Neuronal Autoantibodies in Autism Spectrum Disorder

Special Report: Autism Spectrum Disorder and Inflexible Thinking—Affecting Patients Across the Lifespan

Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. ASD affects one in 54 children in the United States, one in 89 children in Europe, and one in 277 children in Asia, with an estimated worldwide prevalence of 1–2%. While there is increasing consensus that ASD results from complex gene x environment interactions, the identity of specific environmental risk factors and the mechanisms by which environmental and genetic factors interact to determine individual risk remain critical gaps in our understanding of ASD etiology. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been linked to altered neurodevelopment in humans. Preclinical studies demonstrate that PCBs modulate signaling pathways implicated in ASD and phenocopy the effects of ASD risk genes on critical morphometric determinants of neuronal connectivity, such as dendritic arborization. Here, we review human and experimental evidence identifying PCBs as potential risk factors for ASD and discuss the potential for PCBs to influence not only core symptoms of ASD, but also comorbidities commonly associated with ASD, via effects on the central and peripheral nervous systems, and/or peripheral target tissues, using bladder dysfunction as an example. We also discuss critical data gaps in the literature implicating PCBs as ASD risk factors. Unlike genetic factors, which are currently irreversible, environmental factors are modifiable risks. Therefore, data confirming PCBs as risk factors for ASD may suggest rational approaches for the primary prevention of ASD in genetically susceptible individuals.

Autism spectrum disorder is a neurodevelopmental disorder defined by deficits in social communication and the presence of restricted and repetitive behaviors and interests. This article provides the tools to diagnose and manage patients with autism spectrum disorder. Autism spectrum disorder is a heterogeneous condition with varying presentations, multiple etiologies, and a number of comorbidities that impact the course and management of the disorder. This article defines the core features of social communication deficits, including problems with social reciprocity, decreased nonverbal communication, and difficulties in developing and maintaining relationships. The second domain of repetitive behaviors and restricted interests, which includes the presence of stereotyped behaviors or speech, insistence on sameness and behavioral rigidity, intense or out of the ordinary interests, and unusual responses to sensory stimulation, is also delineated. Comorbidities commonly seen with autism spectrum disorder include medical, neurologic, and psychiatric conditions. Despite intense research efforts, the etiology of autism spectrum disorder remains unknown in most cases, but it is clear that a strong genetic component exists that interacts with various environmental risk factors. Current research is identifying overlapping neurobiological pathways that are involved in pathogenesis. Treatment involves intensive behavioral therapy and educational programming along with traditional ancillary services, such as speech/language, occupational, and physical therapies. Psychopharmacologic treatments are also used to target certain symptoms and comorbid conditions. Neurologists can play an important role in diagnosing autism spectrum disorder according to clinical criteria through a comprehensive evaluation that includes a thorough medical and developmental history, behavioral and play observations, and a review of standardized cognitive and language evaluations. Neurologists are also responsible for investigating etiologies, recommending and advocating for appropriate behavioral and educational interventions, and identifying and often managing comorbidities.

“A developmental disability that hinders the normal functioning of the brain, affecting, in varying degrees, communication skills and social interaction. Repetitive behaviours, and different ways of learning, paying attention, or reacting to things are often distinctive signs”. This standard definition of autism fails to describe the complexity of a condition that ranges in its manifestations from severe intellectual impairment to superior cognitive skills, like in the Asperger syndrome. To comprise such diversity, autism disorders are now covered under the umbrella term “autism spectrum disorder” (ASD). In most cases, ASD manifests during the first 5 years of life, with boys significantly more likely to be diagnosed than girls. ASD usually goes together with several other problems that frequently include anxiety, sleep disorders, or epilepsy. No cure exists; treatment, such as speech therapy, just attempts to alleviate specific deficits of autistic patients. > Nothing is simple in autism. Even the real number of people affected is uncertain. Nothing is simple in autism. Even the real number of people affected is uncertain. The US CDC estimates that about 1 in 68 (or 1.5%) of children in the USA are living with ASD (http://www.cdc.gov/ncbddd/autism/data.html). The WHO has a more conservative estimate, last revised in January this year, of 1 in 160 children, based on a larger set of epidemiological surveys (http://www.who.int/mediacentre/factsheets/autism-spectrum-disorders/en/). Needless to say, most studies were conducted in developed countries, and the prevalence of ASD in many low‐ and middle‐income countries remains largely unknown. > Along the years, many potential causes have been indicated, including genetic and environmental factors, exposure to toxins during pregnancy, wide gaps between parent ages, and so on Although the general consensus is that prevalence rates are increasing globally, this point is debated too. Some analyses indicate that a large percentage of the increase in ASD owes to improved awareness and …

