1. {{Neurodevelopmental disorders: Whole-exome sequencing elucidates genetic architecture of autism spectrum disorder}}. {Nat Rev Neurol};2014 (Nov 18)
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2. Balan S, Iwayama Y, Maekawa M, Toyota T, Ohnishi T, Toyoshima M, Shimamoto C, Esaki K, Yamada K, Iwata Y, Suzuki K, Ide M, Ota M, Fukuchi S, Tsujii M, Mori N, Shinkai Y, Yoshikawa T. {{Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects}}. {Mol Autism};2014;5(1):49.
BACKGROUND: Histone H3 methylation at lysine 9 (H3K9) is a conserved epigenetic signal, mediating heterochromatin formation by trimethylation, and transcriptional silencing by dimethylation. Defective GLP (Ehmt1) and G9a (Ehmt2) histone lysine methyltransferases, involved in mono and dimethylation of H3K9, confer autistic phenotypes and behavioral abnormalities in animal models. Moreover, EHMT1 loss of function results in Kleefstra syndrome, characterized by severe intellectual disability, developmental delays and psychiatric disorders. We examined the possible role of histone methyltransferases in the etiology of autism spectrum disorders (ASD) and suggest that rare functional variants in these genes that regulate H3K9 methylation may be associated with ASD. METHODS: Since G9a-GLP-Wiz forms a heteromeric methyltransferase complex, all the protein-coding regions and exon/intron boundaries of EHMT1, EHMT2 and WIZ were sequenced in Japanese ASD subjects. The detected variants were prioritized based on novelty and functionality. The expression levels of these genes were tested in blood cells and postmortem brain samples from ASD and control subjects. Expression of EHMT1 and EHMT2 isoforms were determined by digital PCR. RESULTS: We identified six nonsynonymous variants: three in EHMT1, two in EHMT2 and one in WIZ. Two variants, the EHMT1 ankyrin repeat domain (Lys968Arg) and EHMT2 SET domain (Thr961Ile) variants were present exclusively in cases, but showed no statistically significant association with ASD. The EHMT2 transcript expression was significantly elevated in the peripheral blood cells of ASD when compared with control samples; but not for EHMT1 and WIZ. Gene expression levels of EHMT1, EHMT2 and WIZ in Brodmann area (BA) 9, BA21, BA40 and the dorsal raphe nucleus (DoRN) regions from postmortem brain samples showed no significant changes between ASD and control subjects. Nor did expression levels of EHMT1 and EHMT2 isoforms in the prefrontal cortex differ significantly between ASD and control groups. CONCLUSIONS: We identified two novel rare missense variants in the EHMT1 and EHMT2 genes of ASD patients. We surmise that these variants alone may not be sufficient to exert a significant effect on ASD pathogenesis. The elevated expression of EHMT2 in the peripheral blood cells may support the notion of a restrictive chromatin state in ASD, similar to schizophrenia.
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3. Dickinson K, Place M. {{A Randomised Control Trial of the Impact of a Computer-Based Activity Programme upon the Fitness of Children with Autism}}. {Autism Res Treat};2014;2014:419653.
The poor levels of fitness in children with autism are prompting concern for the children’s future health. This study looked to assess if a computer-based activity programme could improve fitness levels (as reflected in cardiopulmonary function) of these children, and achieve a reduction in their body mass index. In a randomised controlled trial, 50 children with autism (of which 33 were under the age of 11 years and 39 were boys) were allocated to an intervention group which encouraged them to use the Nintendo Wii and the software package « Mario and Sonics at the Olympics » in addition to their routine physical education classes. 50 children with autism (34 under the age of 11 years and 40 being boys) acted as controls. At the end of one year, analysis of the changes in scores using analysis of covariance (ANCOVA) on the Eurofit fitness tests showed that the intervention group had made statistically significant improvement on all tests other than flexibility. These improvements were also significantly better than controls. This type of intervention appears to be an effective addition to standard fitness training in order to help children with autism improve their fitness levels.
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4. Jalnapurkar I, Rafika N, Tassone F, Hagerman R. {{Immune mediated disorders in women with a fragile X expansion and FXTAS}}. {Am J Med Genet A};2014 (Nov 14)
Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late-onset neurodegenerative disorder, fragile X-associated tremor ataxia syndrome (FXTAS) and/or the fragile X-associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms-often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre-existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. (c) 2014 Wiley Periodicals, Inc.
