1. Bergbaum A, Mackie-Ogilvie C. {{Autism and chromosome abnormalities – A Review}}. {Clin Anat}. 2016.
The neuro-behavioral disorder of autism was first described in the 1940s and was predicted to have a biological basis. Since that time, with the growth of genetic investigations particularly in the area of pediatric development, an increasing number of children with autism and related disorders (autistic spectrum disorders, ASD) have been the subject of genetic studies both in the clinical setting and in the wider research environment. However, a full understanding of the biological basis of ASDs has yet to be achieved. Early observations of children with chromosomal abnormalities detected by G-banded chromosome analysis (karyotyping) and in situ hybridization revealed, in some cases, ASD associated with other features arising from such an abnormality. The introduction of higher resolution techniques for whole genome screening, such as array comparative genome hybridization (aCGH), allowed smaller imbalances to be detected, some of which are now considered to represent autism susceptibility loci. In this review, we describe some of the work underpinning the conclusion that ASDs have a genetic basis; a brief history of the developments in genetic analysis tools over the last fifty years; and the most common chromosomal abnormalities found in association with ASDs. Introduction of next generation sequencing (NGS) into the clinical diagnostic setting is likely to provide further insights into this complex field but it will not be covered in this review. This article is protected by copyright. All rights reserved.
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2. Ford TC, Crewther DP. {{A Comprehensive Review of the (1)H-MRS Metabolite Spectrum in Autism Spectrum Disorder}}. {Front Mol Neurosci}. 2016; 9: 14.
Neuroimaging studies of neuropsychiatric behavior biomarkers across spectrum disorders are typically based on diagnosis, thus failing to account for the heterogeneity of multi-dimensional spectrum disorders such as autism (ASD). Control group trait phenotypes are also seldom reported. Proton magnetic resonance spectroscopy ((1)H-MRS) measures the abundance of neurochemicals such as neurotransmitters and metabolites and hence can probe disorder phenotypes at clinical and sub-clinical levels. This detailed review summarizes and critiques the current (1)H-MRS research in ASD. The literature reports reduced N-acetylaspartate (NAA), glutamate and glutamine (Glx), gamma-aminobutyric acid (GABA), creatine and choline, and increased glutamate for children with ASD. Adult studies are few and results are inconclusive. Overall, the literature has several limitations arising from differences in (1)H-MRS methodology and sample demographics. We argue that more consistent methods and greater emphasis on phenotype studies will advance understanding of underlying cortical metabolite disturbance in ASD, and the detection, diagnosis, and treatment of ASD and other multi-dimensional psychiatric disorders.
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3. Frye RE, Delhey L, Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E. {{Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups}}. {Front Neurosci}. 2016; 10: 80.
Folate receptor alpha (FRalpha) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). They disrupt the transportation of folate across the blood-brain barrier by binding to the FRalpha. Children with ASD and FRAAs have been reported to respond well to treatment with a form of folate known as folinic acid, suggesting that they may be an important ASD subgroup to identify and treat. There has been no investigation of whether they manifest unique behavioral and physiological characteristics. Thus, in this study we measured both blocking and binding FRAAs, physiological measurements including indices of redox and methylation metabolism and inflammation as well as serum folate and B12 concentrations and measurements of development and behavior in 94 children with ASD. Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs while children positive for the blocking FRAA were found to have relatively better redox metabolism and inflammation markers as compared to those negative for blocking FRAAs. In addition, ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale. This study suggests that FRAAs are associated with specific physiological and behavioral characteristics in children with ASD and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments.
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4. Kaushik G, Zarbalis KS. {{Prenatal Neurogenesis in Autism Spectrum Disorders}}. {Front Chem}. 2016; 4: 12.
An ever-increasing body of literature describes compelling evidence that a subset of young children on the autism spectrum show abnormal cerebral growth trajectories. In these cases, normal cerebral size at birth is followed by a period of abnormal growth and starting in late childhood often by regression compared to unaffected controls. Recent work has demonstrated an abnormal increase in the number of neurons of the prefrontal cortex suggesting that cerebral size increase in autism is driven by excess neuronal production. In addition, some affected children display patches of abnormal laminar positioning of cortical projection neurons. As both cortical projection neuron numbers and their correct layering within the developing cortex requires the undisturbed proliferation of neural progenitors, it appears that neural progenitors lie in the center of the autism pathology associated with early brain overgrowth. Consequently, autism spectrum disorders associated with cerebral enlargement should be viewed as birth defects of an early embryonic origin with profound implications for their early diagnosis, preventive strategies, and therapeutic intervention.
