Autism Spectrum Disorder Subtype Research Articles

Amino Acid Dysregulation Metabotypes: Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder

BackgroundAutism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children’s Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. MethodsDysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. ResultsWe identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. ConclusionsIdentification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.

Role of the Immune System in Autism Spectrum Disorders (ASD)

The evidence based supports that multifactorial and complex immune interactions play a role in autism spectrum disorders (ASD), but contradictory findings are also reported. The aim of this selective review was to identify trends in the research literature on this topic, focusing on immunology and other aberrations with respect to the different ASD subtypes. This selective review is based on original and review articles written in English and identified in literature searches of PubMed. Several studies have found that the risk of ASD is greater among children whose mothers suffered from autoimmune diseases while pregnant. Moreover, individuals with ASD show increased levels of antibodies that are specific for several specific proteins. Studies also show that mothers of children with ASD have antibodies against fetal brain proteins. There are also reports on the associations between increased levels of proinflammatory cytokines and ASD. Finally, infections in mothers during pregnancy are linked to an increased risk of ASD. We propose that the large inconsistencies in findings among studies in the field are due to differences in subdiagnoses among the included children with ASD. Well-phenotyped ASD samples are needed to understand the biological and immunological mechanisms underpinning ASD and its subdiagnoses. Future research should apply new strategies to scrutinize the link between ASD and changes in immune responsivity. Important new research avenues are to investigate the associations (a) between different ASD phenotypes and aberrations in (auto)immune pathways and (b) between reduced natural regulatory autoimmune responses during pregnancy, which are in turn associated with increased oxidative and nitrosative stress in maternal blood and putative detrimental effects in the offspring.

Another Step Toward Defining an Immune-Mediated Subtype of Autism Spectrum Disorder

Another Step Toward Defining an Immune-Mediated Subtype of Autism Spectrum Disorder

Determinants of Parent Satisfaction with Emergency or Urgent Care When the Patient Has Autism.

The purpose of this study was to identify factors that predict parent satisfaction (PS) with their child with autism spectrum disorder (ASD)'s visit to a hospital emergency department (ED) or urgent care (UC) center. Parents recruited through a national database whose child (3-21 years; N = 378) with ASD had been treated in an ED/UC center within the previous 3 years completed an anonymous on-line questionnaire. They answered questions about whether they were satisfied overall with the visit and the care provided, their demographics, patient characteristics, their expectations and preparation for the visit, and the ED/UC center experience itself, including their observations of staff interpersonal and communication skills (ICSs) and behaviors, and whether the patient was disruptive (D). Multiple correspondence analysis (MCA) was used to demonstrate the relative effects of individual variables on PS. Among the 10 most important determinants of PS with the visit were the 9 assessed staff ICS behaviors. These were followed by shorter than expected waiting time and the patient not being disruptive (ND) during the visit. PS was not associated with any of the 3 measures of patient disability severity (ASD subtype, communicative competence, or restrictiveness of educational placement), whether the patient is hyperreactive to sensory stimuli, reason for the visit, or parent's education. PS with an ED/UC center visit when the patient has autism depends mostly on the quality of staff interactions with the patient and family. It is important for ED/UC center administrators to ensure that staff understand how to interact and communicate effectively with patients with ASD and their families.

Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorder (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at midgestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/− mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.

F69. Salience Network Connectivity in Children With Nonverbal Learning Disability or Autism Spectrum Disorder

NonVerbal Learning Disability (NVLD) is characterized by deficits in spatial reasoning, executive functioning, fine-motor skills, math, and social functioning. Due to a number of clinical similarities, there is debate as to whether NVLD should be classified as a sub-type of Autism Spectrum Disorder (ASD) or as a discrete diagnosis. Herein, we use resting state fMRI (rsfMRI) to assess whether the social deficits seen in NVLD and ASD arise from different patterns of brain connectivity.

Cluster analysis of autism spectrum disorder symptomatology: Qualitatively distinct subtypes or quantitative degrees of severity of a single disorder?

The decision to collapse several related disorders into a single diagnosis of Autism Spectrum Disorder (ASD) generated significant controversy and debate. There has been mixed evidence as to whether various ASD subtypes are qualitatively distinct or if they exist on a spectrum of symptom severity. The present study conducted a two-step cluster analysis of major ASD symptoms in a sample of 147 young males with ASD aged between 6yr and 18yr with IQ > 70. Results indicated that a two-cluster solution (high and low severity of ASD symptomatology) was reliable and valid. Further, the construct of challenging behaviour was not a necessary component of the two-cluster solution, verifying the new conceptualisation of ASD. Further replication of these findings with other subsets of individuals with ASD is needed.

Prevalence and Risk Factors of Anxiety in a Clinical Dutch Sample of Children with an Autism Spectrum Disorder.

