Iodine in autism spectrum disorders

ObjectiveThe aim of our study was to assess the iodine status of Polish boys with severe autism compared to their healthy peers and evaluate the relationship between urinary iodine, thyroid hormones, body mass index and Autism Spectrum Disorder (ASD) symptomatology.Subjects and methodsTests were performed in 40 boys with ASD and 40 healthy boys, aged 2–17 from the same geographic region in Poland. Urinary iodine (UI), free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), BMI, and individual symptoms measured by the Childhood Autism Rating Scale (CARS) were correlated.Validated ion chromatography method with pulsed amperometric detection was applied for the determination of urinary iodine after optimized alkaline digestion in a closed system assisted with microwaves.Results19 out of 40 children with ASD had mild to moderate iodine deficiency. Statistically significant lower levels of UI, fT3 and fT4 and higher levels of TSH were found in the autistic group when compared with the control group. Concentration of iodine in urine was negatively associated with clinician’s general impression for children between 11 and 17 years. Emotional response, adaptation to environmental change, near receptor responsiveness, verbal communication, activity level, and intellectual functioning are more associated with UI than other symptoms listed in CARS.ConclusionThe severity of certain symptoms in autism is associated with iodine status in maturing boys. Thyroid hormones were within normal reference ranges in both groups while urinary iodine was significantly lower in autistic boys suggesting that further studies into the nonhormonal role of iodine in autism are required.     

Selective attention to visual compound stimuli in squirrel monkeys (Saimiri sciureus)

Five squirrel monkeys served under a simultaneous discrimination paradigm with visual compound stimuli that allowed measurement of excitatory and inhibitory control exerted by individual stimulus components (form and luminance/“color”), which could not be presented in isolation (i.e., form could not be presented without color). After performance exceeded a criterion of 75% correct during training, unreinforced test trials with stimuli comprising recombined training stimulus components were interspersed while the overall reinforcement rate remained constant for training and testing. The training-testing series was then repeated with reversed reinforcement contingencies. The findings were that color acquired greater excitatory control than form under the original condition, that no such difference was found for the reversal condition or for inhibitory control under either condition, and that overall inhibitory control was less pronounced than excitatory control. The remarkably accurate performance throughout suggested that a forced 4-s delay between the stimulus presentation and the opportunity to respond was effective in reducing “impulsive” responding, which has implications for suppressing impulsive responding in children with autism and with attention deficit disorder.     

Biological implications of genetic variations in autism spectrum disorders from genomics studies

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition characterized by atypical social interaction and communication together with repetitive behaviors and restricted interests. The prevalence of ASD has been increased these years. Compelling evidence has shown that genetic factors contribute largely to the development of ASD. However, knowledge about its genetic etiology and pathogenesis is limited. Broad applications of genomics studies have revealed the importance of gene mutations at protein-coding regions as well as the interrupted non-coding regions in the development of ASD. In this review, we summarize the current evidence for the known molecular genetic basis and possible pathological mechanisms as well as the risk genes and loci of ASD. Functional studies for the underlying mechanisms are also implicated. The understanding of the genetics and genomics of ASD is important for the genetic diagnosis and intervention for this condition.     

Mining the 30UTR of Autism-implicated Genes for SNPs Perturbing MicroRNA Regulation

Autism spectrum disorder（ASD） refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including microRNAs（miRNAs）, a class of noncoding RNAs 22 nucleotides in length that function to suppress translation by pairing with ‘miRNA recognition elements’（MREs） present in the 30untranslated region（30UTR） of target mRNAs. This emphasizes the role played by miRNAs in regulating neurogenesis, brain development and differentiation and hence any perturbations in this regulatory mechanism might affect these processes as well. Recently, single nucleotide polymorphisms（SNPs） present within 30UTRs of mRNAs have been shown to modulate existing MREs or even create new MREs. Therefore, we hypothesized that SNPs perturbing miRNA-mediated gene regulation might lead to aberrant expression of autism-implicated genes, thus resulting in disease predisposition or pathogenesis in at least a subpopulation of ASD individuals. We developed a systematic computational pipeline that integrates data from well-established databases. By following a stringent selection criterion, we identified 9 MRE-modulating SNPs and another 12 MRE-creating SNPs in the 30UTR of autism-implicated genes. These high-confidence candidate SNPs may play roles in ASD and hence would be valuable for further functional validation.     

高功能自闭症儿童面孔加工的ERP研究

目的:探讨7-9岁高功能自闭症儿童面孔加工时事件相关电位(Electrical event-relateds,ERP)的变化及其意义。方法:选择7-9岁自闭症儿童(实验组)与普通儿童(对照组)各15名,以中国人中性面孔及常见物件为刺激材料,记录和比较两类儿童在面孔刺激下的脑电成分。结果:剔除无效数据后,有效被试:实验组12人、对照组14人,两组年龄和性别组成无显著性差异(P0.05)。而,自闭症组按键反应时间、面孔反应时间显著长于对照组(按键反应F=9.26,P0.05;面孔反应t=5.32,P0.05)。在面孔刺激因素下,自闭症组平均波峰明显小于对照组(t=4.62,P0.05)。在物件刺激因素下,两组平均波峰无显著差异(t=0.21,P0.05)。而两组的潜伏期组别主效应不显著(F=1.63,P0.05)。结论:自闭症儿童面孔结构编码过程异常,对面孔的关注度比普通儿童低。本文证实了自闭症儿童知觉/认知缺陷的存在,为更进一步研究提供了理论依据。     

Urinary Methylxanthine and Autistic Disorder: Absence of Previously Reported Correlation

We were unable to reveal significant difference in the levels of xanthine and methylxanthines in the urine samples from 59 patients diagnosed with autistic symptoms and 64 age‐ and sex‐matched normal volunteers. Our data suggest that abnormalities in xanthine and methylxanthine excretion (US Patent 20020019406 A1, Feb. 12, 2002) represent distincly uncommon symptoms in autism.     

Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P2.2×10~(-16)) in exonic (1.37×10~(-8)) and 3'-UTR regions (1.42×10~(-8)) was revealed in comparison with that of whole genome (1.05×10~(-8)).Using an integrated model,we identified 87 potentially risk genes (P0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.     

Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways

Autism spectrum disorder (ASD) is a group of complex, neurological disorders that affect early cognitive, social, and verbal development. Our understanding of ASD has vastly improved with advances in genomic sequencing technology and genetic models that have identified >800 loci with variants that increase susceptibility to ASD. Although these findings have confirmed its high heritability, the underlying mechanisms by which these genes produce the ASD phenotypes have not been defined. Current efforts have begun to “functionalize” many of these variants and envisage how these susceptibility factors converge at key biochemical and biophysical pathways. In this review, we discuss recent work on intracellular calcium signaling in ASD, including our own work, which begins to suggest it as a compelling candidate mechanism in the pathophysiology of autism and a potential therapeutic target. We consider how known variants in the calcium signaling genomic architecture of ASD may exert their deleterious effects along pathways particularly involving organelle dysfunction including the endoplasmic reticulum (ER), a major calcium store, and the mitochondria, a major calcium ion buffer, and theorize how many of these pathways intersect.