1. Goddard L, Dritschel B, Robinson S, Howlin P. {{Development of autobiographical memory in children with autism spectrum disorders: Deficits, gains, and predictors of performance}}. {Dev Psychopathol};2013 (Nov 27):1-14.
Autobiographical memory (AM) was assessed in 63 children (aged 8-17 years) with an autism spectrum disorder (ASD) and compared with 63 typically developing children matched for age, gender, IQ, and verbal ability. A range of methodologies was employed for eliciting past experience with particular focus on the ability to recall (a) specific events, (b) the recent and remote past, and (c) semantic versus episodic memories across different lifetime periods. Results indicated that the ASD group manifested difficulties in retrieving specific memories to word cues and had poorer access to the remote past. Deficits were found in the context of intact recent memory and preserved general memory abilities, with some impairment of visual memory. Problems in retrieving episodic and semantic AMs across the life span were also evident. Qualitative analysis of memory reports suggested that the ASD group was less likely to refer to emotion in their remote memories but more likely to describe emotions in their recent memories. Important predictors of AM performance in the ASD group were central executive abilities, in particular cognitive flexibility and verbal fluency.
Lien vers le texte intégral (Open Access ou abonnement)
2. Huang W, Luo S, Ou J, Zhu F, Xia Y, Xue J, Pan Q, Wu L, Duan R. {{Correlation between FMR1 expression and clinical phenotype in discordant dichorionic-diamniotic monozygotic twin sisters with the fragile x mutation}}. {J Med Genet};2013 (Nov 27)
BACKGROUND: The clinical phenotypes of females with fragile X full mutations vary drastically. Comparisons of discordant monozygotic twins provide opportunities to ascertain crucial factors that influence disease phenotype penetrance. OBJECTIVE: To identify crucial factors influencing the phenotypic expression of fragile X syndrome (FXS). METHODS AND RESULTS: We describe a pair of discordant monozygotic female twins (dichorionic-diamniotic, Di-Di) with full mutation. The degrees of their phenotypic discordance regarding physical, psychiatric and behavioural features were quantified in a series of neuropsychological tests that varied significantly. Their FMR1 expression levels and whole genome DNA methylation profiling in blood were similar. Their similar life experiences also suggested that environmental factors had limited influence. However, the skewed inactivation of the normal X chromosome in the hair roots of twin A, resulting in large reduction in FMR1 expression compared to that of twin B, could adequately explain their widely variable phenotypes. CONCLUSIONS: The sixfold variation in hair root FMR1 expression, which reflected FMRP (fragile X mental retardation protein) expression in the brain, accounted for the disparate phenotypes in IQ, cognition, and social capability between the twins. Additionally, considering the Di-Di type twinning and different CGG repeat sizes, CGG expansion should occur before splitting at day 3 of gestation.
Lien vers le texte intégral (Open Access ou abonnement)
3. Iourov IY, Vorsanova SG, Voinova VY, Kurinnaia OS, Zelenova MA, Demidova IA, Yurov YB. {{Xq28 (MECP2) microdeletions are common in mutation-negative females with Rett syndrome and cause mild subtypes of the disease}}. {Mol Cytogenet};2013 (Nov 27);6(1):53.
BACKGROUND: Rett syndrome (RTT) is an X-linked neurodevelopmental disease affecting predominantly females caused by MECP2 mutations. Although RTT is classically considered a monogenic disease, a stable proportion of patients, who do not exhibit MECP2 sequence variations, does exist. Here, we have attempted at uncovering genetic causes underlying the disorder in mutation-negative cases by whole genome analysis using array comparative genomic hybridization (CGH) and a bioinformatic approach. RESULTS: Using BAC and oligonucleotide array CGH, 39 patients from RTT Russian cohort (in total, 354 RTT patients), who did not bear intragenic MECP2 mutations, were studied. Among the individuals studied, 12 patients were those with classic RTT and 27 were those with atypical RTT. We have detected five 99.4 kb deletions in chromosome Xq28 affecting MECP2 associated with mild manifestations of classic RTT and five deletions encompassing MECP2 spanning 502.428 kb (three cases), 539.545 kb (one case) and 877.444 kb (one case) associated with mild atypical RTT. A case has demonstrated somatic mosaicism. Regardless of RTT type and deletion size, all the cases exhibited mild phenotypes. CONCLUSIONS: Our data indicate for the first time that no fewer than 25% of RTT cases without detectable MECP2 mutations are caused by Xq28 microdeletions. Furthermore, Xq28 (MECP2) deletions are likely to cause mild subtypes of the disease, which can manifest as both classical and atypical RTT.
Lien vers le texte intégral (Open Access ou abonnement)
4. May T, Cornish K, Conduit R, Rajaratnam SM, Rinehart NJ. {{Sleep in High-Functioning Children With Autism: Longitudinal Developmental Change and Associations With Behavior Problems}}. {Behav Sleep Med};2013 (Nov 27)
Sleep disturbance is common in autism spectrum disorder (ASD), but longitudinal trajectories are poorly defined. This study measured sleep disturbance at baseline and 1 year later examining change over time and associated problem behaviors. Participants were 84 gender-matched children, aged between 7 and 12 years at baseline; 46 children were diagnosed with ASD, and 38 were typically developing (TYP) children. Parent reports on a range of scales were collected. The ASD group had more sleep disturbance than the TYP group. Sleep disturbance decreased over the year in children with ASD, but not in TYP children. Reduced sleep disturbance was associated with improved social ability. Sleep disturbance at baseline predicted later anxiety. Findings indicated different trajectories of sleep disturbance in ASD, and the implications are discussed.
