1. Alabdali A, Al-Ayadhi L, El-Ansary A. {{Association of social and cognitive impairment and biomarkers in autism spectrum disorders}}. {Journal of neuroinflammation}. 2014 Jan 8;11(1):4.
Objectives: The neurological basis for autism is still not fully understood, and the role of the interaction between neuro-inflammation and neurotransmission impairment needs to be clearer. This study aims to test the possible association between impaired levels of gamma aminobutyric acid (GABA), serotonin, dopamine, oxytocin, and interferon-gamma-induced protein-16 (IFI16) and the severity of social and cognitive dysfunctions in individuals with autism spectrum disorders.Materials and methods: GABA, serotonin, dopamine, oxytocin, and IFI16 as biochemical parameters related to neurochemistry and inflammation were determined in the plasma of 52 Saudi autistic male patients, categorized as mild-moderate and severe as indicated by their Childhood Autism Rating Scale (CARS) or social responsiveness scale (SRS), and compared to 30 age- and gender-matched control samples. RESULTS: The data indicated that Saudi patients with autism have remarkably impaired plasma levels of the measured parameters compared to age and gender-matched controls. While serotonin in platelet-free plasma and dopamine did not correlated with the severity in social and cognitive dysfunction, GABA, oxytocin, and IFI16 were remarkably associated with the severity of both tested scores (SRS and CARS). CONCLUSIONS: The relationship between the selected parameters confirms the role of impaired neurochemistry and neuro-inflammation in the etiology of autism spectrum disorders and the possibility of using GABA, oxytocin, and IFI16 as markers of autism severity. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of clinical symptoms and provide significant guidance for future therapeutic strategy to re-establish physiological homeostasis.
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2. Bandino ML, Garfinkle RA, Zickefoose BA, Hsieh DT. {{Epilepsy at a summer cAMP for children and young adults with developmental disabilities: a 3-year experience}}. {Military medicine}. 2014 Jan;179(1):105-10.
The comprehensive care of children with epilepsy involves not only the treatment of seizures but also enhancement of their quality of life. Children with developmental disabilities are often unable to attend traditional summer camps because of safety concerns, as their prevalence of epilepsy is high and tends to be more severe. The goal of the current study is to describe our epilepsy experience at a summer camp adapted for children with developmental disabilities, with which the U. S. military has had a long-standing relationship. A retrospective chart review of all children and young adults attending summer sessions between 2008 and 2010 was performed. A total of 1,526 camp sessions were attended by 818 campers (mean 13.7 years), with 32.3% of campers having epilepsy. Of campers with epilepsy, 46.6% had cerebral palsy, 57.6% intellectual disability, and 28.8% autism spectrum disorders. Seizure frequency was at least weekly in 21.2% and at least daily in 13.3%. A history of status epilepticus was reported in 34.9%. There were seven camp infirmary visits because of seizures (incidence 1.4%), including two for status epilepticus. Thus, despite a high prevalence of severe epilepsy, in the setting of appropriate safety precautions, a safe camp experience can be provided, as seizure-related complications are rare.
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3. Cukier HN, Dueker ND, Slifer SH, Lee JM, Whitehead PL, Lalanne E, Leyva N, Konidari I, Gentry RC, Hulme WF, Van Booven D, Mayo V, Hofmann NK, Schmidt MA, Martin ER, Haines JL, Cuccaro ML, Gilbert JR, Pericak-Vance MA. {{Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders}}. {Molecular autism}. 2014 Jan 10;5(1):1.
BACKGROUND: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. METHODS: To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. RESULTS: We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 x 10-5). CONCLUSIONS: By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
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4. Edmonson C, Ziats MN, Rennert OM. {{Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum}}. {Molecular autism}. 2014 Jan 10;5(1):3.
BACKGROUND: The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. METHODS: We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the DeltaDeltaCt method normalized to housekeeping gene beta-actin, with a two-tailed Student’s t-test P <0.05 between groups considered as significant. RESULTS: Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. CONCLUSIONS: These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns.
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5. He Q, Nomura T, Xu J, Contractor A. {{The Developmental Switch in GABA Polarity Is Delayed in Fragile X Mice}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2014 Jan 8;34(2):446-50.
Delays in synaptic and neuronal development in the cortex are key hallmarks of fragile X syndrome, a prevalent neurodevelopmental disorder that causes intellectual disability and sensory deficits and is the most common known cause of autism. Previous studies have demonstrated that the normal progression of plasticity and synaptic refinement during the critical period is altered in the cortex of fragile X mice. Although the disruptions in excitatory synapses are well documented in fragile X, there is less known about inhibitory neurotransmission during the critical period. GABAergic transmission plays a crucial trophic role in cortical development through its early depolarizing action. At the end of cortical critical period, response properties of GABA transform into their mature hyperpolarizing type due to developmental changes in intracellular chloride homeostasis. We found that the timing of the switch from depolarizing to hyperpolarizing GABA is delayed in the cortex of fragile X mice and there is a concurrent alteration in the expression of the neuronal chloride cotransporter NKCC1 that promotes the accumulation of intracellular chloride. Disruption of the trophic effects of GABA during cortical development could contribute to the altered trajectory of synaptic maturation in fragile X syndrome.
