Genes associated with autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogeneous grouping of neurodevelopmental disorders characterized by impairment in social interaction, verbal communication and repetitive/stereotypic behaviors. Much evidence suggests that ASD is multifactorial with a strong genetic basis, but the underlying mechanisms are far from clear. Recent advances in genetic technologies are beginning to shed light on possible etiologies of ASD. This review discusses current evidence for several widely studied candidate ASD genes, as well as various rare genes that supports their relationship to the etiology of ASD. The majority of the data are based on molecular, cytogenetic, linkage and association studies of autistic subjects, but newer methods, including whole-exome sequencing, are also beginning to make significant contributions to our understanding of autism.     

Psychiatric comorbidity associated with co-occurring autism spectrum disorder and substance use disorder

BackgroundAlthough both autism spectrum disorder (ASD) and substance use disorder (SUD) are both commonly comorbid with other psychiatric conditions, there is a paucity of research on the overlap of these disorders. The primary aim of the present study was to identify the prevalence of psychiatric comorbidities in young adults with SUD and ASD compared to those with ASD only.MethodMultivariate logistic regression controlling for age was used to compare the prevalence of psychiatric disorders in a sample of treatment-seeking adult outpatients with a) ASD without SUD and b) ASD with SUD. Psychiatric and SUD diagnoses were determined by semi-structured interview (SCID for DSM IV).ResultsThe sample included 42 patients with ASD only (mean age ± SD = 26.2 ± 8.9 years) and 21 with ASD and SUD (35.2 ± 12.6). High rates of psychopathology were found in both groups. Comorbid conduct disorder (CD) was significantly more prevalent in the ASD + SUD group (25 %) compared to those without SUD (5%; p < 0.05). There were no other significant differences between groups in the rates of non-conduct comorbid psychopathology.ConclusionIn both groups, rates of psychopathology were high with CD being significantly more common in young adults with ASD and SUD. These findings highlight the importance of screening for CD in individuals with ASD to mitigate the potential development of comorbid SUD. Further research is needed to determine if CD is a true risk factor for SUD in the ASD population and identify other risk factors.     

Differentiating multiple personality disorder and complex partial seizures

A number of reports have suggested that some cases of multiple personality disorder might be due to temporal lobe epileptic discharges. We have administered a structured interview, the Dissociative Disorders Interview Schedule, to 20 subjects with multiple personality disorder, 20 with complex partial seizures, and 28 neurologic controls. Subjects also completed the Dissociative Experiences Scale. Results show that multiple personality can be differentiated from complex partial seizures on a large number of items. The seizure patients did not differ from controls. The data indicate that the phenomenologies of these two disorders are distinct, and, therefore, there is little reason to assume a common etiology.     

Is cesarean section delivery associated with autism spectrum disorder?

Objectives:To investigate a correlation between birth by caesarean section and autism spectrum disorder (ASD).Methods:A case-control study with a case to control ratio of 1:2 was performed in Al-Madina Al-Munawarah city, Kingdom of Saudi Arabia during the year 2016. The cases were selected according to the eligibility criteria and children attending a well-baby clinic in the same hospital, were chosen as the control group subjects. Data was collected from the medical records and an interview-based questionnaire was administered to the mothers. The chi-square test was used for bivariate analysis and logistic regression to estimate the crude and adjusted odds ratios (ORs).Results:Eighty-seven cases of ASD and 174 control group subjects were included in the current study. Approximately 39% (n=34) of the 87 children with ASD were delivered by cesarean section compared to 21% (n=36) of the 174 children in the control group. After adjusting for potentially confounding factors, the adjusted OR was 2.9 (95% confidence interval [CI]: 1.57-5.35).Conclusion:An association between delivery by cesarean section and ASD was found in this study, in support of the findings of other studies. It is recommended that preventive measures are adopted to avoid unnecessary cesarean sections.

Autism spectrum disorder (ASD) comprises a range of conditions that are characterized by impaired social communication and interaction, as well as repetitive behavior. Autism spectrum disorder begins in childhood and continues into adulthood, leading to a significant psychological and financial burden on the caregiver and family. The worldwide prevalence of ASD is estimated to be 0.7%, although wide variability has been reported.1 In addition, it has been reported in several studies that the prevalence of ASD is increasing worldwide. A real increase in ASD cannot be excluded even though it might be explained by improvements in documentation and the diagnosis of milder cases.2,3The pathophysiology of the disease is not well understood but multifactorial etiology is suggested by the current evidence.1 Various genetic and environmental factors have been found to be associated with ASD, including, advanced paternal age and exposure to heavy metals such as lead and inorganic mercury.4 As is the case with many other diseases, it is believed that ASD is caused by an interaction between genetic and environmental factors rather than attributable to a single cause. Deoxyribonucleic acid (DNA) methylation, which can be influenced by diet, stress, drugs, or environmental chemicals, has also been suggested as the mechanism involved in this interaction.5Globally, cesarean section delivery is estimated to account for 19% of all births, ranging from 7% in Africa to 41% in Latin America and the Caribbean.6 An average of 4% global increase in ASD has been reported annually over the last few decades.6 Cesarean section is associated with various short and long-term health challenges, including respiratory morbidities,7 hospitalization for asthma,8 acute lymphoblastic leukemia,9 and neurodevelopmental impairment.10 Conflicting results have been reported in previous studies on an association between cesarean section delivery and the subsequent development of ASD in the infant.11-13 Thus, the current study objective was to investigate the association of birth by cesarean section and the risk of ASD.     