Anxiety is highly prevalent in children with an autism spectrum disorder (ASD). However, there is inconsistency in studies investigating the prevalence and risk factors of anxiety in children with ASD. Therefore, the first aim of this study was to give an overview of the prevalence of anxiety symptoms in a clinical Dutch sample of children with ASD. The second aim was to investigate age, gender, ASD subtype, and IQ as potential risk factors for anxiety in this sample. In total, 172 children with ASD (age, 8–15 years) and their parents participated in this study. Specialized services in which children with ASD were recruited were two mental health institutes and one secondary special education school. The findings showed that more than 60% of the participating children with ASD had at least subclinical anxiety symptoms according to children. More than 80% of the children with ASD had at least subclinical anxiety symptoms according to parents. It was found that younger children and girls with ASD had more anxiety symptoms than older children and boys with ASD. Moreover, it was found that children with a higher performance (non-verbal) IQ and lower verbal IQ had more specific phobia symptoms. The findings suggest that in a clinical context, children with ASD have a high risk to have co-occurring anxiety symptoms, especially girls and younger children with ASD. Therefore, early prevention and treatment of anxiety in children with ASD who are most at risk is important.

Molecular hypotheses to explain the shared pathways and underlying pathobiological causes in catatonia and in catatonic presentations in neuropsychiatric disorders

The pathobiological causes, the shared cellular and molecular pathways in catatonia and in catatonic presentation in neuropsychiatric disorders are yet to be determined. The hypotheses in this paper have been deduced from the latest scientific research findings and clinical observations of patients with genetic disorders, behavioral phenotypes and other family members suffering mental disorders. The first hypothesis postulates that catatonia and the heterogeneity of catatonic signs and symptoms involve nucleolar dysfunction arising from abnormalities of the brain-specific, non-coding micro-RNA, SNORD115 genes (either duplications or deletions) which result in pathobiological dysfunction of various combinations in the downstream pathways (possibly along with other genes in these shared pathways). SNORD115 controls five genes CRHR1, PBRM1, TAF1, DPM2, and RALGPS1 as well as the alternative splicing of serotonin 2C receptor. SNORD115 abnormalities with varying downstream multigene involvement would account for catatonia across the life span within some subtypes of autism spectrum disorders, schizophrenia, bipolar and major depressive disorder, psychosis, genetic disorders, and in immune disorders such as anti-N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis as well as the susceptibility to the neuroleptic malignant syndrome (NMS) if environmentally triggered. Furthermore, SNORD115 genes may underlie a genetic vulnerability when environmental triggers result in excess serotonin producing the serotonin syndrome, a condition similar to NMS in which catatonia may occur. Dysfunction of SNORD115-PBRM1 connecting with SMARCA2 as well as other proven schizophrenia-associated genes might explain why traditionally catatonia has been classified with schizophrenia. SNORD115-TAF1 and SNORD-DPM2 dysfunction introduce possible clues to the parkinsonism and increased creatinine phosphokinase in NMS, while abnormalities of SNORD115-RALGPS1 suggest links to both anti-NMDAR encephalitis and the proven predisposing catatonic SHANK3 gene. The second hypothesis postulates that periodic catatonia (PC) on 15q15 involves abnormalities of vacuolar protein sorting 39 (VPS39), a proven de novo schizophrenic gene in this chromosomal locus and part of the HOPS complex. These will impact the autophagic and endocytic pathways, thereby lowering lysosomal degradation. VPS39 mutations may be considered also to disrupt lysosome-mitochondria tethering and transport of lipids and calcium through membrane contact sites (MCSs). To account for the periodicity in PC it is speculated that the mammalian equivalent of the vacuole and mitochondria patch (vCLAMP) would be altered by VPS39 mutations and subsequently followed by the mammalian equivalent of endoplasmic reticulum mitochondria encounter structure (ERMES) restoring mitochondrial homeostasis. Future precision psychiatry will require accurate pathophysiologically-defined psychiatric diagnoses to accelerate the discovery of specific molecular-targeted medications to improve therapeutic outcomes.

School dysfunction in youth with autistic spectrum disorder in Taiwan: The effect of subtype and ADHD.

Impaired school functions varied in ASD youths with different characteristics. Youths with autism spectrum disorder (ASD) encounter varying levels and domains of impaired performance at schools, such as lower academic performance, negative attitude toward school work, fewer reciprocal friendships, and more behavioral problems. Our results indicate that ASD youths without intellectual disability had better academic performance, but worse attitude toward school than those with intellectual disability. Co-occurrence with ADHD is associated with school dysfunction. In summary, intelligence and comorbid ADHD influences several domains of school functions.

