Enrichment of Elevated Plasma F2t-Isoprostane Levels in Individuals with Autism Who Are Stratified by Presence of Gastrointestinal Dysfunction

Etiology is unknown in the majority of individuals with autism spectrum disorder (ASD). One strategy to investigate pathogenesis is to stratify this heterogeneous disorder based on a prominent phenotypic feature that enriches for homogeneity within population strata. Co-occurring gastrointestinal dysfunction (GID) characterizes a subset of children with ASD. Our current objective was to investigate a potential pathophysiological measure to test the hypothesis that children with both ASD and GID have a more severe metabolic dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable impairment. Plasma levels of F_2t-Isoprostanes (F₂-IsoPs), a gold standard biomarker of oxidative stress, were measured in 87 children in four groups: ASD-GID, ASD-only, GID-only and Unaffected. F₂-IsoP levels were elevated in all 3 clinical groups compared to the Unaffected group, with the ASD-GID group significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and triglyceride levels, F₂-IsoP levels remained significantly different between study groups, with a moderate effect size of η_p ² = 0.187 (p = 0.001). Elevation in peripheral oxidative stress is consistent with, and may contribute to, the more severe functional impairments in the ASD-GID group. With unique medical, metabolic, and behavioral features in children with ASD-GID, the present findings serve as a compelling rationale for both individualized approaches to clinical care and integrated studies of biomarker enrichment in ASD subgroups that may better address the complex etiology of ASD.     

Space‐use strategies of wintering Ovenbirds in Belize: causes and consequences

For long‐distance migrants, territoriality and prey biomass during the non‐breeding season have been linked to body condition that can carry over to affect spring migration and breeding events. For Ovenbirds (Seiurus aurocapilla), studies in Jamaica showed that body condition in mid‐season depended on leaf litter prey biomass and declined seasonally as conditions became drier, and that individuals with sedentary (territorial) and wandering space‐use strategies did not differ in age or body condition. During October and November 2010–2011, we radio‐tracked Ovenbirds in Belize to determine if space‐use patterns differed with age and sex, if space‐use strategy influenced foraging behavior or body condition, and if areas used by wanderers and territory owners differed in food abundance or habitat characteristics. Most Ovenbirds (41 of 51, 80.4%) possessed small (1‐ha) territories with largely non‐overlapping cores, but 22.5% (10 of 51) of birds were wanderers (～7‐ha home range). Early season space use was predicted by age class, with most wanderers (90%, 9 of 10) being first‐year birds and most territory owners (63%) being older birds. Sex ratios of wanderers and territory owners did not differ. We found that wanderers may have been at a disadvantage because they had significantly lower foraging rates and lower relative body masses than territorial birds, although baseline corticosterone levels did not differ. Habitat characteristics of areas used by wanderers and territory owners did not differ nor did biomass of ground‐surface arthropods, likely because ranges of most wanderers overlapped those of territory owners. Using stable hydrogen isotopes in feathers, we found that first‐year Ovenbirds that were wanderers tended to have a more northern natal origins than sedentary birds, though the difference was not significant. Longer migration distances could delay arrival and reduce competitive ability. Our results suggest that wandering may not be an alternative and equally successful strategy, at least early in the season, and instead young birds may be competitively excluded from territory ownership.     

The Clinical Impact of Chromosomal Microarray on Paediatric Care in Hong Kong

Objective

To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong.

Methods

We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their “clinical actionability” based on established criteria.

Results

Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p<0.001). Nineteen out of the 28 management recommendations are “evidence-based” on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12).

Conclusion

The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing.     

Trends in the Prevalence of Autism Spectrum Disorder,Cerebral Palsy,Hearing Loss,Intellectual Disability,and Vision Impairment,Metropolitan Atlanta, 1991–2010

This study examined the prevalence and characteristics of autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss (HL), intellectual disability (ID), and vision impairment (VI) over a 15–20 year time period, with specific focus on concurrent changes in ASD and ID prevalence. We used data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta. From 1991–2010, prevalence estimates of ID and HL were stable with slight increases in VI prevalence. CP prevalence was constant from 1993–2010. The average annual increase in ASD prevalence was 9.3% per year from 1996–2010, with a 269% increase from 4.2 per 1,000 in 1996 to 15.5 per 1,000 in 2010. From 2000–2010, the prevalence of ID without ASD was stable; during the same time, the prevalence of ASD with and without co-occurring ID increased by an average of 6.6% and 9.6% per year, respectively. ASD prevalence increases were found among both males and females, and among nearly all racial/ethnic subgroups and levels of intellectual ability. Average annual prevalence estimates from 1991–2010 underscore the significant community resources needed to provide early intervention and ongoing supports for children with ID (13.0 per 1,000), CP, (3.5 per 1,000), HL (1.4 per 1,000) and VI (1.3 in 1,000), with a growing urgency for children with ASD.     