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5. Leigh JP, Grosse SD, Cassady D, Melnikow J, Hertz-Picciotto I. {{Spending by California’s Department of Developmental Services for Persons with Autism across Demographic and Expenditure Categories}}. {PLoS One}. 2016; 11(3): e0151970.
BACKGROUND: Few autism spectrum disorder (ASD) studies have estimated non-medical costs for treatment or addressed possible differences in provision of services across gender, race-ethnic, age or demographic or expenditure categories, especially among adults. METHODS: The California Department of Developmental Services (CDDS) provides services to residents with developmental disabilities. CDDS provided aggregate data on primarily non-medical spending for fiscal year 2012-2013 for persons with ASD with or without intellectual disability (ID) (main sample, n = 42,274), and two sub-samples: ASD only (n = 30,164), and ASD+ID (n = 12,110). Demographic variables included sex, age and race-ethnicity. Spending categories included Employment Support, Community Care Facilities, Day Care, Transportation, and in-home and out-of-home Respite. RESULTS: Per-person spending for males and females were approximately the same: $10,488 and $10,791 for males and females for ages 3-17 and $26,491 and $26,627 for ages 18+. Among race/ethnicity categories, the ranking from highest to lowest among ages 3-17 was white non-Hispanics ($11,480), Asian non-Hispanics ($11,036), « Others » ($11,031), Hispanics ($9,571), and African-American non-Hispanics ($9,482). For ages 18+, the ranking was whites ($31,008), African-Americans ($26,831), « Others » ($25,395), Asians ($22,993), and Hispanics ($18,083). The ASD+ID sub-sample exerted disproportionate influence on findings from the main sample for persons 18+. Combining all ages, the top two expenditure categories for per-person spending were Community Care Facilities ($43,867) and Day Care ($11,244). For most adult age groups, the percentage of recipients participating were highest for Day Care (44.9% – 62.4%) and Transportation (38.6% – 50.9%). Per-person spending for Day Care, Transportation, and Employment Support was relatively low for children but relatively high for adults. CONCLUSION: White non-Hispanics received the highest per-person spending and Hispanics among the least. Amounts within spending categories varied considerably across age groups. Our estimates may be useful as baseline measures for stakeholders preparing for increasing ASD prevalence, especially among adults.
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6. Tabolacci E, Mancano G, Lanni S, Palumbo F, Goracci M, Ferre F, Helmer-Citterich M, Neri G. {{Genome-wide methylation analysis demonstrates that 5-aza-2-deoxycytidine treatment does not cause random DNA demethylation in fragile X syndrome cells}}. {Epigenetics Chromatin}. 2016; 9: 12.
BACKGROUND: Fragile X syndrome (FXS) is caused by CGG expansion over 200 repeats at the 5′ UTR of the FMR1 gene and subsequent DNA methylation of both the expanded sequence and the CpGs of the promoter region. This epigenetic change causes transcriptional silencing of the gene. We have previously demonstrated that 5-aza-2-deoxycytidine (5-azadC) treatment of FXS lymphoblastoid cell lines reactivates the FMR1 gene, concomitant with CpG sites demethylation, increased acetylation of histones H3 and H4 and methylation of lysine 4 on histone 3. RESULTS: In order to check the specificity of the 5-azadC-induced DNA demethylation, now we performed bisulphite sequencing of the entire methylation boundary upstream the FMR1 promoter region, which is preserved in control wild-type cells. We did not observe any modification of the methylation boundary after treatment. Furthermore, methylation analysis by MS-MLPA of PWS/AS and BWS/SRS loci demonstrated that 5-azadC treatment has no demethylating effect on these regions. Genome-wide methylation analysis through Infinium 450K (Illumina) showed no significant enrichment of specific GO terms in differentially methylated regions after 5-azadC treatment. We also observed that reactivation of FMR1 transcription lasts up to a month after a 7-day treatment and that maximum levels of transcription are reached at 10-15 days after last administration of 5-azadC. CONCLUSIONS: Taken together, these data demonstrate that the demethylating effect of 5-azadC on genomic DNA is not random, but rather restricted to specific regions, if not exclusively to the FMR1 promoter. Moreover, we showed that 5-azadC has a long-lasting reactivating effect on the mutant FMR1 gene.
