1. Fakhoury M. {{Autistic spectrum disorders: A review of clinical features, theories and diagnosis}}. {Int J Dev Neurosci};2015 (Apr 8)
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders that is among the most severe in terms of prevalence, morbidity and impact to the society. It is characterized by complex behavioral phenotype and deficits in both social and cognitive functions. Although the exact cause of ASD is still not known, the main findings emphasize the role of genetic and environmental factors in the development of autistic behavior. Environmental factors are also likely to interact with the genetic profile and cause aberrant changes in brain growth, neuronal development, and functional connectivity. The past few years have seen an increase in the prevalence of ASD, as a result of enhanced clinical tests and diagnostic tools. Despite growing evidence for the involvement of endogenous biomarkers in the pathophysiology of ASD, early detection of this disorder remains a big challenge. This paper describes the main behavioral and cognitive features of ASD, as well as the symptoms that differentiate autism from other developmental disorders. An attempt will be made to integrate all the available evidence which point to reduced brain connectivity, mirror neurons deficits, and inhibition-excitation imbalance in individuals with ASD. Finally, this review discusses the main factors involved in the pathophysiology of ASD, and illustrates some of the most important markers used for the diagnosis of this debilitating disorder.
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2. Kharrat M, Hsairi I, Fendri-Kriaa N, Kenoun H, Othmen HB, Mahmoud AB, Ghorbel R, Abid I, Triki C, Fakhfakh F. {{A Novel Mutation p.A59P in N-Terminal Domain of Methyl-CpG-Binding Protein 2 Confers Phenotypic Variability in 3 Cases of Tunisian Rett Patients: Clinical Evaluations and In Silico Investigations}}. {J Child Neurol};2015 (Apr 10)
Rett syndrome is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. The aim of this study was to search for mutations of MECP2 gene in Tunisian Rett patients and to evaluate the impact of the found variants on structural and functional features of MeCP2. The result of mutation analysis revealed that 3 Rett patients shared the same novel heterozygous point mutation c.175G>C (p.A59P). The p.A59P mutation was located in a conserved amino acid in the N-terminal segment of MeCP2. This novel mutation confers a phenotypic variability with different clinical severity scores (3, 8, and 9) and predicted by Sift and PolyPhen to be damaging. Modeling results showed that p.A59P adds 2 hydrogen bonds and changes the structural conformation of MeCP2 with a significant root mean square deviation value (9.66 A), suggesting that this mutation could probably affect the conformation, function and stability of MeCP2.
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3. Muotri AR. {{The Human Model: Changing Focus on Autism Research}}. {Biol Psychiatry};2015 (Mar 17)
The lack of live human brain cells for research has slowed progress toward understanding the mechanisms underlying autism spectrum disorders. A human model using reprogrammed patient somatic cells offers an attractive alternative, as it captures a patient’s genome in relevant cell types. Despite the current limitations, the disease-in-a-dish approach allows for progressive time course analyses of target cells, offering a unique opportunity to investigate the cellular and molecular alterations before symptomatic onset. Understanding the current drawbacks of this model is essential for the correct data interpretation and extrapolation of conclusions applicable to the human brain. Innovative strategies for collecting biological material and clinical information from large patient cohorts are important for increasing the statistical power that will allow for the extraction of information from the noise resulting from the variability introduced by reprogramming and differentiation methods. Working with large patient cohorts is also important for understanding how brain cells derived from diverse human genetic backgrounds respond to specific drugs, creating the possibility of personalized medicine for autism spectrum disorders.
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4. Pozzo-Miller L, Pati S, Percy AK. {{Rett Syndrome: Reaching for Clinical Trials}}. {Neurotherapeutics};2015 (Apr 11)
Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.
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5. Valicenti-McDermott M, Lawson K, Hottinger K, Seijo R, Schechtman M, Shulman L, Shinnar S. {{Parental Stress in Families of Children With Autism and Other Developmental Disabilities}}. {J Child Neurol};2015 (Apr 10)
The level of parental stress in families of children with autism and other developmental disabilities and its association with child comorbid symptoms was studied in an ethnically diverse population, in a cross-sectional study with structured interview. The sample included 50 families of children with autism and 50 families of children with other developmental disabilities, matched by age/gender. Interview included Parenting Stress Index-Short Form, Gastrointestinal Questionnaire, Child Sleep Habits Questionnaire, and Aberrant Behavior Checklist. In this ethnically diverse sample, parental stress was significantly higher for the autism group and for non-Hispanic and US-born mothers. In both study groups, parental stress was related to child irritability. Parental stress was also related to gastrointestinal problems in the autism group and to sleep difficulties in the developmental disabilities group. Targeting child irritability may be particularly important in reducing parental stress for families of children with autism and other developmental disabilities.