Differences in venom composition between orb-weaving and wandering Hawaiian Tetragnatha (Araneae)

Spider venoms are complex mixtures of toxins that are used primarily for immobilizing prey. There is evidence of chemical variation in spider venoms among close relatives, yet few studies have analysed their evolution within an ecological and phylogenetic framework. On the Hawaiian archipelago, Tetragnatha, a cosmopolitan orb-weaving genus, has undergone a radiation in which a monophyletic lineage has abandoned web-building and become obligately wandering foragers. This study compares venom composition and details of feeding behaviour between orb-weaving and wandering Hawaiian Tetragnatha. Protein gel electrophoresis patterns indicated that relative to orb-weavers, wandering species had a reduced concentration of low molecular weight (<14kDa) components. Both orb-weaving and wandering Tetragnatha captured flying prey (adult lepidopterans, dipterans), but wandering spiders also captured non-flying prey (insect larvae, spiders). There were no distinct differences between orb-weavers and wanderers in prey capture and immobilization sequences, or in the paralytic effects of bites on prey. However, prey bitten by wanderers took longer to be permanently immobilized than prey bitten by orb-weavers. Contrary to predictions, there was no indication that web-loss in this group was associated with an increase in venom potency.     

Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings

Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children''s Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.     

Early Mortality and Primary Causes of Death in Mothers of Children with Intellectual Disability or Autism Spectrum Disorder: A Retrospective Cohort Study

Introduction

Mothers of children with intellectual disability or autism spectrum disorder (ASD) have poorer health than other mothers. Yet no research has explored whether this poorer health is reflected in mortality rates or whether certain causes of death are more likely. We aimed to calculate the hazard ratios for death and for the primary causes of death in mothers of children with intellectual disability or ASD compared to other mothers.

Methods

The study population comprised all mothers of live-born children in Western Australia from 1983–2005. We accessed state-wide databases which enabled us to link socio-demographic details, birth dates, diagnoses of intellectual disability or ASD in the children and dates and causes of death for all mothers who had died prior to 2011. Using Cox Regression with death by any cause and death by each of the three primary causes as the event of interest, we calculated hazard ratios for death for mothers of children intellectual disability or ASD compared to other mothers.

Results and Discussion

During the study period, mothers of children with intellectual disability or ASD had more than twice the risk of death. Mothers of children with intellectual disability were 40% more likely to die of cancer; 150% more likely to die of cardiovascular disease and nearly 200% more likely to die from misadventure than other mothers. Due to small numbers, only hazard ratios for cancer were calculated for mothers of children with ASD. These mothers were about 50% more likely to die from cancer than other mothers. Possible causes and implications of our results are discussed.

Conclusion

Similar studies, pooling data from registries elsewhere, would improve our understanding of factors increasing the mortality of mothers of children with intellectual disability or ASD. This would allow the implementation of informed services and interventions to improve these mothers'' longevity.     

Socioeconomic Disparities and Prevalence of Autism Spectrum Disorders and Intellectual Disability

Background and Objectives

Study of the impact of socioeconomic status on autism spectrum disorders (ASD) and severe intellectual disabilities (ID) has yielded conflicting results. Recent European studies suggested that, unlike reports from the United States, low socioeconomic status is associated with an increased risk of ASD. For intellectual disabilities, the links with socioeconomic status vary according to the severity. We wished to clarify the links between socioeconomic status and the prevalence of ASD (with or without ID) and isolated severe ID.

Methods

500 children with ASD and 245 children with severe ID (IQ <50) aged 8 years, born 1995 to 2004, were recruited from a French population-based registry. Inclusions were based on clinical diagnoses reported in medical records according to the International Classification of Diseases, 10^th Revision. Socioeconomic status was measured by indicators available at block census level which characterize the population of the child’s area of residence. Measures of deprivation, employment, occupation, education, immigration and family structure were used. Prevalences were compared between groups of census units defined by the tertiles of socioeconomic level in the general population.

