Superior discrimination of speech pitch and its relationship to verbal ability in autism spectrum disorders

Whilst hypersensitivity to pitch information appears to be characteristic of many individuals with autism spectrum disorders little is known about the implications of such a tendency for language acquisition and development. Discrimination of systematically varied pitch differences between pairs of words, nonwords, and nonspeech pitch contour analogues was assessed in children with autism spectrum disorders (ASD) and matched controls. The findings revealed superior performance in ASD, although, like controls, discrimination of pitch in speech stimuli was poorer in this group than for nonspeech stimuli. Whilst it was hypothesized that enhanced processing of speech pitch would correlate negatively with receptive language skills in ASD, the findings did not fully support this, and enhanced discrimination skills were observed in individuals without significant language impairment. The implications of these findings for understanding heterogeneity of language ability in ASD are discussed.     

Executive dysfunction and its relation to language ability in verbal school-age children with autism

This study examined executive dysfunction and its relation to language ability in verbal school-age children with autism. Participants were 37 children with autism and 31 nonautistic comparison participants who were matched on age and on verbal and nonverbal IQ but not on language ability, which was lower in the autism group. Children with autism exhibited deficits compared to the comparison group across all 3 domains of executive function that were assessed including working memory (Block Span Backward; Isaacs & Vargha-Khadem, 1989), working memory and inhibitory control (NEPSY Knock-Tap; Korkman, Kirk, & Kemp, 1998), and planning (NEPSY Tower; Korkman et al., 1998). Children with autism were less developed than the comparison group in their language skills, but correlational analyses revealed no specific association between language ability and executive performance in the autism group. In contrast, executive performance was positively correlated with language ability in the comparison group. This pattern of findings suggest that executive dysfunction in autism is not directly related to language impairment per se but rather involves an executive failure to use of language for self-regulation.     

Impaired ability to organize information in individuals with autism spectrum disorders and their siblings

Despite rigorous research on disturbances of executive function and social cognition in autism spectrum disorders (ASD), little information has been available concerning higher cognitive functions, such as the ability to focus and associate relevant features to form categories, or 'organizing of information'. The purpose of this study was to investigate this issue by using the Wisconsin Card Sorting Test (WCST) and the Verbal Learning Task (VLT). Cognitive assessments were conducted in 22 individuals with ASD, 14 non-affected siblings, and 15 age-matched control subjects. Overall, individuals with ASD performed significantly worse on the WCST and VLT compared to their siblings and normal control subjects. Although siblings performed generally well on both tasks, they exhibited similar degree of perseverative responses in the WCST compared to the probands. A linear increase of the memory organization score in the VLT was also absent in siblings as well as the ASD group. These results suggest an impaired ability to organize information is one of the cognitive endophenotypes for ASD.     

Neuroinflammation in autism spectrum disorders

Objectives

The neurobiological basis for autism remains poorly understood. However, research suggests that environmentalfactors and neuroinflammation, as well as genetic factors, are contributors. This study aims to test the role that might be played by heat shock protein (HSP)70, transforming growth factor (TGF)-β₂, Caspase 7 and interferon-γ (IFN-γ)in the pathophysiology of autism.

Materials and methods

HSP70, TGF-β_2, Caspase 7 and INF-γ as biochemical parameters related to inflammation were determined in plasma of 20 Saudi autistic male patients and compared to 19 age- and gender-matched control samples.

Results

The obtained data recorded that Saudi autistic patients have remarkably higher plasma HSP70, TGF-β_2, Caspase 7 and INF-γ compared to age and gender-matched controls. INF-γ recorded the highest (67.8%) while TGF-β recorded the lowest increase (49.04%). Receiver Operating Characteristics (ROC) analysis together with predictiveness diagrams proved that the measured parameters recorded satisfactory levels of specificity and sensitivity and all could be used as predictive biomarkers.