Autism in DSM-5

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, restricted interests, and repetitive behaviors. The etiology of ASD is multifactorial, involving genetic, environmental, and maternal factors. Recent studies have suggested maternal factors, such as advanced maternal age, high BMI, smoking, and depression during pregnancy, as significant risk factors for ASD. Objective: This study aims to investigate the maternal risk factors that contribute to ASD in children at Diyala, Iraq. Patients and Methods: This case-control study was conducted on 150 children, comprising 75 children diagnosed with ASD and 75 healthy children as a control group. The study was carried out from August 2023 to May 2024 in Diyala, Iraq. Data collection included comprehensive demographic, social, obstetric, and maternal health histories. ASD diagnosis was confirmed using the Childhood Autism Rating Scale 2 (CARS-2). A logistic regression analysis was performed to assess the association between maternal risk factors and ASD. Results: The study revealed several significant maternal risk factors for ASD. Advanced maternal age at pregnancy (mean age 28.1 years in cases vs. 22.9 years in controls, p=0.001), high maternal BMI (mean BMI 26.9 in cases vs. 24.4 in controls, p=0.0001), maternal smoking (6.7% in cases vs. 0% in controls, p=0.023), and maternal depression during pregnancy (22.7% in cases vs. 0% in controls, p=0.0001) were all significantly associated with an increased risk of ASD. The use of stimulating hormones before pregnancy also showed a significant association (21.3% in cases vs. 4% in controls, p=0.001). Parity, particularly having 1-2 pregnancies, was also a significant risk factor (p=0.002). Conclusion: This study identifies advanced maternal age, high BMI, smoking, depression, and the use of stimulating hormones before pregnancy as significant maternal risk factors for ASD in children. Keywords: Autism, ASD, maternal age and autism, maternal illness and autism.

Within cohorts of children with autism spectrum disorder (ASD) there is considerable variation in terms of language ability. In the past, it was believed that children with ASD either had delayed articulation and phonology skills or excelled in those areas compared to other language domains. Very little is known about speech sound ability in relation to language ability and non-verbal ability in Swedish preschool children with ASD. The current study aimed to describe language variation in a group of 4-6-year-old children with ASD, focusing on in-depth analyses of speech sound error patterns with and without non-phonological language disorder and concomitant non-verbal delays. We examined and analysed the speech sound skills (including consonant inventory, percentage of correct consonants and speech sound error patterns) in relation to receptive language skills in a sample of preschool children who had screened positive for ASD in a population-based screening at 2.5 years of age. Seventy-three children diagnosed with ASD participated and were divided into subgroups based on their receptive language (i.e., non-phonological language) and non-verbal abilities. The subgroup division revealed that 29 children (40%) had language delay/disorder without concurrent non-verbal general cognitive delay (ALD), 27 children (37%) had language delay/disorder with non-verbal general cognitive delay (AGD), and 17 children (23%) had language and non-verbal abilities within the normal range (ALN). Results revealed that children with ALD and children with AGD both had atypical speech sound error patterns significantly more often than the children with ALN. This study showed that many children who had screened positive for ASD before age 3 years - with or without non-verbal general cognitive delays - had deficits in language as well as in speech sound ability. However, individual differences were considerable. Our results point to speech sound error patterns as a potential clinical marker for language problems (disorder/delay) in preschool children with ASD. What is already known on the subject Children with autism spectrum disorder (ASD) have deficits in social communication, restricted interests and repetitive behaviour. They show very considerable variation in both receptive and expressive language abilities. Previously, articulation and phonology were viewed as either delayed in children with ASD or superior compared with other (non-phonological) language domains. What this paper adds to existing knowledge Children with ASD and language disorders also have problems with speech sound error patterns. What are the potential or actual clinical implications of this work? About 75% of children with ASD experience language delays/disorders, as well as speech sound problems, related to speech sound error patterns. Understanding/acknowledging these phonological patterns and their implications can help in the diagnosis and intervention of speech sound disorders in children with ASD. Direct intervention targeting phonology might lead to language gains, but more research is needed.