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6. Ibanez LV, Grantz CJ, Messinger DS. {{The Development of Referential Communication and Autism Symptomatology in High-Risk Infants}}. {Infancy : the official journal of the International Society on Infant Studies}. 2013 Sep;18(5).
Non-verbal referential communication is impaired in children with Autism Spectrum Disorders (ASD). However, the development of difficulties with referential communication in the younger siblings of children with ASD (High-Risk Siblings)-and the degree to which early referential communication predicts later autism symptomatology-is not clear. We modeled the early developmental trajectories of three types of referential communication: responding to joint attention (RJA), initiating joint attention (IJA), and initiating behavioral requests (IBR) across 8, 10, 12, 15, and18 months of age in High-Risk Siblings (n = 40) and the infant siblings of children without ASD (Low-Risk Siblings; n = 21). Hierarchical Linear Modeling indicated that High-Risk Siblings exhibited lower levels of baseline RJA and IJA and a lower rate of linear change in IBR than Low-Risk Siblings. When the 10 High-Risk Siblings who received an ASD diagnosis were excluded from analyses, group differences in the development of referential communication remained significant only for RJA. Baseline levels of IJA were associated with later ASD symptomatology among High-Risk Siblings, suggesting that individual differences in referential communication development at 8 months may index early manifestations of ASD.
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7. Kronenberg LM, Goossens PJ, van Etten DM, van Achterberg T, van den Brink W. {{Need for Care and Life Satisfaction in Adult Substance Use Disorder Patients With and Without Attention Deficit Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD)}}. {Perspectives in psychiatric care}. 2014 Jan 10.
PURPOSE: To identify care needs of adult substance use disorder (SUD) patients with and without co-occurring attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). DESIGN AND METHODS: An exploratory study using the European Addiction Severity Index, the Camberwell Assessment of Needs, and the Manchester Short Assessment of Quality of Life to assess and compare care needs and perceived quality of life. FINDINGS: All patients are dissatisfied with parts of their existence. SUD patients have fewer care needs than SUD patients with co-occurring ADHD or ASD. The SUD and SUD + ADHD groups report needs in similar domains. The SUD + ASD group shows a greater number of and more extensive care needs. PRACTICE IMPLICATIONS: Differences in the care needs of adult SUD patients with and without ADHD or ASD should be taken into account when developing evidence-based nursing care interventions.
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8. Lasalle JM. {{Autism genes keep turning up chromatin}}. {OA autism}. 2013 Jun 19;1(2):14.
Autism-spectrum disorders (ASD) are complex genetic disorders collectively characterized by impaired social interactions and language as well as repetitive and restrictive behaviors. Of the hundreds of genes implicated in ASD, those encoding proteins acting at neuronal synapses have been most characterized by candidate gene studies. However, recent unbiased genome-wide analyses have turned up a multitude of novel candidate genes encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation. Furthermore, the chromatin landscape of the human genome has been shown to influence the location of de novo mutations observed in ASD as well as the landscape of DNA methylation underlying neurodevelopmental and synaptic processes. Understanding the interactions of nuclear chromatin proteins and DNA with signal transduction pathways and environmental influences in the developing brain will be critical to understanding the relevance of these ASD candidate genes and continued uncovering of the « roots » of autism etiology.
9. Maramara LA, He W, Ming X. {{Pre- and Perinatal Risk Factors for Autism Spectrum Disorder in a New Jersey Cohort}}. {Journal of child neurology}. 2014 Jan 10.
This study evaluated the prevalence of pre- and perinatal risk factors in a cohort of children with autism spectrum disorders compared with the New Jersey population. Our cohort included 268 individuals with an autism spectrum disorder. Birth histories were obtained by a self-administered questionnaire. The autism spectrum disorders cohort rates of 7 perinatal risk factors were significantly higher than New Jersey state rates: mother’s age 35 years or older, low birth weight, multiple gestation, prematurity, vaginal bleeding, prolonged labor, and hypoxia. Analysis of clustering of risk factors in the cohort showed no significant differences across maternal and paternal age groups. Older mothers in the cohort had a higher risk of infant hypoxia. Multiple risk factors during pregnancy appear to be associated with a higher risk of autism spectrum disorders in offspring, supporting the hypothesis that environmental influences in conjunction with genetics contribute to the causes of autism spectrum disorders.
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10. Mateu-Huertas E, Rodriguez-Revenga L, Alvarez-Mora MI, Madrigal I, Willemsen R, Mila M, Marti E, Estivill X. {{Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes}}. {Neurobiology of disease}. 2014 Jan 10.
Male premutation carriers presenting between 55-200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5′- UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.
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11. Rodrigues DH, Rocha NP, Sousa LF, Barbosa IG, Kummer A, Teixeira AL. {{Changes in Adipokine Levels in Autism Spectrum Disorders}}. {Neuropsychobiology}. 2013 Dec 31;69(1):6-10.
