ASD Risk Research Articles

Caregiver-reported infant motor and imitation skills predict M-CHAT-R/F

ABSTRACT Altered motor and social-communicative abilities in infancy have been linked to later ASD diagnosis. Most diagnostic instruments for ASD cannot be utilized until 12 months, and the average child is diagnosed substantially later. Imitation combines motor and social-communicative skills and is commonly atypical in infants at risk for ASD. However, few measures have been developed to assess infant imitation clinically. One barrier to the diagnostic age gap of ASD is accessibility of screening and diagnostic services. Utilization of caregiver report to reliably screen for ASD mitigates such barriers and could aid in earlier detection. The present study developed and validated a caregiver-report measure of infant imitation at 4, 6, and 9 months and explored the relationship between caregiver-reported imitation and motor abilities with later ASD risk. Participants (N = 571) were caregivers of term and preterm infants recruited as part of a large multi-site study of PediaTrac™, a web-based tool for monitoring and tracking infant development. Caregivers completed online surveys and established questionnaires on a schedule corresponding to well-child visits from birth to 18 months, including the M-CHAT-R/F at 18 months. Distinct imitation factors were derived from PediaTrac at 4, 6, and 9 months via factor analysis. The results supported validity of the imitation factors via associations with measures of infant communication (CSBS; ASQ). Imitation and motor skills at 9 months predicted 18-month ASD risk over and above gestational age. Implications for assessment of infant imitation, detecting ASD risk in the first year, and contributing to access to care are discussed.

Social validity of telepractice in families with children with autism

This research evaluates the social validity (SV) of Telepractice as an intervention modality in families with children with ASD. The study analyzed the SV perceived by families according to the characteristics of the intervention and service delivery. A total of 168 Spanish families with a child with ASD or developmental delay at risk for ASD receiving support services from 45 centers in 44 cities around Spain. Structural equation modeling was used to study the impact of service characteristics on families’ perception of SV of telepractice in terms of effectiveness, feasibility, usefulness, caregiver confidence and competence, and future intentions. Results showed that families with children with ASD had an overall positive social validity of telepractice. Videoconference combined with phone calls and email was the modality with higher social validity scores, and the perceived technology skills was directly related to SV scores. Families receiving multiple telepractice sessions per week during longer periods of time tend to show a more passive role and lower perceptions of social validity. Implications for practice are presented, such as weekly videoconferencing sessions with an active family role in order to allow specialists observe the family's interactions with the child, monitor progress, and build caregiver capacity.

No evidence for differential saccadic adaptation in children and adults with an autism spectrum diagnosis.

Altered patterns of eye-movements during scene exploration, and atypical gaze preferences in social settings, have long been noted as features of the Autism phenotype. While these are typically attributed to differences in social engagement and interests (e.g., preferences for inanimate objects over face stimuli), there are also reports of differential saccade measures to non-social stimuli, raising the possibility that fundamental differences in visuo-sensorimotor processing may be at play. Here, we tested the plasticity of the eye-movement system using a classic saccade-adaptation paradigm to assess whether individuals with ASD make typical adjustments to their eye-movements in response to experimentally introduced errors. Saccade adaptation can be measured in infants as young as 10 months, raising the possibility that such measures could be useful as early neuro-markers of ASD risk. Saccade amplitudes were measured while children and adults with ASD (N = 41) and age-matched typically developing (TD) individuals (N = 68) made rapid eye-movements to peripherally presented targets. During adaptation trials, the target was relocated from 20-degrees to 15-degrees from fixation once a saccade to the original target location was initiated, a manipulation that leads to systematic reduction in saccade amplitudes in typical observers. Neither children nor adults with ASD showed any differences relative to TD peers in their abilities to appropriately adapt saccades in the face of persistently introduced errors. Of the three studies to date of saccade adaptation in ASD, none have shown deficits in saccade adaptation that are sufficient to generalize to the whole or a subgroup of the ASD population. Unlike prior studies, we found no evidence for a slower adaptation rate during the early adaptation phase, and no of evidence greater variance of saccade amplitudes in ASD. In post hoc analysis, there was evidence for larger primary saccades to non-adapted targets, a finding requiring replication in future work.