Lien vers le texte intégral (Open Access ou abonnement)
5. Nguyen MV, Felice CA, Du F, Covey MV, Robinson JK, Mandel G, Ballas N. {{Oligodendrocyte lineage cells contribute unique features to rett syndrome neuropathology}}. {J Neurosci};2013 (Nov 27);33(48):18764-18774.
Mutations in the methyl-CpG binding protein 2 gene, Mecp2, affect primarily the brain and lead to a wide range of neuropsychiatric disorders, most commonly Rett syndrome (RTT). Although the neuropathology of RTT is well understood, the cellular and molecular mechanism(s), which lead to the disease initiation and progression, has yet to be elucidated. RTT was initially attributed only to neuronal dysfunction, but our recent studies and those of others show that RTT is not exclusively neuronal but rather also involves interactions between neurons and glia. Importantly, studies have shown that MeCP2-restored astrocytes and microglia are able to attenuate the disease progression in otherwise MeCP2-null mice. Here we show that another type of glia, oligodendrocytes, and their progenitors are also involved in manifestation of specific RTT symptoms. Mice that lost MeCP2 specifically in the oligodendrocyte lineage cells, although overall normal, were more active and developed severe hindlimb clasping phenotypes. Inversely, restoration of MeCP2 in oligodendrocyte lineage cells, in otherwise MeCP2-null mice, although only mildly prolonging their lifespan, significantly improved the locomotor deficits and hindlimb clasping phenotype, both in male and female mice, and fully restored the body weight in male mice. Finally, we found that the level of some myelin-related proteins was impaired in the MeCP2-null mice. Expression of MeCP2 in oligodendrocytes of these mice only partially restored their expression, suggesting that there is a non-cell-autonomous effect by other cell types in the brains on the expression of myelin-related proteins in oligodendrocytes.
Lien vers le texte intégral (Open Access ou abonnement)
6. Schaevitz LR, Gomez NB, Zhen DP, Berger-Sweeney JE. {{MeCP2 R168X male and female mutant mice exhibit Rett-like behavioral deficits}}. {Genes Brain Behav};2013 (Oct);12(7):732-740.
Rett syndrome (RTT) is a regressive developmental disorder characterized by motor and breathing abnormalities, anxiety, cognitive dysfunction and seizures. Approximately 95% of RTT cases are caused by more than 200 different mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). While numerous transgenic mice have been created modeling common mutations in MeCP2, the behavioral phenotype of many of these male and, especially, female mutant mice has not been well characterized. Thorough phenotyping of additional RTT mouse models will provide valuable insight into the effects of Mecp2 mutations on behavior and aid in the selection of appropriate models, ages, sexes and outcome measures for preclinical trials. In this study, we characterize the phenotype of male and female mice containing the early truncating MeCP2 R168X nonsense point mutation, one of the most common in RTT individuals, and compare the phenotypes to Mecp2 null mutants. Mecp2(R168X) mutants mirror many clinical features of RTT. Mecp2(R168X/y) males exhibit impaired motor and cognitive function and reduced anxiety. The behavioral phenotype is less severe and with later onset in Mecp2(R168X/+) females. Seizures were noted in 3.7% of Mecp2(R168X) mutant females. The phenotype in Mecp2(R168X/y) mutant males is remarkably similar to our previous characterizations of Mecp2 null males, whereas Mecp2(R168X/+) females exhibit a number of phenotypic differences from females heterozygous for a null Mecp2 mutation. This study describes a number of highly robust behavioral paradigms that can be used in preclinical drug trials and underscores the importance of including Mecp2 mutant females in preclinical studies.
Lien vers le texte intégral (Open Access ou abonnement)
7. Yasuda H, Tsutsui T. {{Assessment of Infantile Mineral Imbalances in Autism Spectrum Disorders (ASDs)}}. {Int J Environ Res Public Health};2013;10(11):6027-6043.
The interactions between genes and the environment are now regarded as the most probable explanation for autism. In this review, we summarize the results of a metallomics study in which scalp hair concentrations of 26 trace elements were examined for 1,967 autistic children (1,553 males and 414 females aged 0-15 years-old), and discuss recent advances in our understanding of epigenetic roles of infantile mineral imbalances in the pathogenesis of autism. In the 1,967 subjects, 584 (29.7%) and 347 (17.6%) were found deficient in zinc and magnesium, respectively, and the incidence rate of zinc deficiency was estimated at 43.5% in male and 52.5% in female infantile subjects aged 0-3 years-old. In contrast, 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals were found to suffer from high burdens of aluminum, cadmium and lead, respectively, and 2.8% or less from mercury and arsenic. High toxic metal burdens were more frequently observed in the infants aged 0-3 years-old, whose incidence rates were 20.6%, 12.1%, 7.5%, 3.2% and 2.3% for aluminum, cadmium, lead, arsenic and mercury, respectively. These findings suggest that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may be critical and induce epigenetic alterations in the genes and genetic regulation mechanisms of neurodevelopment in the autistic children, and demonstrate that a time factor « infantile window » is also critical for neurodevelopment and probably for therapy. Thus, early metallomics analysis may lead to early screening/estimation and treatment/prevention for the autistic neurodevelopment disorders.
