1. Acikel B, Yar A, Herguner S. {{Functional Vomiting Treated Successfully with Aripiprazole in a Child with Autism Spectrum Disorder}}. {J Child Adolesc Psychopharmacol};2016 (Mar 3)
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2. El-Ansary A, Al-Ghamdi M, Bhat RS, Al-Daihan S, Al-Ayadhi L. {{Potency of pre-post treatment of coenzyme Q10 and melatonin supplement in ameliorating the impaired fatty acid profile in rodent model of autism}}. {Food Nutr Res};2016;60:28127.
BACKGROUND: Abnormalities in fatty acid metabolism and membrane fatty acid composition play a part in a wide range of neurodevelopmental and psychiatric disorders. Altered fatty acid homeostasis as a result of insufficient dietary supplementation, genetic defects, the function of enzymes involved in their metabolism, or mitochondrial dysfunction contributes to the development of autism. OBJECTIVE: This study evaluates the association of altered brain lipid composition and neurotoxicity related to autism spectrum disorders in propionic acid (PA)-treated rats. DESIGN: Forty-eight young male western albino rats were used in this study. They were grouped into six equal groups with eight rats in each. The first group received only phosphate buffered saline (control group). The second group received a neurotoxic dose of buffered PA (250 mg/kg body weight/day for 3 consecutive days). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for 1 week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for 1 week prior to PA (protected groups). Methyl esters of fatty acid were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography. RESULTS: The obtained data proved that fatty acids are altered in brain tissue of PA-treated rats. All saturated fatty acids were increased while all unsaturated fatty acids were significantly decreased in the PA-treated group and relatively ameliorated in the pre-post melatonin and coenzyme Q groups. CONCLUSIONS: Melatonin and coenzyme Q were effective in restoring normal level of most of the impaired fatty acids in PA-intoxicated rats which could help suggest both as supplements to ameliorate the autistic features induced in rat pups.
3. Kwok YK, Wong KM, Lo FM, Kong GW, Moore JK, Wu S, Lam ST, Schermer M, Leung TY, Kwong WC. {{Validation of a robust PCR-based assay for quantifying fragile X CGG repeats}}. {Clin Chim Acta};2016 (Mar 3)
BACKGROUND: Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats. METHODS: We performed an analytical and clinical validation of a new PCR-based method that utilizes a low-cost capillary electrophoresis instrument and the FragilEase reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed. RESULTS: All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat. CONCLUSION: This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories.
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4. Marinopoulou M, Lugnegard T, Hallerback MU, Gillberg C, Billstedt E. {{Asperger Syndrome and Schizophrenia: A Comparative Neuropsychological Study}}. {J Autism Dev Disord};2016 (Mar 3)
There has been an increasing interest in possible connections between autism spectrum disorder (ASD) and schizophrenia in the last decade. Neuropsychological comparison studies have, however, been few. The present study examined similarities and differences in intellectual and executive functioning between adults with Asperger syndrome (AS) and adults with schizophrenic psychosis (SP). A group with AS and a group with SP were assessed neuropsychologically with WAIS-III and D-KEFS. Similarities were found between groups, as displayed by an uneven cognitive profile, limitations in working memory, processing speed and some aspects of executive functioning. Full Scale IQ was higher in the AS group. These results add to the current research illuminating similarities and differences between ASD and schizophrenia on a cognitive level.
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5. McCoy SM, Jakicic JM, Gibbs BB. {{Comparison of Obesity, Physical Activity, and Sedentary Behaviors Between Adolescents With Autism Spectrum Disorders and Without}}. {J Autism Dev Disord};2016 (Mar 3)
Body mass index classification, physical activity (PA), and sedentary behaviors were compared in adolescents with autism spectrum disorder (ASD) to typically developing adolescents. Participants included 42,747 adolescents (ASD, n = 915) from the 2011-2012 National Survey of Children’s Health. After controlling for covariates, adolescents were more likely to be overweight and obese, and less likely to engage in regular PA versus typically developing adolescents (p’s < 0.05). Increased odds for overweight and obesity were attenuated after adjustment for PA. Higher autism severity was associated with increased odds of overweight and obesity and decreased odds of PA, sport, and club participation. These findings suggest adolescents with ASD are in need of targeted programs to decrease obesity and increase physical activity.
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6. Packer A. {{Neocortical Neurogenesis and the Etiology of Autism Spectrum Disorder}}. {Neurosci Biobehav Rev};2016 (Mar 3)
Researchers have now identified many highly penetrant genetic risk factors for autism spectrum disorder (ASD). Some of these genes encode synaptic proteins, lending support to the hypothesis that ASD is a disorder of synaptic homeostasis. Less attention, however, has been paid to the genetic risk factors that converge on events that precede synaptogenesis, including the proliferation of neural progenitor cells and the migration of neurons to the appropriate layers of the developing neocortex. Here I review this evidence, focusing on studies of mutant mouse phenotypes, human postmortem data, systems biological analyses, and non-genetic risk factors. These findings highlight embryonic neurogenesis as a potentially important locus of pathology in ASD. In some instances, this pathology may be driven by alterations in chromatin biology and canonical Wnt signaling, which in turn affect fundamental cellular processes such as cell-cycle length and cell migration. This view of ASD suggests the need for a better understanding of the relationship between variation in neuron number, laminar composition, and the neural circuitry most relevant to the disorder.