Prenatal air pollution, maternal immune activation, and autism spectrum disorder

BackgroundAutism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) and maternal immune activation (MIA) conditions. Because these exposures may share common biological effect pathways, we hypothesized that synergistic associations of prenatal air pollution and MIA-related conditions would increase ASD risk in children. ObjectivesThis study examined interactions between MIA-related conditions and prenatal PM2.5 or major PM2.5 components on ASD risk. MethodsIn a population-based pregnancy cohort of children born between 2001 and 2014 in Southern California, 318,751 mother–child pairs were followed through electronic medical records (EMR); 4,559 children were diagnosed with ASD before age 5. Four broad categories of MIA-related conditions were classified, including infection, hypertension, maternal asthma, and autoimmune conditions. Average exposures to PM2.5 and four PM2.5 components, black carbon (BC), organic matter (OM), nitrate (NO3–), and sulfate (SO42-), were estimated at maternal residential addresses during pregnancy. We estimated the ASD risk associated with MIA-related conditions, air pollution, and their interactions, using Cox regression models to adjust for covariates. ResultsASD risk was associated with MIA-related conditions [infection (hazard ratio 1.11; 95% confidence interval 1.05–1.18), hypertension (1.30; 1.19–1.42), maternal asthma (1.22; 1.08–1.38), autoimmune disease (1.19; 1.09–1.30)], with higher pregnancy PM2.5 [1.07; 1.03–1.12 per interquartile (3.73 μg/m3) increase] and with all four PM2.5 components. However, there were no interactions of each category of MIA-related conditions with PM2.5 or its components on either multiplicative or additive scales. ConclusionsMIA-related conditions and pregnancy PM2.5 were independently associations with ASD risk. There were no statistically significant interactions of MIA conditions and prenatal PM2.5 exposure with ASD risk.

Two-sample Mendelian randomization study does not reveal a significant relationship between cytomegalovirus (CMV) infection and autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive.MethodsTo investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project.ResultsOur results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD.ConclusionsOur results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.

Subcortical Brain Alterations in Carriers of Genomic Copy Number Variants.

Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.

DeepASDPred: a CNN-LSTM-based deep learning method for Autism spectrum disorders risk RNA identification

BackgroundAutism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by difficulty communicating with society and others, behavioral difficulties, and a brain that processes information differently than normal. Genetics has a strong impact on ASD associated with early onset and distinctive signs. Currently, all known ASD risk genes are able to encode proteins, and some de novo mutations disrupting protein-coding genes have been demonstrated to cause ASD. Next-generation sequencing technology enables high-throughput identification of ASD risk RNAs. However, these efforts are time-consuming and expensive, so an efficient computational model for ASD risk gene prediction is necessary.ResultsIn this study, we propose DeepASDPerd, a predictor for ASD risk RNA based on deep learning. Firstly, we use K-mer to feature encode the RNA transcript sequences, and then fuse them with corresponding gene expression values to construct a feature matrix. After combining chi-square test and logistic regression to select the best feature subset, we input them into a binary classification prediction model constructed by convolutional neural network and long short-term memory for training and classification. The results of the tenfold cross-validation proved our method outperformed the state-of-the-art methods. Dataset and source code are available at https://github.com/Onebear-X/DeepASDPred is freely available.ConclusionsOur experimental results show that DeepASDPred has outstanding performance in identifying ASD risk RNA genes.

Fixation-induced surgical segment’s high stiffness and the damage of posterior structures together trigger a higher risk of adjacent segment disease in patients with lumbar interbody fusion operations

BackgroundAdjacent segment disease (ASD) is a commonly reported complication after lumbar interbody fusion (LIF); changes in the mechanical environment play an essential role in the generation of ASD. Traditionally, fixation-induced high stiffness in the surgical segment was the main reason for ASD. However, with more attention paid to the biomechanical significance of posterior bony and soft structures, surgeons hypothesize that this factor may also play an important role in ASD.MethodsOblique and posterior LIF operations have been simulated in this study. The stand-alone OLIF and OLIF fixed by bilateral pedicle screw (BPS) system have been simulated. The spinal process (the attachment point of cranial ligamentum complex) was excised in the PLIF model; the BPS system has also been used in the PLIF model. Stress values related to ASD have been computed under physiological body positions, including flexion, extension, bending, and axial rotations.ResultsCompared to the stand-alone OLIF model, the OLIF model with BPS fixation suffers higher stress values under extension body position. However, there are no apparent differences under other loading conditions. Moreover, significant increases in stress values can be recorded in flexion and extension loading conditions in the PLIF model with posterior structures damage.ConclusionsFixation-induced surgical segment’s high stiffness and the damage of posterior soft tissues together trigger a higher risk of ASD in patients with LIF operations. Optimizing BPS fixation methods and pedicle screw designs and reducing the range of posterior structures excision may be an effective method to reduce the risk of ASD.

