1. Aliaga SM, Slater HR, Francis D, Du Sart D, Li X, Amor DJ, Alliende AM, Santa Maria L, Faundes V, Morales P, Trigo C, Salas I, Curotto B, Godler DE. {{Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis}}. {Clinical chemistry}. 2015 Dec 29.
BACKGROUND: FMR1 full mutations (FMs) (CGG expansion >200) in males mosaic for a normal (<45 CGG) or gray-zone (GZ) (45-54 CGG) allele can be missed with the standard 2-step fragile X syndrome (FXS) testing protocols, largely because the first-line PCR tests showing a normal or GZ allele are not reflexed to the second-line test that can detect FM. METHODS: We used methylation-specific quantitative melt analysis (MS-QMA) to determine the prevalence of cryptic FM alleles in 2 independent cohorts of male patients (994 from Chile and 2392 from Australia) referred for FXS testing from 2006 to 2013. All MS-QMA- positive cases were retested with commercial triplet primed PCR, methylation-sensitive Southern blot, and a methylation-specific EpiTYPER-based test. RESULTS: All 38 FMs detected with the standard 2-step protocol were detected with MS-QMA. However, MS-QMA identified methylation mosaicism in an additional 11% and 15% of patients in the Chilean and Australian cohorts, respectively, suggesting the presence of a cryptic FM. Of these additional patients, 57% were confirmed to carry cryptic expanded alleles in blood, buccal mucosa, or saliva samples. Further confirmation was provided by identifying premutation (CGG 55-199) alleles in mothers of probands with methylation-sensitive Southern blot. Neurocognitive assessments showed that low-level mosaicism for cryptic FM alleles was associated with cognitive impairment or autism. CONCLUSIONS: A substantial number of mosaic FM males who have cognitive impairment or autism are not diagnosed with the currently recommended 2-step testing protocol and can be identified with MS-QMA as a first-line test. Lien vers le texte intégral (Open Access ou abonnement)
2. Duvekot J, van der Ende J, Constantino JN, Verhulst FC, Greaves-Lord K. {{Symptoms of autism spectrum disorder and anxiety: shared familial transmission and cross-assortative mating}}. {Journal of child psychology and psychiatry, and allied disciplines}. 2015 Dec 30.
BACKGROUND: In order to shed more light on the frequent co-occurrence of Autism Spectrum Disorder (ASD) and anxiety in children, the aims of the study were (a) to examine whether ASD and anxiety share familial transmission indicated by cross-symptom associations between parental and children’s symptoms (e.g., parental anxiety predicting children’s ASD) in addition to associations for similar symptoms; (b) to investigate the possibility that cross-assortative mating (i.e., whether ASD symptoms in one parent are positively associated with anxiety symptoms in the other parent) increases the risk for both ASD and anxiety in children. METHOD: In 231 families of clinically referred children, parents rated both their own and the other parent’s ASD and anxiety symptoms and one parent those of the index child and siblings (n = 447, aged 2.5-18 years). ASD symptoms were assessed using the Social Responsiveness Scale (SRS-2) and anxiety symptoms using the Achenbach System of Empirically Based Assessment (ASEBA) instruments. RESULTS: Parental ASD and anxiety symptoms predicted similar symptoms in children, dependent on the informant type. Additionally, parental anxiety symptoms across both self-report and informant-report predicted children’s ASD symptoms and maternal self-reported ASD symptoms predicted children’s anxiety symptoms. ASD and anxiety symptoms were correlated within parents, but we found only one cross-symptom association between parents. CONCLUSIONS: Cross-symptom associations between parental and children’s ASD and anxiety symptoms suggest shared familial transmission of ASD and anxiety, but further research is needed to clarify the underlying mechanisms. Cross-assortative mating does not seem a likely explanation for the co-occurrence of ASD and anxiety in children.
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3. Freitag CM, Jensen K, Elsuni L, Sachse M, Herpertz-Dahlmann B, Schulte-Ruther M, Hanig S, von Gontard A, Poustka L, Schad-Hansjosten T, Wenzl C, Sinzig J, Taurines R, Geissler J, Kieser M, Cholemkery H. {{Group-based cognitive behavioural psychotherapy for children and adolescents with ASD: the randomized, multicentre, controlled SOSTA – net trial}}. {Journal of child psychology and psychiatry, and allied disciplines}. 2015 Dec 30.
