Risk Factors For Autism Spectrum Disorder Research Articles

Humoral immunity and autism spectrum disorders

Abnormal immune activation, particularly of a humoral nature, has consistently been described in the etiopathogenesis of autism spectrum disorders (ASD). In this journal, Mead and Ashwood (2015) reviewed immune abnormalities in autism and linked them to severity of classic autistic symptoms. However, there remains a lack of clarity as to how environmental risk factors in ASD may contribute to such immunophenotypes. The evidence presented herein highlights these immune deficits of a humoral nature in ASD. Moreover, aligned with prior research showing a link between chronic air pollution and suppression of humoral immunity, the author of this commentary has proposed that environmental exposure to pervasive air pollutants, particularly nitrous oxide (N2O), may target several anti-inflammatory biomarkers, including alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibition and stimulation of kappa opioid receptor (KOR) activity. Given that these physiological targets, in particular, may promote the oft-noted humoral immunophenotypes in ASD, including B cell survival and muted antibody responses, this correspondence supports an existing line of evidence that air pollution, and particularly exposure to environmental N2O, may be an important etiological risk factor in ASD.

Autism spectrum disorder in sub-saharan africa: A comprehensive scoping review.

Autism spectrum disorder (ASD) is recognized as a global public health concern, yet almost everything we know about ASD comes from high-income countries. Here we performed a scoping review of all research on ASD ever published in sub-Saharan Africa (SSA) in order to identify ASD knowledge gaps in this part of the world. Fifty-three publications met inclusion criteria. Themes included the phenotype, genetics and risk factors for ASD in SSA, screening and diagnosis, professional knowledge, interventions for ASD, parental perceptions, and social-cognitive neuroscience. No epidemiological, early intervention, school-based or adult studies were identified. For each identified theme, we aimed to summarize results and make recommendations to fill the knowledge gaps. The quality of study methodologies was generally not high. Few studies used standardized diagnostic instruments, and intervention studies were typically small-scale. Overall, findings suggest a substantial need for large-scale clinical, training, and research programmes to improve the lives of people who live with ASD in SSA. However, SSA also has the potential to make unique and globally-significant contributions to the etiology and treatments of ASD through implementation, interventional, and comparative genomic science. Autism Res 2017, 10: 723-749. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

The Changing Epidemiology of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.

Gestational vitamin D deficiency and autism-related traits: the Generation R Study

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l−1. Compared with the 25OHD sufficient group (25OHD>50 nmol l−1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, β=0.06, P<0.001; cord blood n=1712, β=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

Risk of Autism Associated With Hyperbilirubinemia and Phototherapy.

Whether neonatal hyperbilirubinemia and/or phototherapy increase the risk of autism spectrum disorder (ASD) is unclear. We sought to quantify the risk of ASD associated with elevated total serum bilirubin (TSB) levels and with phototherapy. In a retrospective cohort study of 525 409 infants born at ≥35 weeks' gestation in 15 Kaiser Permanente Northern California (KPNC) hospitals, 1995-2011, we obtained all TSB levels and determined which infants received phototherapy. From the KPNC Autism Registry, we identified patients with ASD diagnosed at a KPNC Autism Center, by a clinical specialist, or by a pediatrician. We calculated Cox proportional hazard ratios (HRs) for time to diagnosis of ASD, adjusting for confounding factors. Among infants in the birth cohort, 2% had at least 1 TSB level ≥20 mg/dL, and 8% received phototherapy. The rate of ASD was 13 per 1000 births. Crude analyses revealed an association between TSB ≥20 and ASD (relative risk: 1.4; 95% confidence interval [CI]: 1.1-1.6), and between phototherapy and ASD (relative risk: 1.7; 95% CI: 1.5-1.8). After adjusting for confounders, TSB ≥20 (HR: 1.09; 95% CI: 0.89-1.35) and phototherapy (HR: 1.10; 95% CI: 0.98-1.24) were no longer significantly associated with ASD. Independent risk factors for ASD included maternal and paternal age; maternal and paternal higher education; male sex; birth weight <2500 g or ≥4200 g; and later year of birth. After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.

Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population.