Molecular and in silico analyses of SYN III gene variants in autism spectrum disorder.

Defects in neurotransmission and synaptogenesis are noteworthy in the pathogenesis of ASD. Synapsin III (SYN III) is defined as a synaptic vesicle protein that plays an important role in synaptogenesis and regulation of neurotransmitter release and neurite outgrowth. Therefore, SYN III may associate with many neurodevelopmental diseases, including ASD. The aim of this study was to investigate whether the SYN III gene -631 C > G (rs133946) and -196 G > A (rs133945) polymorphisms are associated with susceptibility to ASD. SYN III variants and the risk of ASD were investigated in 26 healthy children and 24 ASD children. SYN III gene variants were genotyped by PCR-RFLP methods. The differences in genotype and allele frequencies between the ASD and control groups were calculated using the chi-square (χ2). We analysed the SYN III gene using web-based tools. Our results suggest that the presence of the AA genotype of the SYN III -196 G > A (rs133945) polymorphism affects the characteristics and development of ASD in children (p = 0.012). SYN III -631 C > G (rs133946) polymorphism was not associated with ASD (p = 0.524). We have shown the prediction of gene-gene interaction that SYN III is co-expressed with 17 genes, physical interaction with 3 genes, and co-localization with 12 genes. The importance of different genes (SYN I, II, III, GABRD, NOS1AP, GNAO1) for ASD pathogenesis was revealed by GO analysis. Considering the role of SYN III and related genes, especially in the synaptic vesicle pathway and neurotransmission, its effect on ASD can be further investigated.

Photographs and Parent Training to Support Conversations about Past Events between Caregivers and Children with Autism.

Children with autism spectrum disorder experience communication difficulties that can make it challenging to engage in conversations. Their caregivers also often struggle with finding ways to support the child's communication. Parent-implemented interventions and visual supports are evidence-based practices to support the communication skills of children with autism. A multi-method design (single-case multiple probe and qualitative) was used to evaluate the effects of family photographs, training, and telecoaching on parental implementation of communication strategies. Three parents and their children with and at risk for autism participated. Results indicate that the use of photographs increased the communication strategies used by all parents. Telecoaching further increased the overall strategy use for two parents. Interviews with the parents indicate spontaneous generalization and maintenance of strategy use. Family photos and naturalistic developmental behavior intervention approaches have the potential to improve communication about past events between parents and children with and at risk for ASD.

51. An Emerging Landscape of Genomic Regions Where an Excess of Low Frequency Sequence Variants and Pathogenic CNVs are Associated With ASD and Schizophrenia Risk

51. An Emerging Landscape of Genomic Regions Where an Excess of Low Frequency Sequence Variants and Pathogenic CNVs are Associated With ASD and Schizophrenia Risk

Association of early childhood constipation with the risk of autism spectrum disorder in Taiwan: Real-world evidence from a nationwide population-based cohort study.

Autism spectrum disorder (ASD) is a neurodevelopmental problem that presents with limited interests, repetitive behaviors, and deficits in reciprocal communication and social interactions. Mounting evidence indicates that an imbalanced gut microbiota contributes to autism via the gut-brain axis. Constipation may result in alteration of the gut microbiota. The clinical influence of constipation on ASD has not been fully researched. Thus, in this study we aimed to evaluate whether early childhood constipation influenced the risk of developing ASD using a nationwide population-based cohort study. We identified 12,935 constipated children aged 3 years or younger from the National Health Insurance Research Database (NHIRD) in Taiwan from 1997 to 2013. Non-constipated children were also selected from the database and propensity score matching of age, gender, and underlying comorbidities was conducted with a ratio of 1:1. Kaplan-Meier analysis was applied to determine different levels of constipation severity and cumulative incidence of autism. Subgroup analysis was also applied in this study. The incidence rate of ASD was 12.36 per 100,000 person-months in the constipation group, which was higher than the rate of 7.84 per 100,000 person-months noted in the non-constipation controls. Constipated children had a significantly higher risk of autism when compared to the non-constipation group (crude relative risk = 1.458, 95% CI = 1.116-1.904; adjusted hazard ratio = 1.445, 95% CI = 1.095-1.907).Moreover, among constipated children, a higher number of laxative prescriptions, male gender, constipation during infancy, and atopic dermatitis were significantly associated with higher risks of ASD when compared to the non-constipation group. Constipation in early childhood was correlated with a significantly increased risk of ASD. Clinicians should pay attention to the possibility of ASD in constipated children. Further research is necessary to study the possible pathophysiological mechanisms of this association.