Results

Prevalence of ASD with associated ID was higher in areas with the highest level of deprivation and the highest percentage of unemployed adults, persons with no diploma, immigrants and single-parent families. No association was found when using occupational class. Regarding ASD without associated ID, a higher prevalence was found in areas with the highest percentage of immigrants. No association was found for other socioeconomic indicators. The prevalence of isolated severe ID was likely to be higher in the most disadvantaged groups defined by all indicators.

Conclusion

The prevalence of ASD with associated ID and of severe isolated ID is more likely to be higher in areas with the highest level of deprivation.     

Neural basis of self and other representation in autism: an FMRI study of self-face recognition

Background

Autism is a developmental disorder characterized by decreased interest and engagement in social interactions and by enhanced self-focus. While previous theoretical approaches to understanding autism have emphasized social impairments and altered interpersonal interactions, there is a recent shift towards understanding the nature of the representation of the self in individuals with autism spectrum disorders (ASD). Still, the neural mechanisms subserving self-representations in ASD are relatively unexplored.

Methodology/Principal Findings

We used event-related fMRI to investigate brain responsiveness to images of the subjects'' own face and to faces of others. Children with ASD and typically developing (TD) children viewed randomly presented digital morphs between their own face and a gender-matched other face, and made “self/other” judgments. Both groups of children activated a right premotor/prefrontal system when identifying images containing a greater percentage of the self face. However, while TD children showed activation of this system during both self- and other-processing, children with ASD only recruited this system while viewing images containing mostly their own face.

Conclusions/Significance

This functional dissociation between the representation of self versus others points to a potential neural substrate for the characteristic self-focus and decreased social understanding exhibited by these individuals, and suggests that individuals with ASD lack the shared neural representations for self and others that TD children and adults possess and may use to understand others.     

Alternative male reproductive tactics in a natural population of prairie voles <Emphasis Type="Italic">Microtus ochrogaster</Emphasis>

Alternative reproductive tactics have been described in male mammals, but little information exists regarding fitness benefits and whether males change tactics. Adult male prairie voles Microtus ochrogaster (Wagner, 1842) display alternative tactics described as resident and wanderer. Enclosure studies provide conflicting data concerning the relative success of each tactic and whether males display one tactic throughout adulthood. To characterize further residents and wanderers in this species, we examined data collected during 5 years of monitoring a natural population in Illinois, USA. We found that during the breeding period, wandering males survived longer, moved longer distances, and were more likely than residents to have scrotal testes. During the nonbreeding period, wandering and resident males differed only in whether or not they established residency. Data on sources and fates of resident and wandering males revealed that a substantial proportion of males switched tactics. Our estimate of the reproductive contribution of wandering males to the population, which is based on the premise that wandering males typically mate with single females, suggests that wanderers contribute 34–38% of young recruited during March through October and 4–12% in November, when single females are less common. Parentage studies in natural populations are necessary to test our estimates.     

Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities

Objective

Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD.

Methods

We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene.

Results

We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24).

Significance

We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort.     

Autism and intellectual disability are differentially related to sociodemographic background at birth

Background

Research findings investigating the sociodemographics of autism spectrum disorder (ASD) have been inconsistent and rarely considered the presence of intellectual disability (ID).

Methods

We used population data on Western Australian singletons born from 1984 to 1999 (n = 398,353) to examine the sociodemographic characteristics of children diagnosed with ASD with or without ID, or ID without ASD compared with non-affected children.

Results

The profiles for the four categories examined, mild-moderate ID, severe ID, ASD without ID and ASD with ID varied considerably and we often identified a gradient effect where the risk factors for mild-moderate ID and ASD without ID were at opposite extremes while those for ASD with ID were intermediary. This was demonstrated clearly with increased odds of ASD without ID amongst older mothers aged 35 years and over (odds ratio (OR) = 1.69 [CI: 1.18, 2.43]), first born infants (OR = 2.78; [CI: 1.67, 4.54]), male infants (OR = 6.57 [CI: 4.87, 8.87]) and increasing socioeconomic advantage. In contrast, mild-moderate ID was associated with younger mothers aged less than 20 years (OR = 1.88 [CI: 1.57, 2.25]), paternal age greater than 40 years (OR = 1.59 [CI: 1.36, 1.86]), Australian-born and Aboriginal mothers (OR = 1.60 [CI: 1.41, 1.82]), increasing birth order and increasing social disadvantage (OR = 2.56 [CI: 2.27, 2.97]). Mothers of infants residing in regional or remote areas had consistently lower risk of ASD or ID and may be linked to reduced access to services or under-ascertainment rather than a protective effect of location.

