Annette Estes

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ∼550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Early social attention impairments in autism: social orienting, joint attention, and attention to distress.

This study investigated social attention impairments in autism (social orienting, joint attention, and attention to anothers distress) and their relations to language ability. Three- to four-year-old children with autism spectrum disorder (ASD; n = 72), 3- to 4-year-old developmentally delayed children (n = 34), and 12- to 46-month-old typically developing children (n = 39), matched on mental age, were compared on measures of social orienting, joint attention, and attention to anothers distress. Children with autism performed significantly worse than the comparison groups in all of these domains. Combined impairments in joint attention and social orienting were found to best distinguish young children with ASD from those without ASD. Structural equation modeling indicated that joint attention was the best predictor of concurrent language ability. Social orienting and attention to distress were indirectly related to language through their relations with joint attention. These results help to clarify the nature of social attention impairments in autism, offer clues to developmental mechanisms, and suggest targets for early intervention.

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10-8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10-8 to 2.1 × 10-10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Parenting stress and psychological functioning among mothers of preschool children with autism and developmental delay

Parents of children with developmental disabilities, particularly autism spectrum disorders (ASDs), are at risk for high levels of distress. The factors contributing to this are unclear. This study investigated how child characteristics influence maternal parenting stress and psychological distress. Participants consisted of mothers and developmental-age matched preschool-aged children with ASD (N = 51) and developmental delay without autism (DD) ( N = 22). Evidence for higher levels of parenting stress and psychological distress was found in mothers in the ASD group compared to the DD group. Childrens problem behavior was associated with increased parenting stress and psychological distress in mothers in the ASD and DD groups. This relationship was stronger in the DD group. Daily living skills were not related to parenting stress or psychological distress. Results suggest clinical services aiming to support parents should include a focus on reducing problem behaviors in children with developmental disabilities.

Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

OBJECTIVE Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. METHOD The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. RESULTS The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. CONCLUSIONS These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Head circumference and height in autism : A study by the collaborative program of excellence in autism

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty‐eight probands with autism‐spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites. All subjects with autism met ADI‐R, ADOS‐G, DSM‐IV, and ICD‐10 criteria. The results show the distribution of standardized head circumference in autism is normal in shape, and the mean, variance, and rate of macrocephaly but not microcephaly are increased. Head circumference tends to be large relative to height in autism. No site, gender, age, SES, verbal, or non‐verbal IQ effects were present in the autism sample. In addition to autism itself, standardized height and average parental head circumference were the most important factors predicting head circumference in individuals with autism. Mean standardized head circumference and rates of macrocephaly were similar in probands with autism and their parents. Increased head circumference was associated with a higher (more severe) ADI‐R social algorithm score. Macrocephaly is associated with delayed onset of language. Although mean head circumference and rates of macrocephaly are increased in autism, a high degree of variability is present, underscoring the complex clinical heterogeneity of the disorder. The wide distribution of head circumference in autism has major implications for genetic, neuroimaging, and other neurobiological research.

Neurocognitive Function and Joint Attention Ability in Young Children with Autism Spectrum Disorder Versus Developmental Delay

Studies have shown that young children with autism are not impaired on prefrontal tasks relative to what would be expected for their mental age, raising questions about the executive dysfunction hypothesis of autism. These studies did not include ventromedial prefrontal tasks, however. The present study examined whether young children with autism spectrum disorder (ASD) are impaired on ventromedial prefrontal tasks, and whether performance on such tasks is correlated with a core autism symptom, joint attention ability. Seventy-two 3- to 4-year-old children with ASD, 34 3- to 4-year-old developmentally delayed children, and 39 12- to 46-month-old typically developing children, matched on mental age, were administered ventromedial and dorsolateral prefrontal tasks and joint attention tasks. Children with ASD performed similarly to comparison groups on all executive function tasks, indicating that at this early age, there is no autism-specific pattern of executive dysfunction. Ventromedial, but not dorsolateral, prefrontal task performance was strongly correlated with joint attention ability, however. The ventromedial prefrontal cortex is hypothesized to play a role in the development of joint attention and possibly some aspects of the autistic syndrome.

Effects of a Brief Early Start Denver Model (ESDM)–Based Parent Intervention on Toddlers at Risk for Autism Spectrum Disorders: A Randomized Controlled Trial

OBJECTIVE This study was carried out to examine the efficacy of a 12-week, low-intensity (1-hour/wk of therapist contact), parent-delivered intervention for toddlers at risk for autism spectrum disorders (ASD) aged 14 to 24 months and their families. METHOD A randomized controlled trial involving 98 children and families was carried out in three different sites investigating the efficacy of a parent delivery of the Early Start Denver model (P-ESDM), which fosters parental use of a child-centered responsive interaction style that embeds many teaching opportunities into play, compared to community treatment as usual. Assessments were completed at baseline and 12 weeks later, immediately after the end of parent coaching sessions. RESULTS There was no effect of group assignment on parent-child interaction characteristics or on any child outcomes. Both groups of parents improved interaction skills, and both groups of children demonstrated progress. Parents receiving P-ESDM demonstrated significantly stronger working alliances with their therapists than did the community group. Children in the community group received significantly more intervention hours than those in the P-ESDM group. For the group as a whole, both younger child age at the start of intervention and a greater number of intervention hours were positively related to the degree of improvement in childrens behavior for most variables. CONCLUSIONS Parent-implemented intervention studies for early ASD thus far have not demonstrated the large effects seen in intensive-treatment studies. Evidence that both younger age and more intervention hours positively affect developmental rates has implications for clinical practice, service delivery, and public policy.

Neurocognitive and electrophysiological evidence of altered face processing in parents of children with autism: Implications for a model of abnormal development of social brain circuitry in autism

Neuroimaging and behavioral studies have shown that children and adults with autism have impaired face recognition. Individuals with autism also exhibit atypical event-related brain potentials to faces, characterized by a failure to show a negative component (N170) latency advantage to face compared to nonface stimuli and a bilateral, rather than right lateralized, pattern of N170 distribution. In this report, performance by 143 parents of children with autism on standardized verbal, visual-spatial, and face recognition tasks was examined. It was found that parents of children with autism exhibited a significant decrement in face recognition ability relative to their verbal and visual spatial abilities. Event-related brain potentials to face and nonface stimuli were examined in 21 parents of children with autism and 21 control adults. Parents of children with autism showed an atypical event-related potential response to faces, which mirrored the pattern shown by children and adults with autism. These results raise the possibility that face processing might be a functional trait marker of genetic susceptibility to autism. Discussion focuses on hypotheses regarding the neurodevelopmental and genetic basis of altered face processing in autism. A general model of the normal emergence of social brain circuitry in the first year of life is proposed, followed by a discussion of how the trajectory of normal development of social brain circuitry, including cortical specialization for face processing, is altered in individuals with autism. The hypothesis that genetic-mediated dysfunction of the dopamine reward system, especially its functioning in social contexts, might account for altered face processing in individuals with autism and their relatives is discussed.