Pupillary Response and Phenotype in ASD: Latency to Constriction Discriminates ASD from Typically Developing Adolescents

Milder forms of autism spectrum disorder (ASD) can be difficult to diagnose based on behavioral testing alone. This study used eye-tracking equipment and a hand-held penlight to measure the pupil reflex in adolescents with "high functioning" ASD and in adolescents without ASD. The ASD group showed a delay in pupil response. This is the first eye-tracking study to conduct this test as typically performed by a clinical provider, demonstrating differences in older individuals with a subtype of ASD.

Are gastrointestinal and sleep problems associated with behavioral symptoms of autism spectrum disorder?

Many children with autism spectrum disorder (ASD) suffer from concurrent medical symptoms, including gastrointestinal (GI) and sleeping problems. However, there is limited information on the correlation between co-morbidities and autistic behavioral symptoms. In this study, we estimated the prevalence of GI and sleep problems in Chinese ASD children, examined the impacts of GI and sleep problems on autistic behavioral symptoms, and investigated the factors associated with GI and sleep problems. The survey included 169 ASD and 172 healthy children. Data regarding demographic characteristics, GI symptoms, sleep disturbances and behavioral symptoms were collected through questionnaires. GI and sleep problems were prevalent in Chinese ASD children. Moreover, ASD children with GI symptoms reported more severe ASD core symptoms than others. Autistic children's GI symptoms were associated with maternal sleep problems during pregnancy, child's 0–6 month food sources and picky eating. ASD children with sleep disturbances had lower performance in daily living skills, social cognition, social communication and intellectual development than ASD children without sleep disturbances. Sleep disturbances were associated with extra nutrient supply during lactation and feeding, and child's picky eating. Autistic children with GI or/and sleep problems may represent clinically relevant subtypes of ASD, for which targeted treatments may be needed.

Intellectual Functioning and Autism Spectrum Disorder: Can Profiles Inform Identification of Subpopulations?

Profiles of scores on measures of intellectual functioning may aid in understanding etiology and developing targeted intervention in autism spectrum disorder (ASD) by providing details about specific phenotypes or subpopulations of ASD. Research investigating the relationship between ASD symptoms and intellectual functioning suggests that scores on the factors comprising global measures of intellectual functioning may be related to ASD symptoms (e.g., Joseph et al. J Child Psychol Psychiatry 43:807–821, 2002). Research has been limited by methodological problems, such as defining samples using unreliable subtypes of ASD and an overreliance on variable-centered methodological strategies. In the current paper, the authors provide a summary of existing research related to ASD symptoms and measures of intellectual functioning, review recent research identifying subpopulations in ASD, and provide goals for future areas of research in this area.

Level 2 Screening With the PDD Behavior Inventory: Subgroup Profiles and Implications for Differential Diagnosis

The PDD Behavior Inventory (PDDBI) has recently been shown, in a large multisite study, to discriminate well between autism spectrum disorder (ASD) and other groups when its scores were examined using a machine learning tool, Classification and Regression Trees (CART). Discrimination was good for toddlers, preschoolers, and school-age children; generalized across clinical diagnostic sites; and agreed well with Autism Diagnostic Observation Schedule (ADOS) classifications. Results also revealed three subtypes of ASD: minimally verbal, verbal, and atypical that differed in developmental history, behavior profiles, and biomedical findings. Seven subtypes of Not-ASD children were identified, two of which were relatively common. Three of the remaining five relatively rare Not-ASD subgroups had highly atypical profiles marked either by extreme aggressiveness or by extreme ritualistic behaviors. PDDBI profiles of these rare subgroups were not previously characterized. In this study, profiles of all CART subgroups based on parent and teacher PDDBIs are described, along with their implications for diagnosis and assessment.

The Putative Role of Environmental Mercury in the Pathogenesis and Pathophysiology of Autism Spectrum Disorders and Subtypes.

Exposure to organic forms of mercury has the theoretical capacity to generate a range of immune abnormalities coupled with chronic nitro-oxidative stress seen in children with autism spectrum disorder (ASD). The paper discusses possible mechanisms explaining the neurotoxic effects of mercury and possible associations between mercury exposure and ASD subtypes. Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune-inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect. Retrospective studies, on the other hand, reported no relationship between a range of ethylmercury-containing vaccines and chronic neuropathology or ASD. On the basis of these results, we would argue that more clinically relevant research is required to examine whether environmental mercury is associated with ASD or subtypes. Specific recommendations for future research are discussed.

How Useful Is Electroencephalography in the Diagnosis of Autism Spectrum Disorders and the Delineation of Subtypes: A Systematic Review.