Conclusions

The different risk profiles observed between groups may be related to aetiological differences or ascertainment factors or both. Untangling these pathways is challenging but an urgent public health priority in view of the supposed autism epidemic.     

孤独症谱系障碍儿童早期神经发育水平和智能特征分析

目的:探讨孤独症谱系障碍(Autism spectrum disorder,ASD)儿童早期神经发育水平及智能分区特征,为提高ASD的早期识别和诊断提供理论依据。方法:运用Gesell发育评估量表对18月龄至48月龄以内的27例ASD患儿和30例发育迟缓(Mental retardation, MR)患儿的发育商(Development quotient,DQ)进行测评,比较两组患儿的年龄、性别、平均DQ和各能区DQ。结果:两组患儿的年龄和性别未见明显差异(P>0.05),ASD患儿平均DQ落后于MR患儿(P<0.05),ASD患儿的语言和个人-社交明显落后于MR患儿(P<0.05),ASD患儿的语言和个人-社交明显落后于大运动、精细动作(P<0.05),语言明显落后于个人-社交和适应性(P<0.05),MR患儿的各能区未见明显差异(P>0.05)。结论:ASD患儿智能特征表现为整体发育水平落后且显著不平衡,以语言和个人-社交落后最明显。     

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background

Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.

Methodology/Principal Findings

Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.

Conclusion/Significance

Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.     

THE ROLE OF INBREEDING DEPRESSION IN MAINTAINING THE MIXED MATING SYSTEM OF THE COMMON MORNING GLORY,IPOMOEA PURPUREA

Theoretical studies show that, although inbreeding depression (ID) will counterbalance the transmission advantage of selfing, it can only maintain a mixed mating system in plants when at least one of the following two conditions is met: (1) there is a positive association between selfing rates and the level of ID; and (2) ID is greater than 0.5 for the female component of fitness, while the average ID for male and female fitness is less than 0.5. This study tests whether these two conditions hold in the common morning glory, Ipomoea purpurea, which has a mixed mating system with 30% self-fertilization. Inbreeding depression was found in all but one fitness component measured in two groups of plants with distinct anther-stigma distances (ASD), a character that influences selfing rates. However, when examined separately, a negative association was found between selfing rates and ID; plants with large ASD (low-selfing-rate genotypes) tended to have higher ID than ones with small ASD (high-selfing-rate genotypes). Furthermore, the overall lifetime ID for male (12.5%) and female (24%) components of fitness, averaged across two ASD groups, were lower than what is necessary for ID to maintain an evolutionarily stable mixed mating system. Therefore, although inbreeding depression contributes to balancing the transmission advantage of selfing, it is not likely to be the primary mechanism maintaining the mixed mating system of I. purpurea. The contribution of other mechanisms is discussed.     

Hydrocarbon accumulation and lipid biosynthesis during larval development in the cabbage looper,Trichoplusia ni

Larvae of the cabbage looper, Trichoplusia ni, were analyzed for the accumulation and biosynthesis of cuticular and internal hydrocarbon at closely spaced and accurately timed intervals during the fourth and fifth stadia. Large differences in the incorporation of [1-¹⁴C]acetate into hydrocarbon were observed at different times during larval development. Much higher incorporation was observed during feeding stages as compared to wandering stages, while lowest rates of biosynthesis occurred just prior to ecdysis. Fourth stadia wanderers accumulated increased amounts of internal hydrocarbon, which is apparently used to cover the newly forming cuticle. During the fourth to fifth stadium moult insects lost all cuticular hydrocarbon that was present on the old cuticle (about 8 μg/insect) and had about 8 μg/insect on the surface of the newly exposed cuticle. During the fourth stadium incorporation of [1-¹⁴C]acetate into total lipid declined between feeding and wandering stages from 24% of injected radiolabel to 7%. Similar decreases in lipid biosynthesis were observed between feeders and wanderers in fifth stadium larvae with the greatest decrease found in the triacylglycerol fraction. These results document dramatic changes in the accumulation and biosynthesis of hydrocarbon and other lipids during larval development.     

Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

Background

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.

Methodology/Principal Findings

We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.

Conclusions/Significance

Although all patients'' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism.     

Appropriateness of array‐CGH in the ADHD clinics: A comparative study

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorder with a worldwide prevalence of about 5%. The disorder is characterized by inattentive, hyperactive and impulsive behavior and is often comorbid with other neuropsychiatric conditions. Array comparative genomic hybridization (array‐CGH) testing has been proved to be useful to detect chromosomal aberrations in several neuropsychiatric conditions including autism spectrum disorders (ASD) and intellectual disability (ID). The usefulness of array‐CGH in the ADHD clinics is still debated and no conclusive evidence has been reached to date. We performed array‐CGH in 98 children and adolescents divided in two similarly sized groups according to the clinical diagnosis: (a) one group diagnosed with ADHD as primary diagnosis; (b) the other group in which ADHD was co‐morbid with ASD and/or ID. We detected pathogenetic and likely pathogenetic copy number variants (CNVs) in 12% subjects in which ADHD was co‐morbid with autism and/or intellectual disability and in 8.5% subjects diagnosed with ADHD as primary diagnosis. Detection of CNVs of unknown clinical significance was similar in the two groups being 27% and 32%, respectively. Benign and likely benign CNVs accounted for 61% and 59.5% in the first and second group, respectively. Differences in the diagnostic yield were not statistically significant between the two groups (P > .05). Our data strongly suggest that array‐CGH (a) is a valuable diagnostic tool to detect clinically significant CNVs in individuals with ADHD even in the absence of comorbidity with ASD and/or ID and (b) should be implemented routinely in the ADHD clinics.     

Down syndrome as a genetic model to evaluate the role of oxidative stress and transsulfuration abnormalities in autism spectrum disorder: A 10‐year longitudinal cohort study

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which evidence reveals oxidative stress and transsulfuration pathway abnormalities. Down syndrome (DS) is a genetic disorder characterized by similar oxidative stress and transsulfuration pathway abnormalities. This hypothesis‐testing longitudinal cohort study determined whether transsulfuration abnormalities and oxidative stress are important susceptibility factors in ASD etiology by evaluating the rate of ASD diagnoses in DS as compared to the general population. The Independent Healthcare Research Database was analyzed for healthcare records prospectively generated in Florida Medicaid. A cohort of 101,736 persons (born: 1990–1999) with ≥10 outpatient office visits and continuously followed for 120 months after birth was examined. There were 942 children in the DS cohort (ICD‐9 code: 758.0) and 100,749 children in the undiagnosed cohort (no DS diagnosis). ASD diagnoses were defined as autistic disorder (ICD‐9 code: 299.00) or Asperger's disorder/pervasive developmental disorder—not otherwise specified (ICD‐9 code: 299.80). ASDs were diagnosed in 5.31% of the DS cohort and 1.34% of the undiagnosed cohort. The risk ratio of being diagnosed with an ASD in the DS cohort as compared to the undiagnosed cohort was 3.97‐fold significantly increased with a risk difference of 3.97%. Among children diagnosed with DS, less than 6% were also diagnosed with an ASD. Among children diagnosed with an ASD, less than 5% were also diagnosed with DS. Children diagnosed with DS are apparently more susceptible to ASD diagnosis relative to the general population suggesting oxidative stress and transsulfuration pathway abnormalities are important susceptibility factors in ASD.     

Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability

We used whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) in a cohort of 256 patients with developmental delay (DD)/intellectual disability (ID) with or without dysmorphic features, additional neurodevelopmental abnormalities, and/or congenital malformations. In 69 patients, we identified 84 non-polymorphic copy-number variants, among which 41 are known to be clinically relevant, including two recently described deletions, 4q21.21q21.22 and 17q24.2. Chromosomal microarray analysis revealed also 15 potentially pathogenic changes, including three rare deletions, 5q35.3, 10q21.3, and 13q12.11. Additionally, we found 28 copy-number variants of unknown clinical significance. Our results further support the notion that copy-number variants significantly contribute to the genetic etiology of DD/ID and emphasize the efficacy of the detection of novel candidate genes for neurodevelopmental disorders by whole-genome array CGH.