistics features, whereas women heterozygous for the full mutation are typically less severely affected; about half have a normal or borderline intelligence quotient (IQ). Previous findings have shown a strong association between ID and ASD in both men and women with FXS. We describe here the case of two sisters with ASD and FXS but without ID. One of the sisters presented with high-functioning autism, the other one with pervasive developmental disorder not otherwise specified and low normal IQ. METHODS: The methylation status of the mutated FMR1 alleles was examined by Southern blot and methylation-sensitive polymerase chain reaction. The X-chromosome inactivation was determined by analyzing the methylation status of the androgen receptor at Xq12. RESULTS: We present the phenotype of the two sisters and other family members. Both sisters carried a full mutation in the FMR1 gene, with complete methylation and random X chromosome inactivation. CONCLUSIONS: These findings suggest that autistic behaviors and cognitive impairment can manifest as independent traits in FXS. Mutations in FMR1, known to cause syndromic autism, may also contribute to the etiology of high-functioning, non-syndromic ASD, particularly in women. Thus, screening for FXS in patients with ASD should not be limited to those with comorbid ID.
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4. Lesca G, Rudolf G, Labalme A, Hirsch E, Arzimanoglou A, Genton P, Motte J, de Saint Martin A, Valenti MP, Boulay C, De Bellescize J, Keo-Kosal P, Boutry-Kryza N, Edery P, Sanlaville D, Szepetowski P. {{Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes the link with autism}}. {Epilepsia}. 2012.
Purpose: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency ( approximately 20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 x 10(-7) ). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.
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5. Nakanishi M, Deardorff MA, Clark D, Levy SE, Krantz I, Pipan M. {{Investigation of autistic features among individuals with mild to moderate Cornelia de Lange syndrome}}. {Am J Med Genet A}. 2012.
Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Autism has been reported to occur frequently in CdLS, but the frequency of autism in individuals with the milder CdLS phenotype is not well studied. We investigated autistic features by using a screening tool and a diagnostic interview in 49 individuals with the mild to moderate phenotype from a CdLS research database at the Children’s Hospital of Philadelphia. The Social Communication Questionnaire (SCQ), a screening instrument for autistic disorder, was completed for all individuals. For individuals who screened positive and a subset of those that screened negative, the Autism Diagnostic Interview-Revised (ADI-R) was administered. Autistic symptom severity was not significantly different by gender, age groups, and genotypes. There was a significant correlation between higher levels of adaptive functioning and lower scores of autistic symptoms. The estimated prevalence of significant autistic features by ADI-R criteria was 43% in our cohort of individuals with the mild to moderate CdLS phenotype, which suggests that prevalence of autistic disorder may be higher than previously described among individuals with mild to moderate phenotype of CdLS. Clinicians who take care of individuals with CdLS should have a high index of suspicion for autistic features, and refer for further evaluation when these features are present in order to expedite appropriate intervention. (c) 2012 Wiley Periodicals, Inc.
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6. Pilling S, Baron-Cohen S, Megnin-Viggars O, Lee R, Taylor C. {{Recognition, referral, diagnosis, and management of adults with autism: summary of NICE guidance}}. {BMJ}. 2012; 344: e4082.
7. Prandini P, Pasquali A, Malerba G, Marostica A, Zusi C, Xumerle L, Muglia P, Da Ros L, Ratti E, Trabetti E, Franco Pignatti P. {{The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families}}. {Psychiatr Genet}. 2012; 22(4): 177-81.
OBJECTIVE: The objective of this study was to replicate an association study on a newly collected Italian autism spectrum disorder (ASD) cohort by studying the genetic markers associated with ASDs from recent genome-wide and candidate gene association studies. METHODS: We have genotyped 746 individuals from 227 families of the Italian Autism Network using allelic discrimination TaqMan assays for seven common single-nucleotide polymorphisms: rs2292813 (SLC25A12 gene), rs35678 (ATP2B2 gene), rs4307059 (between CDH9 and CDH10 genes), rs10513025 (between SEMA5A and TAS2R1 genes), rs6872664 (PITX1 gene), rs1861972 (EN2 gene), and rs4141463 (MACROD2 gene). A family-based association study was conducted. RESULTS: A significant association was found for two of seven markers: rs4307059 T allele (odds ratio: 1.758, SE=0.236; P-value=0.017) and rs35678 TC genotype (odds ratio: 0.528, SE=0.199; P-value=0.0013). CONCLUSION: A preferential allele transmission of two markers located at loci previously associated with social and verbal communication skill has been confirmed in patients of a new ASD family sample.
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8. Stewart SL, Baiden P, Theall-Honey L. {{Factors associated with the use of intrusive measures at a tertiary care facility for children and youth with mental health and developmental disabilities}}. {Int J Ment Health Nurs}. 2012.
This study seeks to identify some of the explanatory factors associated with the use of intrusive measures among children with mental health and developmental disabilities in psychiatric facilities. Intrusive intervention data were collected using an organizational database that was developed internally at a tertiary care facility. The sample was composed of 338 children/youth aged between 6 and 18 years (mean = 12.33, standard deviation = 2.70) admitted within a 2-year period. Logistic regression was used to examine the relationship between chemical restraint, physical restraint and secure isolation, and programme type after controlling for demographic and other relevant client characteristics. The study found that the number of chemical restraints and secure isolations was higher for clients with developmental disabilities than for clients with mental health, whereas the number of physical restraints was lower for clients with developmental disabilities than clients with mental health issues. Demographic variables also predicted specific types of intrusive measures. The results of this study outline the differential factors associated with specific types of intrusive measures to control aggressive and self-harm behaviours. The paper also outlines cultural change initiatives, organizational interventions, and policy implications for best practice services for children/youth in psychiatric facilities to further reduce intrusive measures.