Factors associated with stress in families of children with autism spectrum disorder

ABSTRACT

Purpose: The purpose of this study was to identify key factors associated with severe stress in families raising a child with autism spectrum disorder (ASD). Methods: Questionnaires were mailed to families with one or more children with a diagnosis of ASD. Data from 543 surveys were analyzed using univariate and multivariate logistic regression. Results: Forty-four percent (n = 241) of the caregivers reported severe family stress related to raising a child with ASD. Severe family stress was associated with (1) reduced ability to socialize; (2) not having accessed individual therapy; (3) negative co-parent relationships; and (4) high out of pockets costs due to the child’s ASD. The specific ASD diagnosis, comorbid conditions, socio-demographic variables, and social support were not associated with severe family stress. Conclusion: The findings of the current study highlight the importance of a systemic approach to family stress, whereby individual, family, and ecological factors are investigated.     

Febrile seizures in patients with complex partial seizures

Febrile seizures occurred in 14 of 155 (9%) out-patients with complex partial seizures. Twelve patients had prolonged or recurrent febrile seizures, convulsive status epilepticus or a transient postictal neurological deficit. Febrile seizures were associated with perinatal abnormalities, an earlier onset of epilepsy and with a poor seizure control. Recurrent febrile seizures or those with complicating features are associated with an unfavourable therapeutic outcome in adult patients with complex partial seizures.     

Autonomic and brain responses associated with empathy deficits in autism spectrum disorder

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio‐emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio‐emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high‐functioning adults with ASD and seventeen matched controls while they performed an empathy‐for‐pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD. Hum Brain Mapp 36:3323–3338, 2015. © 2015 The Authors Human Brain Mapping Published byWiley Periodicals, Inc.     

Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder

Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, γ-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy.This article is part of a Special Issue entitled “Autism and Epilepsy”.     

Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome

Background

XYY syndrome is a sex chromosome aneuploidy that occurs in ~?1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data.

Methods

We evaluated a single-center cohort of 64 individuals with XYY aged 5–25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis.

Results

Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features.

Conclusions

By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology.

Trial registrations

ClinicalTrials.gov NCT00001246, “89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls.”

     

Sleep in children with autism spectrum disorder

Children with autism spectrum disorder demonstrate an increased prevalence of difficulties with sleep initiation and maintenance. The consequences may include alterations in daytime behavior, memory, and learning in patients, and significant stress in caretakers. The dysregulation of melatonin synthesis, sensitization to environmental stimuli, behavioral insomnia syndromes, delayed sleep phase syndrome, rapid eye movement sleep behavior disorder, and comorbid anxiety, depression, and epilepsy comprise common etiologic factors. The clinical assessment of sleep problems in this population and a management algorithm are presented.     

A familial case of LEOPARD syndrome associated with a high-functioning autism spectrum disorder

A connection between LEOPARD syndrome (a rare autosomal dominant disorder) and autism spectrum disorders (ASDs) may exist. Of four related individuals (father and three sons) with LEOPARD syndrome, all patients exhibited clinical symptoms consistent with ASDs. Findings included aggressive behavior and impairment of social interaction, communication, and range of interests. The coexistence of LEOPARD syndrome and ASDs in the related individuals may be an incidental familial event or indicative that ASDs is associated with LEOPARD syndrome. There have been no other independent reports of the association of LEOPARD syndrome and ASDs. Molecular and biochemical mechanisms that may suggest a connection between LEOPARD syndrome and ASDs are discussed.     

Epilepsy in autism spectrum disorder

The purpose of this review is to provide an overview of the research on epilepsy in autism spectrum disorder (ASD). Topics explored are the prevalence of epilepsy in ASD, the importance of studying epilepsy, as well as the questionnaire measures used to assess epilepsy side-effects. Research on the relationships between epilepsy and parental stress and psychological distress, developmental regression, language and communication, adaptive behavior, social skills, autism severity, challenging behavior, comorbid psychopathology, gastrointestinal symptoms, sleep problems, sensory issues and quality of life are also discussed. Finally, recommendations for treatment are given as well as areas where future research is needed.     