BACKGROUND: Group-based psychotherapy in Autism Spectrum Disorder (ASD) has predominantly been studied in the United States by small studies in school-aged children without long-term follow-up. We report results of a large, confirmatory, multicentre randomized-controlled phase-III trial in children and adolescents studying the ASD specific, manualized group-based cognitive behavioural SOSTA-FRA approach. METHODS: High-functioning ASD individuals aged 8-19 years old were randomized to 12 sessions SOSTA-FRA or treatment as usual. Primary outcomes were change in total raw score of the parent-rated Social Responsiveness Scale (pSRS) between baseline (T2) and end of intervention (T4), and between T2 and 3 months after end of intervention (T5). TRIAL REGISTRATION: ISRCTN94863788. RESULTS: Between 20/5/2010 and 14/2/2013, n = 320 ASD patients were screened, n = 228 patients were randomized, and N = 209 analysed. Mean pSRS difference between groups at T4 was -6.5 (95% CI -11.6 to – 1.4; p = .013), and at T5 -6.4 (-11.5 to -1.3, p = .015). Pre-treatment SRS and IQ were positively associated with stronger improvement at T4 and T5. CONCLUSIONS: Short-term ASD-specific add-on group-based psychotherapy has shown postintervention efficacy with regard to parent-rated social responsiveness predominantly in male high-functioning children and adolescents with ASD. Future studies should implement blinded standardized observational measures of peer-related social interaction.
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4. Goncalves TF, Santos JM, Goncalves AP, Tassone F, Mendoza-Morales G, Ribeiro MG, Kahn E, Boy R, Goncalves Pimentel MM, Santos-Reboucas CB. {{Finding FMR1 mosaicism in Fragile X syndrome}}. {Expert review of molecular diagnostics}. 2015 Dec 30.
OBJECTIVE: Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism. METHODS: Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR). RESULTS: Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions. CONCLUSION: The authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated.
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5. Hara Y, Ago Y, Taruta A, Katashiba K, Hasebe S, Takano E, Onaka Y, Hashimoto H, Matsuda T, Takuma K. {{Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism}}. {Autism research : official journal of the International Society for Autism Research}. 2015 Dec 30.
Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the alpha2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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6. Hori K, Nagai T, Shan W, Sakamoto A, Abe M, Yamazaki M, Sakimura K, Yamada K, Hoshino M. {{Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory}}. {PloS one}. 2015;10(12):e0145979.
Mutations in the Autism susceptibility candidate 2 gene (AUTS2) have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.
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7. Loth E, Spooren W, Ham LM, Isaac MB, Auriche-Benichou C, Banaschewski T, Baron-Cohen S, Broich K, Bolte S, Bourgeron T, Charman T, Collier D, de Andres-Trelles F, Durston S, Ecker C, Elferink A, Haberkamp M, Hemmings R, Johnson MH, Jones EJ, Khwaja OS, Lenton S, Mason L, Mantua V, Meyer-Lindenberg A, Lombardo MV, O’Dwyer L, Okamoto K, Pandina GJ, Pani L, Persico AM, Simonoff E, Tauscher-Wisniewski S, Llinares-Garcia J, Vamvakas S, Williams S, Buitelaar JK, Murphy DG. {{Identification and validation of biomarkers for autism spectrum disorders}}. {Nature reviews Drug discovery}. 2015 Dec 31;15(1):70-3.
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8. Majoko T. {{Inclusion of Children with Autism Spectrum Disorders: Listening and Hearing to Voices from the Grassroots}}. {Journal of autism and developmental disorders}. 2015 Dec 29.
The current significantly high prevalence rates of autism spectrum disorder (ASD) coupled with the paradigm shift from exclusive to inclusive education warrants research on inclusion of children with ASD in mainstream classrooms in Zimbabwe. A qualitative methodology was used to interview 21 regular primary school teachers regarding social barriers and enablers of inclusion of 6-12 year old children with ASD in mainstream classrooms in Harare educational province of Zimbabwe. Data analysis comprised pattern coding and cross-case analysis. Social rejection, communication impairments and behavioural challenges of children with ASD interfered with inclusion in mainstream classrooms. Regular teachers’ training, stakeholder collaboration and institutionalization of social support services and programmes would facilitate the inclusion of children with ASD in mainstream classrooms.
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9. Travasso C. {{Non-specialist health workers can deliver autism treatment in Asia, finds study}}. {BMJ (Clinical research ed)}. 2015;351:h6987.