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5. Kim KC, Choi CS, Kim JW, Han SH, Cheong JH, Ryu JH, Shin CY. {{MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism}}. {Mol Neurobiol};2014 (Nov 18)
Males are predominantly affected by autism spectrum disorders (ASD) with a prevalence ratio of 5:1. However, the underlying pathological mechanisms governing the male preponderance of ASD remain unclear. Recent studies suggested that epigenetic aberrations may cause synaptic dysfunctions, which might be related to the pathophysiology of ASD. In this study, we used rat offspring prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found male-selective abnormalities in the kinetic profile of the excitatory glutamatergic synaptic protein expressions linked to N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4. Furthermore, VPA exposure showed a male-specific attenuation of the methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of offspring and in the gender-isolated neural progenitor cells (NPCs). In the gender-isolated NPCs culture, higher concentration of VPA induced an increased glutamatergic synaptic development along with decreased MeCP2 expression in both genders suggesting the role of MeCP2 in the modulation of synaptic development. In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA inhibited the MeCP2 expression in male- but not in female-derived NPCs with concomitant induction of postsynaptic proteins such as PSD95. Taken together, we suggest that the male-inclined reduction of MeCP2 expression is involved in the abnormal development of glutamatergic synapse and male preponderance in the VPA animal models of ASD.
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6. Li Z, Tang J, Li H, Chen S, He Y, Liao Y, Wei Z, Wan G, Xiang X, Xia K, Chen X. {{Shorter telomere length in peripheral blood leukocytes is associated with childhood autism}}. {Sci Rep};2014;4:7073.
Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an established real-time polymerase chain reaction method. We observed significantly shorter RTL in patients with childhood autism than in controls (p = 0.006). Individuals with shorter RTL had a significantly increased presence of childhood autism compared with those who had long RTL. In patients, we found that family training interventions have a significant effect on telomere length (P = 0.012), but no correlations between RTL and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) were observed in this study. These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism. The molecular mechanism underlying telomere length may be implicated in the development of autism.
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7. Orekhova EV, Elsabbagh M, Jones EJ, Dawson G, Charman T, Johnson MH. {{EEG hyper-connectivity in high-risk infants is associated with later autism}}. {J Neurodev Disord};2014;6(1):40.
BACKGROUND: It has been previously reported that structural and functional brain connectivity in individuals with autism spectrum disorders (ASD) is atypical and may vary with age. However, to date, no measures of functional connectivity measured within the first 2 years have specifically associated with a later ASD diagnosis. METHODS: In the present study, we analyzed functional brain connectivity in 14-month-old infants at high and low familial risk for ASD using electroencephalography (EEG). EEG was recorded while infants attended to videos. Connectivity was assessed using debiased weighted phase lag index (dbWPLI). At 36 months, the high-risk infants were assessed for symptoms of ASD. RESULTS: As a group, high-risk infants who were later diagnosed with ASD demonstrated elevated phase-lagged alpha-range connectivity as compared to both low-risk infants and high-risk infants who did not go on to ASD. Hyper-connectivity was most prominent over frontal and central areas. The degree of hyper-connectivity at 14 months strongly correlated with the severity of restricted and repetitive behaviors in participants with ASD at 3 years. These effects were not attributable to differences in behavior during the EEG session or to differences in spectral power. CONCLUSIONS: The results suggest that early hyper-connectivity in the alpha frequency range is an important feature of the ASD neurophysiological phenotype.
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8. Rose D, Ashwood P. {{Potential cytokine biomarkers in autism spectrum disorders}}. {Biomark Med};2014 (Oct);8(9):1171-1181.
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impairments in three core behavioral areas. As prevalence rates for ASD continue to rise there is also increasing interest in finding biomarkers associated with ASD. The use of biomarkers could help identify those at risk for ASD or ASD-associated comorbid conditions and help to predict the developmental course of these children. Due to the heterogeneity of ASD, biomarkers may help to identify subpopulations within ASD that share similar traits or profiles. Such work could lead to specialized therapy and help to develop biomarkers whereby the benefits of treatments/therapies for individuals could be monitored over time and through clinical trials. Over the last 10 years, the evidence of immune involvement in ASD has been steadily growing and many investigators have begun to look at possible immune biomarkers, such as immune cytokine profiles, in children with ASD.
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9. Schmitt LM, Cook EH, Sweeney JA, Mosconi MW. {{Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem}}. {Mol Autism};2014;5(1):47.
BACKGROUND: Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem – two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades. METHODS: A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance. RESULTS: Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups. CONCLUSIONS: Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.
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10. Westmark CJ. {{Soy Infant Formula may be Associated with Autistic Behaviors}}. {Autism Open Access};2013 (Nov 18);3
The effects of soy-based infant formulas on childhood development are not well understood. This exploratory study evaluates the severity of autistic behaviors in association with the use of soy-based infant formula in a population of high-functioning autistic children. Medical record data were analyzed from the Simons Foundation Autism Research Initiative Simplex Collection, which included data on infant formula use and autism diagnostic scores for 1,949 autistic children. We found exploratory associations between the use of soy-based infant formula and several autistic behaviors as assessed by line-item analysis of the Aberrant Behavior Checklist, Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. This study provides preliminary data that the use of soy-based infant formula may be associated with specific autistic behaviors.