孤独谱系障碍患儿的感觉特征

目的 使用中文版儿童感觉剖析量表探讨孤独谱系障碍(ASD)患儿的感觉特点.方法 采用中文版儿童感觉剖析量表对66例ASD患儿和66名健康发育儿童进行评定,由监护人完成.分析孤独症患儿与健康儿童在感觉方面的差异.结果 除感觉剖析量表的口腔感觉处理和影响活动水平的运动的调节部分外,ASD患儿在其他部分及全量表的得分均与健康儿童的差异有统计学意义(P<0.01).结论 除口腔感觉处理和影响活动水平的运动的调节外,ASD患儿的各项感觉特征与健康发育儿童均存在一定差异.中文版儿童感觉剖析量表对区别ASD患儿与健康发育儿童有一定的鉴别力.     

Patterns of autism spectrum symptomatology in individuals with Down syndrome without comorbid autism spectrum disorder

Background

Prevalence estimates of autism spectrum disorder (ASD) in Down syndrome (DS) are highly varied. This variation is partly due to the difficulty of screening for and diagnosing comorbid ASD in individuals with a syndrome that carries its own set of social communicative and behavioral difficulties that are not well documented. The aim of this study was to identify the typical range of social communicative impairments observed in children, adolescents, and young adults with DS who do not have comorbid ASD.

Methods

We examined patterns of scores from the five subscales of the Social Responsiveness Scale (SRS) in 46 individuals with DS (ages 10–21 years) without comorbid ASD relative to the published normative sample. We also explored the correlations between SRS symptomatology and age, nonverbal cognition, and receptive language.

Results

SRS scores were elevated (i.e., more ASD symptoms endorsed), with mean scores falling into the clinically significant range. Analysis by subscale revealed a specific pattern, with Autistic Mannerisms and Social Cognition scores significantly more elevated than Social Communication scores, which were significantly more elevated than Social Awareness and Social Motivation scores. Correlations between SRS scores and the other measures varied by subscale.

Conclusions

General elevated ASD symptomatology on the SRS indicates the need for developing population-based norms specific to DS. The pattern of scores across subscales should inform clinicians of the typical range of behaviors observed in DS so that individuals with atypical patterns of behavior can be more easily identified and considered for a full ASD evaluation.     

Factors associated with negative co-parenting experiences in families of a child with autism spectrum disorder

Purpose: The purpose of this study was to identify key factors associated with negative co-parenting experiences in parents raising a child with autism spectrum disorder. Methods: Questionnaires were sent to families with one or more children with a diagnosis of autism spectrum disorder. Parents of 142 children with autism spectrum disorder indicated that the diagnosis had a very negative impact on their co-parent relationship. A multivariate logistic regression model was run to analyze the association of these experiences with various demographic, family and community factors. Results: Three factors were associated with negative co-parenting relationships: (1) family stress due to the child’s diagnosis, (2) effects of the diagnosis on parents’ relationship with their other children and (3) distance travelled to the nearest medical facility. Conclusions: Findings highlight the need to further explore family dynamics, particularly the relationships between the co-parenting alliance, other family members and the extra-familial environment.     

Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience

Early diagnosis of autism spectrum disorder (ASD) is highly important as it enables an early start to intervention. The current study examined familial (parental ages; education; having an older sibling) and child (gender; reported and observed autism symptoms severity; adaptive skills) related variables that might predict the age of ASD diagnosis. The study included 551 participants, age range 15–72 months, diagnosed with ASD who underwent comprehensive medical and behavioral assessment using standardized tests. Of the child's examined variables, the severity of the social interaction impairment reported by the parents and having a history of developmental regression was associated with an earlier age of ASD diagnosis. In contrast, the severity of the restricted and repetitive behaviors was associated with delayed age of ASD diagnosis. Vineland Adaptive Behavior Scales scores lower or higher than the group's mean (70 points) were associated with a relatively delayed age of ASD diagnosis. Of the familial variables, only having an older sibling was associated with an earlier diagnosis. Professionals should be aware that subtle signs of ASD, developmental delay and close to normal adaptive functioning might delay age of ASD diagnosis. Educating parents on “red flags” for ASD and periodic surveillance in early childhood are important.     

Benign infantile epilepsy with complex partial seizures

Benign infantile epilepsy with complex partial seizures is characterized by a high incidence of family history of benign childhood convulsions, normal development prior to onset, infantile onset, no underlying disorders, no neurological abnormalities, normal interictal EEGs, good response to treatment, and complete remission with normal developmental outcome. Seizures often occur in clusters, consisting of motion arrest, decreased responsiveness, staring or blank eyes mostly with simple automatisms, and mild convulsive movements associated with focal paroxysmal discharges, most frequently in the temporal area.