Impact of selected single nucleotide polymorphisms in OXTR and AVPR1a genes on their expression in persons with ASD.

IntroductionAutism spectrum disorder is a heterogeneous group of disorders that affects virtually every population, regardless of their ethnic or socioeconomic origin. In recent years, the attention of researchers has been drawn to the participation of the oxytocinergic and vasopressinergic systems in the development of autism spectrum disorders. A relatively large number of studies have investigated the association of SNPs in these genes with the development of ASD, however, there is a lack of studies in the literature focusing on their actual effect on expression and on the effect of their expression on the risk of ASD.ObjectivesThe aim of this study was to assess the levels of expression of OXTR and AVPR1a genes and evaluate their links with both risk of ASD and genotypes of the most studied polymorphisms.MethodsThe study included 132 people, 77.5% of whom were male (n = 100). 113 participants (85.6%) were diagnosed with autism spectrum disorders confirmed by the ADOS-2 test conducted by a certified diagnostician. In this group, men constituted 76.1% of the population (n = 77). The remaining 28 people did not have a diagnosis of autism spectrum disorders, and in the ADOS-2 study they obtained the result below the cut-off level. The mean age in the whole group was 14.4 years (95% CI: 13.92-14.93).ResultsSignificant decrease in expression of the OXTR gene was found in case of rs53576 where presence of the alternative allele (G) was linked to the 20% decrease in expression (2^(-ΔΔCt) = 0.8). In case of AVPR1a alternative allele (T) of SNP rs10877969 was linked to the 20% increase in the gene expression(2^(-ΔΔCt) = 1.197). SNPs rs2254298 (2^(-ΔΔCt) = 0.97) and rs7294536 (2^(-ΔΔCt) = 0.97) did not influence expression of the appropriate genes in significant way. In comparison between the test and control group in participants with confirmed diagnosis of ASD 13% lower expression of AVPR1a was found (2^(-ΔΔCt) = 0.87).ConclusionsGenotype of SNPs rs53576 and rs10877969 significantly influenced the levels of expression of the genes OXTR and AVPR1a respectively. In case of rs2254298 and rs7294536 observed effects were negligible. Presence of ASD diagnosis was linked to the 13% lower expression of AVPR1a. Abnormalities in AVPR1a expression seem to be more important for the development of autistic traits than the more attention-grabbing gene abnormalities for the oxytocinergic system.Disclosure of InterestNone Declared

Is Breastfeeding Duration Associated with Risk of Developing ASD?

Background: There are few studies in the world on the duration of breastfeeding and the risk of autism. To our knowledge, no study has yet explained the association between breastfeeding duration and ASD in Iran. Aims: The present study evaluated the association between breastfeeding and the risk of ASD in offspring in the west of Iran. Methods: This case-control study was performed on 100 children aged 3-14 years who had a medical record in the Autism Spectrum Disorder Research Center and the Autism Association of Hamadan and were diagnosed with autism according to the Diagnostic and Statistical Manual of mental disorders [DSM-5] criteria. The control group included healthy children who had active family record in comprehensive health service centers. All analyzes were performed using Stata software version 14. The significance level was considered less than 0.05. Results: After adjusting for other variables, each increase in the month of breastfeeding was associated with a 5% decrease in odds of ASD [OR=0.95 [95% CI: 0.91, 0.99], P=0.03]. The odds of ASD in boys were significantly higher [OR=3.85 [95% CI: 1.91, 7.76], P&lt;0.001]. Moreover, drug use [OR=0.01], history of autism [OR=6.62], history of psychiatry disorder [OR=7.2] were significantly associated with increased odds of ASD [P&lt;0.05]. Conclusion: These findings showed that breastfeeding duration can be a protective factor for ASD. Therefore, policymakers and health staff can reduce the risk of autism by promoting increased breastfeeding duration, especially for children with high risk for autism.