Purpose Autism spectrum disorder (ASD) is characterized by deficits in social communication and interaction, restricted interests and repetitive behavior. Humor appreciation in autistic individuals has been examined from the perspective of incongruity-resolution theory but not fully examined in terms of benign violations. Therefore, this study aims to examine the benign violation theory of humor appreciation among autistic individuals. Design/methodology/approach In total, 38 and 462 autistic and non-autistic participants rated the degree of humor appreciation, violation appraisal and benign appraisal of 12 humorous stimuli. Furthermore, participants completed the Social Responsiveness Scale 2 Adult-Self Edition. Findings Restricted interests and repetitive behavior had significant positive effects on humor appreciation, violation appraisal and benign appraisal. Focusing on autistic traits, especially restricted interests and repetitive behavior, is important when considering humor appreciation in autistic individuals because differences in the degree of restricted interests and repetitive behavior are considered a gap in sharing humor. Originality/value This study focused on autistic traits such as deficits in social communication, restricted interests and repetitive behavior and examined their relationships with humor appreciation from the perspective of benign violation theory. The findings suggest that these three autistic traits are involved in the gap in sharing humor between autistic and non-autistic individuals. Therefore, identifying the association between autistic traits and humor appreciation offers a new perspective to support the formation of humorous relationships between autistic and non-autistic individuals.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition that now impacts 1 in 36 children in the United States and is characterized by deficits in social communication, repetitive behaviors, and restricted interests. Children with ASD also frequently experience co-morbidities including anxiety and ADHD, and up to 80% experience gastrointestinal (GI) symptoms such as constipation, diarrhea, and/or abdominal pain. Systemic immune activation and dysregulation, including increased pro-inflammatory cytokines, are frequently observed in ASD. Evidence has shown that the innate immune system may be impacted in ASD, as altered monocyte gene expression profiles and cytokine responses to pattern recognition ligands have been observed compared to typically developing (TD) children. In humans, circulating monocytes are often categorized into three subpopulations-classical, transitional (or "intermediate"), and nonclassical monocytes, which can vary in functions, including archetypal inflammatory and/or reparative functions, as well as their effector locations. The potential for monocytes to contribute to immune dysregulation in ASD and its comorbidities has so far not been extensively studied. This study aims to determine whether these monocyte subsets differ in frequency in children with ASD and if the presence of GI symptoms alters subset distribution, as has been seen for T cell subsets. Whole blood from ASD children with (ASD+GI+) and without gastrointestinal symptoms (ASD+GI-) and their TD counterparts was collected from children enrolled in the Childhood Autism Risk from Genetics and Environment (CHARGE) study. Peripheral blood mononuclear cells were isolated and stained for commonly used subset identifiers CD14 and CD16 as well as activation state markers CCR2, HLA-DR, PD-1, and PD-L1 for flow cytometry analysis. We identified changes in monocyte subpopulations and their expression of surface markers in children with ASD compared to TD children. These differences in ASD appear to be dependent on the presence or absence of GI symptoms. We found that the ASD+GI+ group have a different monocyte composition, evident in their classical, transitional, and nonclassical populations, compared to the ASD+GI- and TD groups. Both the ASD+GI+ and ASD+GI- groups exhibited greater frequencies of classical monocytes compared to the TD group. However, the ASD+GI+ group demonstrated lower frequencies of transitional and nonclassical monocytes than their ASD+GI- and TD counterparts. CCR2+ classical monocyte frequencies were highest in the ASD+GI- group. HLA-DR+ classical, transitional, and nonclassical monocytes were statistically comparable between groups, however, HLA-DR- nonclassical monocyte frequencies were lower in both ASD groups compared to TD. The frequency of classical monocytes displaying exhaustion markers PD-1 and PD-L1 were increased in the ASD+GI+ group compared to ASD+GI- and TD, suggesting potentially impaired ability for clearance of foreign pathogens or debris, typically associated with worsened inflammation. Taken together, the findings of differential proportions of the monocyte subpopulations and altered surface markers may explain some of the characteristics of immune dysregulation, such as in the gastrointestinal tract, observed in ASD.