Background and Objective: The etiopathogenesis of autism spectrum disorders (ASD) is largely unknown, but it seems to involve dysfunction in several biological systems. Among many possible biological pathways, the immune system has emerged as potentially involved. Recent studies have shown association between cytokines (molecules that mediate immune cell interaction) and ASD. Adipokines are cytokines secreted mainly by adipose tissue and may have systemic effects. The main objective of this study was to compare the plasma levels of three adipokines between patients with ASD and healthy controls. Another aim was to correlate the levels of these adipokines and the severity of autistic symptoms as measured by the Social Responsiveness Scale (SRS). Methods: We collected plasma from 30 patients and 19 controls and measured the levels of adiponectin, leptin and resistin using a commercially available kit. We also used the SRS as a tool to assess the severity of autistic symptoms. Results: We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS. Conclusion: There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease. (c) 2013 S. Karger AG, Basel.
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12. Telles LE, Zoratto PH, Day VP, Rosa RF. {{Homicide, fragile X syndrome, and mental retardation}}. {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}. 2013 Oct-Dec;35(4):443-4.
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13. Windham GC, Smith KS, Rosen N, Anderson MC, Grether JK, Coolman RB, Harris S. {{Autism and Developmental Screening in a Public, Primary Care Setting Primarily Serving Hispanics: Challenges and Results}}. {J Autism Dev Disord}. 2014 Jan 10.
We implemented screening of children 16-30 months of age (n = 1,760) from a typically under-served, primarily Hispanic, population, at routine pediatric appointments using the modified checklist for autism in toddlers (M-CHAT) and Ages and Stages Questionnaire. Screen positive rates of 26 and 39 %, respectively, were higher than previous reports. Hispanics were more likely to score M-CHAT positive than non-Hispanics (adjusted OR 1.7, 95 % CI 1.2-2.4), as were those screened in Spanish. About 30 % of screen-positive children were referred for further assessment, but only half were seen. Thus screening in this population is feasible, but may require additional resources. Attention to the cultural applicability of screening instruments, as well as to explaining the results or need for additional services to parents, is critical to serve the growing Hispanic population.
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14. Yang P, Chang CL. {{Glutamate-Mediated Signaling and Autism Spectrum Disorders: Emerging Treatment Targets}}. {Current pharmaceutical design}. 2014 Jan 10.
Autism spectrum disorders (ASD) are developmental disorders which are characterized by deficits in reciprocal social interactions and communication, as well as the presence of impairing repetitive behaviors and restricted interests. Prior work examining human pathology, model systems and genetic studies have led to the current conceptualization of ASD as disorder of synaptic formation and functioning (a « synapsopathy »). In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of glutamate receptors structure and function, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the novel drug development of ASD treatment, and report glutamate-related clinical trials. We will also present the promising techniques of human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotype, cellular responses and glutamate involvement in ASD.
15. Zander E, Sturm H, Bolte S. {{The added value of the combined use of the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule: Diagnostic validity in a clinical Swedish sample of toddlers and young preschoolers}}. {Autism}. 2014 Jan 10.
The diagnostic validity of the new research algorithms of the Autism Diagnostic Interview-Revised and the revised algorithms of the Autism Diagnostic Observation Schedule was examined in a clinical sample of children aged 18-47 months. Validity was determined for each instrument separately and their combination against a clinical consensus diagnosis. A total of N = 268 children (n = 171 with autism spectrum disorder) were assessed. The new Autism Diagnostic Interview-Revised algorithms (research cutoff) gave excellent specificities (91%-96%) but low sensitivities (44%-52%). Applying adjusted cutoffs (lower than recommended based on receiver operating characteristics) yielded a better balance between sensitivity (77%-82%) and specificity (60%-62%). Findings for the Autism Diagnostic Observation Schedule were consistent with previous studies showing high sensitivity (94%-100%) and alongside lower specificity (52%-76%) when using the autism spectrum cutoff, but better balanced sensitivity (81%-94%) and specificity (81%-83%) when using the autism cutoff. A combination of both the Autism Diagnostic Interview-Revised (with adjusted cutoff) and the Autism Diagnostic Observation Schedule (autism spectrum cutoff) yielded balanced sensitivity (77%-80%) and specificity (87%-90%). Results favor a combined usage of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule in young children with unclear developmental problems, including suspicion of autism spectrum disorder. Evaluated separately, the Autism Diagnostic Observation Schedule (cutoff for autism) provides a better diagnostic accuracy than the Autism Diagnostic Interview-Revised.
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16. Zhou T, Yi C. {{Parenting Styles and Parents’ Perspectives on How Their Own Emotions Affect the Functioning of Children with Autism Spectrum Disorders}}. {Family process}. 2014 Jan 9.
The grounded theory method was used to analyze the parenting styles used by caregivers to rear children with autism spectrum disorders (ASD) and to investigate parents’ experiences regarding how to help their child overcome the symptoms. Thirty-two parents from 28 families of children with ASD in mainland China were interviewed. Analysis of interview transcripts revealed four patterns of parenting styles which varied in affiliation to the roles of caretaker and coach. Based on their experience, a sizable group of parents perceived that their own emotions influence the child’s emotions and his/her symptoms. The results suggest the value of developing intervention programs on emotion regulation and positive parenting for the parents of children with ASD.