The role of single nucleotide polymorphisms within genes for oxytocin and vasopressin receptors in the presentation and severity of autistic traits

IntroductionAutism spectrum disorder is a heterogeneous group of disorders that affects virtually every population, regardless of their ethnic or socioeconomic origin. The pathogenesis of ASD is probably multifactorial, based on interactions between genetic and environmental factors. Their key elements are disorders in the field of social communication, establishing and maintaining relationships and the so-called stereotypical and repetitive patterns of interests and activities. However, of the above- mentioned symptoms, the most important are communication disorders, which are the basis for many of the functional difficulties observed in these patients.ObjectivesThe aim of the presented study was to analyze the clinical picture of social cognition deficits in males with autism spectrum disorders, and to link its elements with the frequency of alleles of selected polymorphisms within the OXTR and AVPR1A genes.MethodsThe study included 132 people, 77.5% of whom were male (n = 100). 113 participants (85.6%) were diagnosed with autism spectrum disorders confirmed by the ADOS-2 test conducted by a certified diagnostician. In this group, men constituted 76.1% of the population (n = 77). The remaining 28 people did not have a diagnosis of autism spectrum disorders, and in the ADOS-2 study they obtained the result below the cut-off level. The mean age in the whole group was 14.4 years (95% CI: 13.92-14.93).ResultsA higher frequency of the rs53576 A allele and the rs10877969 C allele could be observed than expected on the basis of the European / world population. In the case of the rs7294536 and rs2254298 polymorphisms, no differences in the distribution of alleles in relation to the expected values were observed. In the network analysis reference allele (T) of SNPs rs10877969 was linked to the higher outcome of the “social affect” domain of ADOS-2 and through it influenced ADOS-2 outcome. All other SNPs did not significantly affect neither domain of ADOS-2. Reference allele (A) of rs53576 was linked with higher odds ratio of clinical diagnosis of ASD in logistic regression. Similarly the rs10877969 polymorphism within the AVPR1a gene significantly shaped the risk of autism spectrum disorders, while in the combined analysis with rs7294536 within the haplotype, the observed effect was significantly stronger.ConclusionsThe studied polymorphisms may constitute an element of larger haplotypes which, depending on the number of mutated alleles, may determine the severity of autism spectrum traits, from the neurotypical population, through people with a broad autism phenotype, to people diagnosed with ASD. Further research is required on the potential clinical application of genotype analysis of the studied polymorphisms and on the exact mechanism of their impact on the risk of ASD and the development of social cognition disorders.Disclosure of InterestNone Declared

Cerebellar dysfunction and autism spectrum disorders – what do we know?

IntroductionAutism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social cognition and repetitive behaviors with onset in early infancy. Deficits in emotion recognition, social perception, and communication have been identified as core symptoms of ASD.Comorbid disorders are frequent, namely psychiatric illness, epilepsy, sleep disruption, and hyperactivity.Immune profile changes during early life may contribute to pathogenesis of ASD. Other risk factors include advanced parental age, fetal environment, fertility treatments, medications, and nutritional and toxic factors.Several brain regions are involved in the pathophysiology of ASD but the cerebellum is the structure most consistently found altered. An increased risk of ASD is associated with cerebellar damage.ObjectivesTo highlight the importance of understanding the key processes of cerebellar development and how altered cerebellar function leads to social and cognitive impairments, and consequently ASD.MethodsNon-systematic review of the literature using Pubmed database. Papers were selected according to their relevance.ResultsFrom imaging studies, we can understand that cerebellum is not just about motor function. Different tasks like adding working memory, emotional and social processing, and language seem to be part of core functions of the cerebellar circuit.Adults with lesions in the cerebellum can develop cerebellar cognitive affective syndrome (CCAS), with core symptoms of impaired executive function, difficulties in spatial cognition, blunted affect, or inappropriate behavior. Some children who have tumor resection surgery for medulloblastomas also exhibit symptoms of CCAS, and some experience posterior fossa syndrome (PFS).The linguistic, cognitive, and behavioral deficits in CCAS and PFS may contribute to explaining how cerebellar alterations are related to ASD, which is a neurodevelopmental disorder characterized by an earlier onset and broader spectrum of these symptoms.ConclusionsThe literature has suggested an important role for cerebellar dysfunction in etiology of ASD, under certain premises: (a) cerebellar expansion temporarily coincides with onset of ASD; (b) cerebellum is prone to lesions during this period; (3) cerebellar lesions contribute to dysfunctional social and language abilities.Disturbances in cerebellar development lead to alterations in higher cognitive functions, due to changes in Purkinje cells. These dysfunctional neurons, once integrated into a brain circuit that controls complex tasks, lead to these functions becoming aberrant.It is therefore fair to say that cerebellum is important for development of the so-called “cognitive and social brain” since it is itself part of this network. So, the cerebellum certainly plays a relevant role in pathophysiology of ASD.Disclosure of InterestNone Declared

Comparison of discover cervical disc arthroplasty and anterior cervical discectomy and fusion for the treatment of cervical degenerative disc diseases: A meta-analysis of prospective, randomized controlled trials.