Conclusion

Alteration of the selected parameters confirm the role of neuroinflammation and apoptosis mechanisms in the etiology of autism together with the possibility of the use of HSP70, TGF-β_2, Caspase 7 and INF-γ as predictive biomarkers that could be used to predict safety, efficacy of a specific suggested therapy or natural supplements, thereby providing guidance in selecting it for patients or tailoring its dose.

     

Molecular genetics of autism spectrum disorders

Autistic disorder belongs to a broad spectrum of pervasive developmental disorders. Autism is a clinically and genetically heterogeneous condition. It is characterized by impairment in a broad range of social interactions, communication, and repetitive patterns of behavior and interest. Although the exact etiology of the condition is not known, family and twin studies strongly support genetic factors in autism. Genome-wide scans suggest several susceptibility loci that may contain one or more predisposing genes. However, no such genes have been identified so far that predispose patients to autism. The condition is over 90% heritable, but the mode of inheritance is not clear. Moreover, it does not seem to be a single gene disorder. There is no cure for autism. Individualized structured education, family support services, and antipsychotic drugs are recommended. These may alleviate some behavioral problems. The identification of autism genes, an understanding of the neurobiology of the condition, and additional clinical studies may help to develop pharmacological interventions in the future.     

Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders

PurposeAutism spectrum disorders represent a range of neurodevelopmental disorders that have been shown to have a strong genetic etiological component. Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques are discovering an increasing number of copy number variations in individuals with autism spectrum disorder.MethodsWe examined the yield of abnormal microarray-based comparative genomic hybridization findings in our laboratory for individuals referred for testing for autism spectrum disorder. We also examined the presence of autistic features among 151 additional individuals who were referred for microarray-based comparative genomic hybridization testing for indications other than autism spectrum disorder but had genomic alterations overlapping those found in cases referred for autism spectrum disorder.ResultsWe identified 1461 individuals referred for testing for autism spectrum disorder, with likely significant abnormalities reported in approximately 11.6% of individuals analyzed with whole-genome arrays. These abnormalities include alterations that encompass novel candidate genes such as SNTG2, SOX5, HFE, and TRIP38. A minority of individuals with overlapping abnormalities (19%) had autistic features, and many of the copy number variations identified in our study are inherited (69% among those found in individuals with autism spectrum disorder).ConclusionsOur results suggest these copy number variations are one of multiple factors contributing to the development of an autism spectrum disorder phenotype. Additionally, the broad phenotypic spectrum of the patients with these copy number variations suggests that these copy number variations are not autism spectrum disorder-specific but likely more generally impair neurodevelopment.     

Neural systems approaches to the neurogenetics of autism spectrum disorders

Autism is generally accepted as the most genetic of all the developmental neuropsychiatric syndromes. However, despite more than several decades of genetic study, the etiology of autism remains unknown, largely due to the genetic and phenotypic diversity, or heterogeneity, of this disorder, and the lack of biologically based classification systems. At the same time, in the neuroimaging literature, the body of research identifying candidate neural systems underlying aspects of autistic impairment has grown considerably, fueled by the advent of technologies such as functional magnetic resonance imaging (fMRI). Yet the findings from these neuroimaging studies have not been incorporated to inform the collection of samples for genetic studies of autism, which are predominantly based on a diagnosis of the disorder. This article presents a review of the genetics of autism and describes the genetic approaches that have been applied, including the phenotypic strategies that have been used to address heterogeneity and optimize the power of these genetic studies. With the increasing recognition that there may be different “autisms” (Geschwind and Levitt, 2007) with unique neural mechanisms, it is argued that neural systems research, using technologies such as fMRI, currently allows for the identification of more biologically informative phenotypes for genetic studies of autism and is positioned to identify informative neuroimaging markers for “neurogenetic” studies of the disorder. To illustrate this, we describe several candidate neural systems for the social communication impairment seen in autism, and the characteristic behavioral and physiological manifestations associated with these that could be incorporated into phenotypic assessments.     