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7. Riddle K, Cascio CJ, Woodward ND. {{Brain structure in autism: a voxel-based morphometry analysis of the Autism Brain Imaging Database Exchange (ABIDE)}}. {Brain Imaging Behav};2016 (Mar 3)
Increased brain volume is a consistent finding in young children with autism spectrum disorders (ASD); however, the regional specificity and developmental course of abnormal brain structure are less clear. Small sample sizes, particularly among voxel-based morphometry (VBM) investigations, likely contribute to this difficulty. Recently established large-scale neuroimaging data repositories have helped clarify the neuroanatomy of neuropsychiatric disorders such as schizophrenia and may prove useful in ASD. Structural brain images from the Autism Brain Imaging Database Exchange (ABIDE), which contains over 1100 participants, were analyzing using DARTEL VBM to investigate total brain and tissue volumes, and regional brain structure abnormalities in ASD. Two, overlapping cohorts were analyzed; an ‘All Subjects’ cohort (n = 833) that included all individuals with usable MRI data, and a ‘Matched Samples’ cohort (n = 600) comprised of ASD and TD individuals matched, within each site, on age and sex. Total brain and grey matter volumes were enlarged by approximately 1-2 % in ASD; however, the effect reached statistical significance in only the All Subjects cohort. Within the All Subjects cohort, VBM analysis revealed enlargement of the left anterior superior temporal gyrus in ASD. No significant regional changes were detected in the Matched Samples cohort. There was a non-significant reduction in the correlation between IQ and TBV in ASD compared to TD. Brain structure abnormalities in ASD individuals age 6 and older consists of a subtle increase in total brain volume due to enlargement of grey matter with little evidence of regionally specific effects.
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8. Schonewolf-Greulich B, Tejada MI, Stephens K, Hadzsiev K, Gauthier J, Brondum-Nielsen K, Pfundt R, Ravn K, Maortua H, Gener B, Martinez-Bouzas C, Piton A, Rouleau G, Clayton-Smith J, Kleefstra T, Bisgaard AM, Tumer Z. {{The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome}}. {Clin Genet};2016 (Mar 3)
Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females the phenotype can also be influenced by the X-inactivation pattern. In this study we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.
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9. Shield A, Pyers J, Martin A, Tager-Flusberg H. {{Relations between language and cognition in native-signing children with autism spectrum disorder}}. {Autism Res};2016 (Mar 3)
Two populations have been found to exhibit delays in theory of mind (ToM): deaf children of hearing parents and children with autism spectrum disorder (ASD). Deaf children exposed to sign from birth by their deaf parents, however, show no such delay, suggesting that early language exposure is key to ToM development. Sign languages also present frequent opportunities with visual perspective-taking (VPT), leading to the question of whether sign exposure could benefit children with ASD. We present the first study of children with ASD exposed to sign from birth by their deaf parents. Seventeen native-signing children with a confirmed ASD diagnosis and a chronological- and mental age-matched control group of 18 typically developing (TD) native-signing deaf children were tested on American Sign Language (ASL) comprehension, two minimally verbal social cognition tasks (ToM and VPT), and one spatial cognition task (mental rotation). The TD children outperformed the children with ASD on ASL comprehension (p < 0.0001), ToM (p = 0.02), and VPT (p < 0.01), but not mental rotation (p = 0.12). Language strongly correlated with ToM (p < 0.01) and VPT (p < 0.001), but not mental rotation (p = ns). Native exposure to sign is thus insufficient to overcome the language and social impairments implicated in ASD. Contrary to the hypothesis that sign could provide a scaffold for ToM skills, we find that signing children with ASD are unable to access language so as to gain any potential benefit sign might confer. Our results support a strong link between the development of social cognition and language, regardless of modality, for TD and ASD children. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Stessman HA, Willemsen MH, Fenckova M, Penn O, Hoischen A, Xiong B, Wang T, Hoekzema K, Vives L, Vogel I, Brunner HG, van der Burgt I, Ockeloen CW, Schuurs-Hoeijmakers JH, Klein Wassink-Ruiter JS, Stumpel C, Stevens SJ, Vles HS, Marcelis CM, van Bokhoven H, Cantagrel V, Colleaux L, Nicouleau M, Lyonnet S, Bernier RA, Gerdts J, Coe BP, Romano C, Alberti A, Grillo L, Scuderi C, Nordenskjold M, Kvarnung M, Guo H, Xia K, Piton A, Gerard B, Genevieve D, Delobel B, Lehalle D, Perrin L, Prieur F, Thevenon J, Gecz J, Shaw M, Pfundt R, Keren B, Jacquette A, Schenck A, Eichler EE, Kleefstra T. {{Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders}}. {Am J Hum Genet};2016 (Mar 3);98(3):541-552.
Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 x 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.
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11. Sudarshan S, Gupta N, Kabra M. {{Genetic Studies in Autism}}. {Indian J Pediatr};2016 (Mar 3)
Autism is a complex neurodevelopmental disorder, which has captured the attention of not only pediatricians but also the parents. From the symptoms until the final diagnosis, parents undergo a diagnostic odyssey that involves a battery of tests without much yield. This has led to an increase in the referrals to the clinical geneticists to rule out the possible genetic etiology that can have implications for the parents for future pregnancy. This chapter focuses on the various genetic causes and their appropriate application in the evaluation of a child with Autism Spectrum Disorders (ASDs).
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12. Sun MK, Hongpaisan J, Alkon DL. {{Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice}}. {J Pharmacol Exp Ther};2016 (Mar 3)
Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder which currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective PKC activator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor (BDNF) expression, 2) the PSD-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without down-regulation of mGluR5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. The mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without down-regulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.