N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.

CHD8 haploinsufficiency results in autistic-like phenotypes in mice.

Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD, with CHD8, a gene encoding a chromatin remodeller, being most frequently affected. Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.

A pilot study of prenatal exposure to perfluoroalkyl substances and social cognition

Background: Perfluoroalkyl substances (PFASs) are ubiquitous, persistent chemicals used in stain and water resistant products. Animal studies suggest that PFASs are neurodevelopmental toxicants, but epidemiologic studies are inconsistent in their findings of exposure-associated changes in children’s cognition and behavior. Objective: To investigate the association of prenatal PFASs with social cognition, a measure of how individuals perceive and respond to social cues, which is impaired in individuals with autism spectrum disorders (ASD). Methods: We collected pilot data from 52 mother-adolescent pairs participating in Project Viva, a longitudinal pre-birth cohort enrolled 1999‒2002, in which we measured perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in maternal plasma collected in early gestation (median=9.4 weeks). Parents rated their children using the Social Responsiveness Scale Version 2 (SRS-2). Results: Mean (interquartile range [IQR]) PFOA and PFOS concentrations were 6.6 ng/ml (3.4) and 30.7 ng/mL (16.6), respectively; mean (range) child age was 14 years (12-15) and mean (SD) SRS-2 score was 23.2 (19.4). In multivariable linear regression adjusted for maternal education and household income, for each IQR increment of prenatal PFOA and PFOS SRS-2 score was higher (poorer social cognition) by 5.2 points (95% CI: 0.9, 9.5) and 5.7 points (1.2, 10.4), respectively. We observed similar associations with the two SRS-derived DSM-V compatible subscales, Social Communication &amp; Interaction and Restricted Interests &amp; Repetitive Behavior. Discussion: Prenatal exposure to PFOA and PFOS was associated with poorer social cognition in a pilot sample of adolescents; estimating associations in the larger cohort will increase precision. Examining quantitative traits like social cognition rather than dichotomous diagnosis offers a statistically powerful and perhaps more valid approach to studying modifiable environmental risk factors for ASD.

Environmental risk factors for autism spectrum disorders.

Autism spectrum disorders (ASD) are syndromes that are predominantly defined by behavioral features such as impaired social interactions, restricted verbal and nonverbal communication, and repetitive or stereotyped behavior. In the past few decades, the reported prevalence of ASD has increased dramatically. This growth can be partially explained by an increased level of awareness of the problem among professionals and better diagnostic methods. Nevertheless, underpinning causes of ASD have not yet been detailed and explained. It is suggested that rather than having asingle causative factor, ASD pathogenesis is influenced by environmental or genetic factors, or a combination of both. The aims of this review are to describe the environmental risk factors associated with ASD so as to provide areference basis for current and future clinical and experimental work. On the basis of a PubMed search, we review the existing knowledge on environmental factors associated with ASD. Aseries of environmental factors have been repeatedly reported as risk factors for ASD in existing studies. Air pollution, organic toxicants, seasonal factors, psychological stress, migration, birth order, and nutrition may have a close relationship with the incidence of ASD.

Development and validation of a streamlined autism case confirmation approach for use in epidemiologic risk factor research in prospective cohorts.

The cost associated with incorporating standardized observational assessments and diagnostic interviews in large-scale epidemiologic studies of autism spectrum disorders (ASD) risk factors can be substantial. Streamlined approaches for confirming ASD case status would benefit these studies. We conducted a multi-site, cross-sectional criterion validity study in a convenience sample of 382 three-year olds scheduled for neurodevelopmental evaluation. ASD case classification as determined by three novel assessment instruments (the Early Video-guided Autism Screener E-VAS; the Autism Symptom Interview, ASI; the Screening Tool for Autism in Toddlers Expanded, STAT-E) each designed to be administered in less than 30 minutes by lay staff, was compared to ADOS scores and DSM-based diagnostic assessment from a qualified clinician. Sensitivity and specificity of each instrument alone and in combination were estimated. Alternative cutpoints were identified under different criteria and two-stage cross validation was used to avoid overfitting. Findings were interpreted in the context of a large, prospective pregnancy cohort study utilizing a two-stage approach to case identification. Under initial cutpoints, sensitivity ranged from 0.63 to 0.92 and specificity from 0.35 to 0.70. Cutpoints giving equal weight to sensitivity and specificity resulted in sensitivity estimates ranging from 0.45 to 0.83 and specificity ranging from 0.49 to 0.86. Several strategies were well-suited for application as a second-stage case-confirmation. These included the STAT-E alone and the parallel administration of both the E-VAS and the ASI. Use of more streamlined methods of case-confirmation in large-scale prospective cohort epidemiologic investigations of ASD risk factors appears feasible. Autism Res 2017, 10: 485-501. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Symptom profiles of autism spectrum disorder in tuberous sclerosis complex.

To determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC. Measures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests. Children with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC. This study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.

Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.

Logistic regression analysis on risk factors of autism spectrum disorders

Objective To explore the possible risk factors for autism spectrum disorders (ASD), and to provide a basis for exploring the etiology of the disease. Methods This case-control study included 68 patients diagnosed as ASD for a first lifetime(according to the fourth edition of the American Diagnostic and Statistical Manual of Mental Disorders for ASD diagnosis) from May 2014 to January 2015, and 77 non-ASD controls (normal children, matched on gender) in Jiangxi Children's Hospital were selected to undergo the risk factor survey for ASD.The survey content included 10 categories: general status, birth, feeding, the past history, mother's pregnancy and her health condition during pregnancy and environmental exposure, parents' occupational exposure, family history and relevant test results.Logistic regression analysis was performed to analyze the results of the survey. Results The possible risk factors for ASD increased if mother had virus infection 2 years before pregnant (OR=7.97, 95%CI: 2.42-26.31), had occupational exposure (OR=3.99, 95%CI: 1.27-12.52), volatile organic compounds exposure during pregnancy (OR=22.21, 95%CI: 2.28-216.09), as well as living closely to transport passage ways during pregnancy (OR=0.59, 95%CI: 0.38-0.93) or having a family heredity history (OR=58.50, 95%CI: 5.81-589.57). Breastfeeding (OR=0.81, 95%CI: 0.66-0.98) might be a protective factor in ASD. Conclusions In addition to genetic factors, the ute-rine environment from conception to birth and growth environment play an important role in the pathogenesis of ASD. Key words: Autism spectrum disorder; Risk factor; Logistic regression analysis

The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD.

The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n = 83), and the other two comprising autism spectrum disorder (ASD) patients (total of n = 2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95%CI = 7.5-2147) but not for ASD (P = 0.4, OR = 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of patients with autistic features in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study.

Template to Perpetrate: An Update on Violence in Autism Spectrum Disorder.

IntroductionFor the past two decades, researchers have been using various approaches to investigate the relationship, if any, between autism spectrum disorder (ASD) and violence. The need to clarify that relationship was reinforced by the tragic mass shooting at Sandy Hook Elementary School in Newtown, Connecticut, in December 2012 by an individual diagnosed with Asperger’s syndrome. The purpose of this article is (1) to provide an updated review of the literature on the association between ASD and violence, and (2) to examine implications for treating, and for preventing violence by, individuals with ASD.MethodA review of all published literature regarding ASD and violence from 1943 to 2014 was conducted using electronic and paper searches.ResultsAlthough some case reports have suggested an increased violence risk in individuals with ASD compared to the general population, prevalence studies have provided no conclusive evidence to support this suggestion. Among individuals with ASD, however, generative (e.g., comorbid psychopathology, social-cognition deficits, emotion-regulation problems) and associational (e.g., younger age, Asperger’s syndrome diagnosis, repetitive behavior) risk factors have been identified or proposed for violent behavior.ConclusionsWhile no conclusive evidence indicates that individuals with ASD are more violent than those without ASD, specific generative and associational risk factors may increase violence risk among individuals with ASD. Further research would help to clarify or confirm these findings, suggest potential directions for evaluation, treatment, and prevention, and potentially provide compelling empirical support for forensic testimony regarding defendants with ASD charged with violent crimes.

Increased Autism Incidence: Is there a Single Cause?