Anxiety in children and adolescents with autism spectrum disorders

Anxiety and poor stress management are common concerns in clinical samples of children with autism spectrum disorders (ASD). Anxiety may worsen during adolescence, as young people face an increasingly complex social milieu and often become more aware of their differences and interpersonal difficulties. This review summarizes the state of research on the prevalence, phenomenology, and treatment of anxiety in youth with autism and related conditions such as Asperger's Disorder. Using search words autism, asperger(s), or pervasive developmental disorder and anxiety or anxious to find reports published between 1990 and 2008, this review identified 40 papers. The results of the review suggest that anxiety, whether measured categorically or dimensionally, is indeed common in children and adolescents with autism spectrum disorders and may be a source of additional morbidity. The assessment of anxiety disorders in ASD should be conducted using multiple informants and modalities, as children with ASD often do not display age-typical symptoms of anxiety. To date, relatively few controlled intervention studies using well-characterized samples have been conducted despite preliminary evidence for efficacy of select pharmacological and psychosocial approaches. Recommendations for future applied research are presented and clinical implications are explored.     

Quantifying the phenotype in autism spectrum disorders.

Twin and family studies suggest that familial transmission in autism extends to a spectrum of social and behavioral deficits that characterize individuals who have significant impairments within the autism spectrum, but do not meet formal criteria for autistic disorder. Standardized diagnostic instruments, including the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS-WPS Edition), offer the opportunity to quantify deficits across the autism spectrum, controlling effects of language and cognitive delay, in individuals with significant impairments. It is suggested that quantitative measures of social reciprocity and repetitive behaviors and interests, with separate quantification of expressive language level and nonverbal intelligence, most accurately reflect the range of behavioral phenotypes in autism spectrum disorders.     

孤独症谱系障碍的遗传学研究进展

孤独症谱系障碍(autism spectrum disorder,ASD)是一组复杂的神经系统发育障碍性疾病的统称,患者通常表现出不同程度的社会沟通交往障碍,并伴有语言发育异常和重复刻板的行为或兴趣。随着测序技术的不断发展,ASD相关的变异、基因、功能通路,以及脑区基因表达模式在不断被发现。本文就ASD相关的各个层面的...     

孤独症谱系障碍儿童的睡眠行为

目的:探讨学前期和学龄期孤独症谱系障碍(autism spectrum disorders,ASD)儿童的睡眠行为的特点和差异。方法:选取符合美国精神障碍诊断与统计手册第4版(DSM-IV)诊断标准的ASD儿童84名和年龄性别匹配的正常儿童91名,使用儿童睡眠习惯问卷(CSHQ)和一周睡眠日记,由儿童主要照顾者记录儿童的睡眠情况。依据CSHQ总分大于41分为睡眠不良,以具体条目中睡眠行为发生频率超过2晚/周的标准界定睡眠行为问题,分3～5岁和6～12岁两个年龄段比较ASD与对照组儿童在睡眠行为和习惯上的差异。结果:3～5岁ASD组儿童CSHQ的睡眠潜伏期[(2.1±0.8)vs.(1.6±0.7)]、睡眠持续情况[(5.4±1.7)vs.(4.8±1.3)]得分高于对照组,入睡困难(77.6%vs.49.0%)、睡眠量不足(63.3%vs.42.9%)、夜醒哭闹(34.7%vs.12.2%)及日间疲乏(36.7%vs.10.2%)的比例较对照组高(均P0.05)。6～12岁ASD儿童平时睡眠总时长短于对照组[(8.68±0.76)h vs.(9.33±1.00)h],CSHQ的入睡抵触[(10.1±2.8)vs.(8.6±2.5)]、睡眠潜伏期[(1.7±0.7)vs.(1.4±0.6)]与睡眠焦虑[(5.4±2.0)vs.(4.5±1.9)]得分高于对照组,入睡困难(54.3%vs.31.0%)、睡眠量不足(60.0%vs.35.7%)、与父母同睡(65.7%vs.38.1%)、入睡需陪伴(68.6%vs.35.7%)的比例较对照组高(均P0.05)。结论:ASD儿童普遍存在睡眠总量少、入睡困难等问题,学龄前期以夜醒后哭闹和白天疲倦较为突出,而学龄期则以睡眠焦虑较为明显。     