Autism spectrum disorders (ASD) are thought to be associated with abnormal neural connectivity. Presently, neural connectivity is a theoretical construct that cannot be easily measured. Research in network science and time series analysis suggests that neural network structure, a marker of neural activity, can be measured with electroencephalography (EEG). EEG can be quantified by different methods of analysis to potentially detect brain abnormalities. The aim of this review is to examine evidence for the utility of three methods of EEG signal analysis in the ASD diagnosis and subtype delineation. We conducted a review of literature in which 40 studies were identified and classified according to the principal method of EEG analysis in three categories: functional connectivity analysis, spectral power analysis, and information dynamics. All studies identified significant differences between ASD patients and non-ASD subjects. However, due to high heterogeneity in the results, generalizations could not be inferred and none of the methods alone are currently useful as a new diagnostic tool. The lack of studies prevented the analysis of these methods as tools for ASD subtypes delineation. These results confirm EEG abnormalities in ASD, but as yet not sufficient to help in the diagnosis. Future research with larger samples and more robust study designs could allow for higher sensitivity and consistency in characterizing ASD, paving the way for developing new means of diagnosis.

Brief Report: Macrocephaly Phenotype and Psychiatric Comorbidity in a Clinical Sample of Mexican Children and Adolescents with Autism Spectrum Disorders.

Autism spectrum disorders (ASD) may present with macrocephaly. Few studies have analyzed the association with psychiatric comorbidity. Participants were 94 children with any ASD with an age range from 2 to 16 years (Mdn 6 years), 82% were boys. It was found that 20% of the sample had macrocephaly and 1% microcephaly. There was no association between the presence of macrocephaly and subtype of ASD. The most associated comorbidity was attention-deficit/hyperactivity disorder (ADHD) 54.2%, followed by specific phobia 34%, dysthimia 29.7%, oppositional defiant disorder 13.83% motor tics 11.7%, separation anxiety 9.5% and Gilles de la Tourette 8.5%. In conclusion, macrocephaly and psychiatric comorbidity in this clinical sample of children with ASD is similar to the international literature results.

What is the Nature of Motor Impairments in Autism, Are They Diagnostically Useful, and What Are the Implications for Intervention?

There is general agreement that alongside the core diagnostic features of autism spectrum disorder (ASD), motor abnormalities and delays in motor development are common features despite the likely presence of multiple etiologies and subtypes of ASD. Whether and to what extent these motor impairments show an ASD-specific profile that can be differentiated from general vulnerability associated with atypical neurodevelopment remains equivocal and a hot topic of debate. This review will critically evaluate the growing body of evidence on motor impairments from prospective studies of infants at high familial risk for ASD, studies of family members with intermediate phenotypes, cross-syndrome and comorbidity studies, and motor-based interventions in ASD. It is argued that a more nuanced view of the pervasiveness of ASD-specific motor abnormalities is needed, and there are a number of significant methodological issues, including comorbidity, small sample sizes, lack of meaningful subtyping, exclusion of cognitively impaired individuals, and lack of longitudinal cross-syndrome designs. To overcome these methodological challenges will require a concerted effort across multiple sites with advances in analytical approaches in neuroimaging and analysis of micro-movements holding a great deal of promise for early diagnosis, development of unified models of pathophysiology, and personalized treatments that are inclusive of the wider spectrum of cognitive abilities in ASD.

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci. Analyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains. Children with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences). Children with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.

In pursuit of neurophenotypes: The consequences of having autism and a big brain.

A consensus has emerged that despite common core features, autism spectrum disorder (ASD) has multiple etiologies and various genetic and biological characteristics. The fact that there are likely to be subtypes of ASD has complicated attempts to develop effective therapies. The UC Davis MIND Institute Autism Phenome Project is a longitudinal, multidisciplinary analysis of children with autism and age-matched typically developing controls; nearly 400 families are participating in this study. The overarching goal is to gather sufficient biological, medical, and behavioral data to allow definition of clinically meaningful subtypes of ASD. One reasonable hypothesis is that different subtypes of autism will demonstrate different patterns of altered brain organization or development i.e., different neurophenotypes. In this Commentary, we discuss one neurophenotype that is defined by megalencephaly, or having brain size that is large and disproportionate to body size. We have found that 15% of the boys with autism demonstrate this neurophenotype, though it is far less common in girls. We review behavioral and medical characteristics of the large-brained group of boys with autism in comparison to those with typically sized brains. While brain size in typically developing individuals is positively correlated with cognitive function, the children with autism and larger brains have more severe disabilities and poorer prognosis. This research indicates that phenotyping in autism, like genotyping, requires a very substantial cohort of subjects. Moreover, since brain and behavior relationships may emerge at different times during development, this effort highlights the need for longitudinal analyses to carry out meaningful phenotyping. Autism Res 2017, 10: 711-722. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.