The Quantitative Threshold Exposure (QTE) hypothesis proposes that Autism Spectrum Disorder (ASD) is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical prenatal and early childhood developmental stages. The hypothesis predicts that the greater the number of risk factors and the quantitative amounts of each to which a child is exposed prenatally and in early postnatal life, the greater the likelihood the child will develop some form of ASD as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. These risk factors have been identified in extensive epidemiological studies to include genetic predisposition, maternal fetal exposure to infectious disease, inflammatory and autoimmune phenomena, as well as exposure to antigenic and proinflammatory environmental factors. The incidence rates of several potential risk factors for ASD correlates with observed increases in ASD incidence over the past several decades, including increased incidence of pediatric infectious disease, increased obesity/ diabetes type-2 in parents of child-bearing age and Increased use of tetrahydrocannabinol (THC) during childbearing years. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates. The model has important predictive value, as it suggests that, rather than attempting to identify a specific causative agent linked to ASD, the combined risk factor profile should be evaluated in population studies in order to specify more accurately the limits of pre- threshold exposure.

Incidence of autism in high risk neonatal follow up.

Objective:To detect autism spectrum disorder (ASD) cases within the High Risk Neonatal Follow up Program (HRNFP), as an indicator of the prevalence of ASD and associated risk factors in the Kingdom of Saudi Arabia (KSA).Methods:We conducted this retrospective medical chart review in a tertiary care hospital in Riyadh, KSA. All patients admitted to the HRNFP were seen at 3 years corrected age between January 2012 and December 2013. Patients diagnosed with ASD from the HRNFP were referred to the King Fahad Medical City (KFMC) Autism Program for further assessment. The following potential risk factors for ASD were documented: low birth weight, gestational age less than 33 weeks, and male gender.Results:In 2012, 59 patients were evaluated in the HRNFP. Three cases were diagnosed with ASD, with an ASD incidence rate of 5.1% (95% confidence interval [CI] calculated by adjusted Wald method: 1.2-14.5%). In 2013, 48 patients were evaluated and 2 cases were diagnosed with ASD, with an ASD incidence rate of 4.2% (95% CI: 0.4%-14.8%). The total ASD incidence rate during the 2-year study period was 4.7% (95% CI: 1.7%-10.8%). Factors associated with a higher likelihood of ASD were: male gender, low birth weight, and gestational age less than 33 weeks.Conclusion:Compared with the community, the prevalence of ASD was higher in the HRNFP. Further investigation is required to evaluate risk factors.

Structure and function of neonatal social communication in a genetic mouse model of autism.

A critical step toward understanding autism spectrum disorder (ASD) is to identify both genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as robust genetic risk factors for ASD, but not all CNV carriers exhibit ASD and the severity of ASD symptoms varies among CNV carriers. Although evidence exists that various environmental factors modulate symptomatic severity, the precise mechanisms by which these factors determine the ultimate severity of ASD are still poorly understood. Here, using a mouse heterozygous for Tbx1 (a gene encoded in 22q11.2 CNV), we demonstrate that a genetically-triggered neonatal phenotype in vocalization generates a negative environmental loop in pup-mother social communication. Wild-type pups used individually diverse sequences of simple and complicated call types, but heterozygous pups used individually invariable call sequences with less complicated call types. When played back, representative wild-type call sequences elicited maternal approach, but heterozygous call sequences were ineffective. When the representative wild-type call sequences were randomized, they were ineffective in eliciting vigorous maternal approach behavior. These data demonstrate that an ASD risk gene alters the neonatal call sequence of its carriers and this pup phenotype in turn diminishes maternal care through atypical social communication. Thus, an ASD risk gene induces, through atypical neonatal call sequences, less than optimal maternal care as a negative neonatal environmental factor.

Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population.

Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers.

BackgroundNeuropsychiatric disorders are present in up to 90 % of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61 % of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients.MethodsWe selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature.ResultsSeventeen out of 42 patients (40.5 %) had a score at the SCQ suggestive of ASD (≥15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender.ConclusionsOur study showed a prevalence of ASD of 40.5 %, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2.