Source memory in children with autism spectrum disorders

The evidence to date regarding memory processes in children with autism spectrum disorders (ASD) remains equivocal. Although children with these neurodevelopmental disorders have been shown to display exceptional memories for fact-based information, they seem to be less able to attach meaning or context to their memories. Thus, this study investigated the specific role of source memory in autism. Children with ASD were compared to a chronological and mental age-matched comparison group of typically developing children. Although children with autism performed similarly to controls on a fact recognition measure, their performance on a source memory task was significantly lower. The findings indicated, however, that the nature of source memory confusion in children with autism does not appear to reflect a generalized deficit in attaching context to memories but rather is dependent on the specific to-be-remembered information that, in this study, involves social aspects of context.     

Attention-deficit / hyperactivity disorder in autism spectrum disorders

According to the DSM-IV-TR, symptoms of inattention and hyperactivity are frequent in children with Autism Spectrum Disorders (ASD). This statement is supported by clinical observation and formal assessment. However, ASD diagnosis is still among the exclusion criteria for the Attention-Deficit/Hyperactivity Disorder (ADHD). Such exclusion generates controversy and questions regarding the need and benefits of maintaining or not these separations; so much so, that the proposed criteria for the DSM-V eliminate that exclusion condition. It is necessary a better understanding of the comorbidity between both entities in order to be able to have an appropriate sequence of the intervention goals. For that reason, if inattention and hyperactivity in individuals with ASD are considered as a representation of a comorbid diagnosis of ADHD, treatment plans for this group would be better adjusted and more likely to offer a real benefit in the outcome of their adaptive functioning.     

Patterns of growth in verbal abilities among children with autism spectrum disorder

Verbal skills were assessed at approximately ages 2, 3, 5, and 9 years for 206 children with a clinical diagnosis of autism (n = 98), pervasive developmental disorders-not otherwise specified (PDD-NOS; n = 58), or nonspectrum developmental disabilities (n = 50). Growth curve analyses were used to analyze verbal skills trajectories over time. Nonverbal IQ and joint attention emerged as strong positive predictors of verbal outcome. The gap between the autism and other 2 groups widened with time as the latter improved at a higher rate. However, there was considerable variability within diagnostic groups. Children with autism most at risk for more serious language impairments later in life can be identified with considerable accuracy at a very young age, while improvement can range from minimal to dramatic.     

Abnormalities of cholesterol metabolism in autism spectrum disorders.

Although Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism [Tierney et al., 2001; Am J Med Genet 98:191-200.], the incidence of SLOS and other sterol disorders among individuals with autism spectrum disorders (ASD) is unknown. This study investigated (1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and (2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol, and its precursor sterols were quantified in 100 samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dl, which is below the 5th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD.     

Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders

Autism spectrum disorders (ASDs) are a heterogeneous group of neuro-developmental disorders. While significant progress has been made in the identification of genes and copy number variants associated with syndromic autism, little is known to date about the etiology of idiopathic non-syndromic autism. Sanger sequencing of 21 known autism susceptibility genes in 339 individuals with high-functioning, idiopathic ASD revealed de novo mutations in at least one of these genes in 6 of 339 probands (1.8%). Additionally, multiple events of oligogenic heterozygosity were seen, affecting 23 of 339 probands (6.8%). Screening of a control population for novel coding variants in CACNA1C, CDKL5, HOXA1, SHANK3, TSC1, TSC2 and UBE3A by the same sequencing technology revealed that controls were carriers of oligogenic heterozygous events at significantly (P < 0.01) lower rate, suggesting oligogenic heterozygosity as a new potential mechanism in the pathogenesis of ASDs.     