How to deal with the transition from Pervasive Developmental Disorders in DSM‐IV to Autism Spectrum Disorder in DSM‐V

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, restricted and repetitive behaviors and interests, with the severity of symptoms varying greatly among individuals. The pathogenesis of ASD is influenced by the complex interaction of genetic and environmental factors. Increasing evidence suggests that dysregulated immune processes represent a crucial aspect in ASD pathology. The CACNA1C gene, which encodes the pore-forming α1C subunit of the L-type calcium channel (LTCC) CaV1.2, is a major genetic risk factor for ASD. CaV1.2 channels modulate neuronal excitability, synaptic plasticity, and neurotransmitter release in the central nervous system (CNS), all of which are essential for brain development and function. CaV1.2 channels are also expressed in generally non-excitable immune cells, including CNS microglia and peripheral immune cells, where they influence activation, differentiation, and cytokine release. These immune functions may contribute to ASD pathogenesis; however, the specific role of CaV1.2 in immune regulation and neuroinflammation in ASD is yet to be elucidated. Here, we will review recent research on the role of CACNA1C in immune mechanisms relevant to ASD. We will summarize current knowledge on the function of CaV1.2 in brain microglia and peripheral immune cells such as T cells, B cells, and dendritic cells that contribute to immune dysfunction in ASD. In addition, we will discuss the therapeutic prospects of targeting CaV1.2 channels in immune cells to manage both behavioral and inflammatory conditions associated with ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Emerging evidence suggests a link between immune dysregulation and ASD. This study investigates alterations in monocyte subpopulations and cytokine production in children with ASD and their potential associations with ASD risk and severity. Initially, the immune status of peripheral blood mononuclear cells was assessed in cohort-I of 96 typically developing (TD) children and 92 children diagnosed with ASD using flow cytometry. Subsequently, the secretion of cytokines IL-6 and IL-10 by monocytes was evaluated following stimulation with a leukocyte activation mixture and intracellular protein staining technique in cohort-II. Children with ASD exhibited significantly higher levels of total monocytes, classical monocytes (CD14hi/CD16-), and non-classical monocytes (CD14low/CD16+) compared to TD children (p<0.001). Elevated levels of classical monocytes (β: 0.395; 95%CI: 0.260-0.530; p<0.001) and non-classical monocytes (β: 0.629; 95%CI: 0.516-0.742; p<0.001) were significantly associated with ASD after adjusting for age, sex and body mass index. Furthermore, increased production of IL-6 by monocytes was observed in children with ASD (p=0.001). Logistic regression analysis revealed that classical monocytes (OR: 1.104; 95%CI: 1.062-1.147; p<0.001), non-classical monocytes (OR: 2.913; 95%CI: 2.130-3.986; p<0.001) and IL-6 production by monocytes (OR: 1.306; 95%CI: 1.096-1.557; p=0.003) are risk factors for ASD. Spearman correlation analysis revealed a negative correlation between classical monocyte levels and adaptive behavior developmental quotient (DQ) (r=-0.377; p=0.001), fine motor DQ (r=-0.329; p=0.003) and personal-social DQ (r=-0.247; p=0.029) in children with ASD. Elevated classical and non-classical monocytes are potential risk factors for ASD and may influence neurodevelopmental outcomes. Further research is needed to elucidate the precise mechanisms and therapeutic implications.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/−) male mice exhibited the core symptoms of autism. Rfwd2+/− male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/− female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/− male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

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Background: Autism spectrum disorders (ASDs) are lifelong developmental disabilities characterized by marked difficulties in social reciprocal interaction and communication, along with restricted and repetitive interests, attitudes and behaviors. Aim: To determine the frequency and spectrum of restrictive and repetitive interests, attitudes and behaviors in patients with ASD. Methods: A Descriptive cross sectional study was carried out at The Children’s Hospital &amp; Institute of Child Health, Lahore for six months. A total of 190 cases were enrolled in this study, Patients assessed for presence of restrictive and repetitive interests, attitudes and behaviors and its types including; Stereotyped or repetitive motor movements, insistence on sameness, highly restricted, fixated interests and Hyper or Hypo reactivity to sensory input. All the data was entered and analyzed on SPSS. Results: The mean age of patients was 6.54±2.29 years. Male to female ratio was 1.63:1. The mean CARS score was 42.12±7.31. The restricted and repetitive interests, attitudes and behaviors were noted in 180(94.7%) patients. Conclusion: Repetitive behavior was noted in 94.7% patients, stereotypies, insistence on sameness, highly restricted interests and hyper of hypo reactivity to sensory input was found in 42.6%, 30.5%, 10.5% and 11.05% respectively Keywords: Repetitive, Behavior, Restricted Interests, Sensory Input