This study aims to evaluate the clinical efficacy and safety between Discover cervical disc arthroplasty (DCDA) and anterior cervical discectomy and fusion (ACDF) in Cervical degenerative disc diseases. Two researchers independently conducted a search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trails (CENTRAL) for randomized controlled trials (RCTs) following the Cochrane methodology guidelines. A fixed-effects or random-effects model was applied based on different heterogeneity. Review Manager (Version 5.4.1) software was used to perform data analysis. A total of 8 RCT studies were included in this meta-analysis. The results indicate that the DCDA group had a higher incidence of reoperation (P = 0.03) and a lower incidence of ASD (P = 0.04) than the CDA group. There was no significant difference between two groups regarding NDI score (P = 0.36), VAS ARM score (P = 0.73), VAS NECK score (P = 0.63), EQ-5D score (P = 0.61) and dysphagia incidence (0.18). DCDA and ACDF have similar results in terms of NDI scores, VAS scores, EQ-5D scores, and dysphagia. In addition, DCDA can reduce the risk of ASD but increases the risk of reoperation.

Exome-wide analysis identify multiple variations in olfactory receptor genes (OR12D2 and OR5V1) associated with autism spectrum disorder in Saudi females.

Autism Spectrum Disorder (ASD) is a multifactorial, neurodevelopmental disorder, characterized by deficits in communication, restricted and repetitive behaviors. ASD is highly heritable in Saudi Arabia; indecencies of affected individuals are increasing. To identify the most significant genes and SNPs associated with the increased risk of ASD in Saudi females to give an insight for early diagnosis. Pilot case-control study mostly emphasized on the significant SNPs and haplotypes contributing to Saudi females with ASD patients (n = 22) compared to controls (n = 51) without ASD. With the use of allelic association analysis tools, 243,345 SNPs were studied systematically and classified according to their significant association. The significant SNPs and their genes were selected for further investigation for mapping of ASD candidate causal variants and functional impact. In females, five risk SNPs at p ≤ 2.32 × 10-05 was identified in association with autism. The most significant exonic variants at chromosome 6p22.1 with olfactory receptor genes (OR12D2 and OR5V1) clustered with high linkage disequilibrium through haplotyping analysis. Comparison between highly associated genes (56 genes) of male and female autistic patients with female autistic samples revealed that 39 genes are unique biomarkers for Saudi females with ASD. Multiple variations in olfactory receptor genes (OR5V1 and OR12D2) and single variations on SPHK1, PLCL2, AKAP9 and LOC107984893 genes are contributing to ASD in females of Arab origin. Accumulation of these multiple predisposed coding SNPs can increase the possibility of developing ASD in Saudi females.

The association between gene polymorphisms in voltage-gated potassium channels Kv2.1 and Kv4.2 and susceptibility to autism spectrum disorder.

Autism spectrum disorder (ASD) is a heritable form of neurodevelopmental disorder that arises through synaptic dysfunction. Given the involvement of voltage-gated potassium (Kv) channels in the regulation of synaptic plasticity, we aimed to explore the relationship between the genetic variants in the KCNB1 and KCND2 genes (encoding Kv2.1 and Kv4.2, respectively) and the risk of developing ASD. A total of 243 patients with ASD and 243 healthy controls were included in the present study. Sixty single nucleotide polymorphisms (SNPs) (35 in KCNB1 and 25 in KCND2) were genotyped using the Sequenom Mass Array. There were no significant differences in the distribution of allele frequencies and genotype frequencies in KCNB1 between cases and controls. However, the differences were significant in the allelic distribution of KCND2 rs1990429 (p Bonferroni < 0.005) and rs7793864 (p Bonferroni < 0.005) between the two groups. KCND2 rs7800545 (p FDR = 0.045) in the dominant model and rs1990429 (p FDR < 0.001) and rs7793864 (p FDR < 0.001) in the over-dominant model were associated with ASD risk. The G/A genotype of rs1990429 in the over-dominant model and the G/A-G/G genotype of rs7800545 in the dominant model were correlated with lower severity in the Autism Diagnostic Interview-Revised (ADI-R) restricted repetitive behavior (RRB) domain. Our results provide evidence that KCND2 gene polymorphism is strongly associated with ASD susceptibility and the severity of RRB.

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein–protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.