Hypothesis: conjugate vaccines may predispose children to autism spectrum disorders

The first conjugate vaccine was approved for use in the US in 1988 to protect infants and young children against the capsular bacteria Haemophilus influenzae type b (Hib). Since its introduction in the US, this vaccine has been approved in most developed countries, including Denmark and Israel where the vaccine was added to their national vaccine programs in 1993 and 1994, respectively.There have been marked increases in the reported prevalence of autism spectrum disorders (ASDs) among children in the US beginning with birth cohorts in the late 1980s and in Denmark and Israel starting approximately 4-5 years later. Although these increases may partly reflect ascertainment biases, an exogenous trigger could explain a significant portion of the reported increases in ASDs. It is hypothesized here that the introduction of the Hib conjugate vaccine in the US in 1988 and its subsequent introduction in Denmark and Israel could explain a substantial portion of the initial increases in ASDs in those countries. The continuation of the trend toward increased rates of ASDs could be further explained by increased usage of the vaccine, a change in 1990 in the recommended age of vaccination in the US from 15 to 2 months, increased immunogenicity of the vaccine through changes in its carrier protein, and the subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae.Although conjugate vaccines have been highly effective in protecting infants and young children from the significant morbidity and mortality caused by Hib and S. pneumoniae, the potential effects of conjugate vaccines on neural development merit close examination. Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response. This period of hypo-responsiveness to carbohydrate antigens coincides with the intense myelination process in infants and young children, and conjugate vaccines may have disrupted evolutionary forces that favored early brain development over the need to protect infants and young children from capsular bacteria.     

Evidence-based assessment of autism spectrum disorders in children and adolescents.

This article reviews evidence-based criteria that can guide practitioners in the selection, use, and interpretation of assessment tools for autism spectrum disorders (ASD). As Mash and Hunsley (2005) discuss in this special section, evidence-based assessment tools not only demonstrate adequate psychometric qualities, but also have relevance to the delivery of services to individuals with the disorder (see also Hayes, Nelson, & Jarrett, 1987). Thus, we use what is known about the symptoms, etiologies, developmental course, and outcome of ASD to evaluate the utility of particular assessment strategies and instruments for diagnosis, treatment planning and monitoring, and evaluation of outcome. The article begins with a review of relevant research on ASD. Next we provide an overview of the assessment process and some important issues that must be considered. We then describe the components of a core (minimum) assessment battery, followed by additional domains that might be considered in a more comprehensive assessment. Domains covered include core autism symptomatology, intelligence, language, adaptive behavior, neuropsychological functions, comorbid psychiatric illnesses, and contextual factors (e.g., parent well-being, family functioning, quality of life). We end with a discussion of how well the extant literature meets criteria for evidence-based assessments.     

Regional homogeneity of fMRI time series in autism spectrum disorders

Functional magnetic resonance imaging (fMRI) and functional connectivity MRI (fcMRI) studies of autism spectrum disorders (ASD) have suggested atypical patterns of activation and long-distance connectivity for diverse tasks and networks in ASD. We explored the regional homogeneity (ReHo) approach in ASD, which is analogous to conventional fcMRI, but focuses on local connectivity. FMRI data of 26 children with ASD and 29 typically developing (TD) children were acquired during continuous task performance (visual search). Effects of motion and task were removed and Kendall's coefficient of concordance (KCC) was computed, based on the correlation of the blood oxygen level dependent (BOLD) time series for each voxel and its six nearest neighbors. ReHo was lower in the ASD than the TD group in superior parietal and anterior prefrontal regions. Inverse effects of greater ReHo in the ASD group were detected in lateral and medial temporal regions, predominantly in the right hemisphere. Our findings suggest that ReHo is a sensitive measure for detecting cortical abnormalities in autism. However, impact of methodological factors (such as spatial resolution) on ReHo require further investigation.