Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Brief report: effect of maternal age on severity of autism.

The etiology of autism is complex, consisting of unknown genetic and environmental factors. Previous studies have revealed that maternal age is increased in autism compared to controls, making it a possible risk factor. This study examined the effects of maternal age on autism severity using IQ as a measure of cognitive severity and selected subtests of the Child Behavior Checklist (CBCL) as measures of social severity. A sample of 154 subjects with autism spectrum disorders was obtained from the Stanford Neuropsychiatry/Pervasive Developmental Disorder (PDD) clinic. Results indicate that there is no relationship between IQ or selected CBCL subtests and maternal age, suggesting that maternal age does not influence the severity of autism as measured by these indicators.

Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography.

STUDY OBJECTIVES: Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups. METHODS: One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant. RESULTS: PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d). CONCLUSIONS: Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages.

Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, deficits in verbal and nonverbal communication, and a restricted repertoire of activities or interests. We performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. Here we report findings on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown.

Investigation of neuroanatomical differences between autism and Asperger syndrome.

BACKGROUND: Autism and Asperger syndrome (ASP) are neurobiological conditions with overlapping behavioral symptoms and of unknown etiologies. Results from previous autism neuroimaging studies have been difficult to replicate, possibly owing to site differences in subject samples, scanning procedures, and image-processing methods. We sought (1) to determine whether low-functioning autism (LFA; IQ<70), high-functioning autism (HFA; IQ>or=70), and ASP constitute distinct biological entities as evidenced by neuroanatomical measures, and (2) to assess for intersite differences. METHODS: Case-control study examining coronally oriented 124-section spoiled gradient echo images acquired on 3 magnetic resonance imaging (MRI) systems, and processed by BrainImage 5.X. Participants were recruited and underwent scanning at 2 academic medicine departments. Participants included 4 age-matched groups of volunteer boys aged 7.8 to 17.9 years (13 patients with LFA, 18 with HFA, 21 with ASP, and 21 control subjects), and 3 volunteer adults for neuroimaging reliability. Main outcome measures included volumetric measures of total, white, and gray matter for cerebral and cerebellar tissues. RESULTS: Intersite differences were seen for subject age, IQ, and cerebellum measures. Cerebral gray matter volume was enlarged in both HFA and LFA compared with controls (P =.009 and P =.04, respectively). Cerebral gray matter volume in ASP was intermediate between that of HFA and controls, but nonsignificant. Exploratory analyses revealed a negative correlation between cerebral gray matter volume and performance IQ within HFA but not ASP. A positive correlation between cerebral white matter volume and performance IQ was observed within ASP but not HFA. CONCLUSIONS: Lack of replication between previous autism MRI studies could be due to intersite differences in MRI systems and subjects' age and IQ. Cerebral gray tissue findings suggest that ASP is on the mild end of the autism spectrum. However, exploratory assessments of brain-IQ relationships reveal differences between HFA and ASP, indicating that these conditions may be neurodevelopmentally different when patterns of multiple measures are examined. Further investigations of brain-behavior relationships are indicated to confirm these findings.

White matter structure in autism: preliminary evidence from diffusion tensor imaging.

BACKGROUND: Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism. METHODS: In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects. RESULTS: Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum. CONCLUSIONS: Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.

Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient.

Recent genetic investigations of autism have studied multiplex families, typically including families with multiple siblings who meet criteria for a diagnosis of autism. However, little is known about the specific behavioral characteristics of siblings with autism in these multiplex families. We investigated the behavioral phenotypic variability and similarity of 351 siblings with autism in 171 multiplex families using cluster analysis and correlations. The results of cluster analyses showed that the individuals with autism could be characterized on a severity gradient: a continuum based on severity of symptoms and impairment as measured by Autism Diagnostic Interview-Revised (ADI-R) scores, verbal-nonverbal status, and nonverbal IQ scores. Clusters based on scores from the ADI-R for the autism diagnostic criteria of the DSM-IV and nonverbal IQ scores still represented a severity gradient when the effects of verbal-nonverbal status were removed. The severity gradient was shown to be heritable, with a sib correlation of 30% or a heritability of 60%. In summary, in a sample of 171 autism multiplex families, there was no evidence of discrete behaviorally defined subgroups of affected individuals or families characterized by distinct patterns of behavioral symptoms. Rather, the clusters could be characterized along a single, heritable, continuous severity dimension.

Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families.

A recent report suggested that the HoxA1 and/or HoxB1 genes play a role in susceptibility to autism. To determine whether these findings could be confirmed, we screened these genes for DNA polymorphisms by sequencing all exons in 24 individuals with autism. We identified the same sequence variants in the genes that appeared in this report, which include one single-base substitution variant in HoxA1 and a common haplotype in HoxB1. We performed an association study by applying the transmission disequilibrium test to detect possible association of these variants to autism in 110 multiplex families. Our results demonstrated no deviation from the null hypothesis of no association. We have also separately examined transmissions within individual mating types, for paternal versus maternal alleles, to affected versus unaffected children, and for transmission to affected boys versus girls. None of these subsets revealed significant deviation from the null expectation. Our interpretation of these findings is that it is unlikely that HoxA1 and HoxB1 play a significant role in the genetic predisposition to autism.

Emotional attribution in high-functioning individuals with autistic spectrum disorder: a functional imaging study.

OBJECTIVE: To determine whether expertise in the attribution of emotion from basic facial expressions in high-functioning individuals with autistic spectrum disorder (ASD) is supported by the amygdala, fusiform, and prefrontal regions of interest (ROI) and is comparable to that of typically developing individuals. METHOD: Functional magnetic resonance imaging scans were acquired from 14 males with ASD and 10 matched adolescent controls while performing emotion match (EM) (perceptual), emotion label (EL) (linguistic), and control tasks. Accuracy, response time, and average activation were measured for each ROI. RESULTS: There was no significant difference in accuracy, response time, or ROI activation between groups performing the EL task. The ASD group was as accurate as the control group performing the EM task but had a significantly longer response time and lower average fusiform activation. CONCLUSIONS: Expertise in the attribution of emotion from basic facial expressions was task-dependent in the high-functioning ASD group. The hypothesis that the high-functioning ASD group would be less expert and would have reduced fusiform activation was supported in the perceptual task but not the linguistic task. The reduced fusiform activation in the perceptual task was not explained by reduced expertise; it is therefore concluded that reduced fusiform activation is associated with the diagnosis of ASD.

Pseudologia Fantastica associated with Pervasive Developmental Disorder.

This case study describes the association of Pseudologia Fantastica (PF) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) in a 14-year-old girl. PF is seen in a number of diagnostic entities, but has not previously been reported in PDD spectrum disorders. Treatment implications are discussed along with a formulation of the psychological and cognitive functions of PF in a person with a PDD diagnosis.

Prenatal and perinatal risk factors in a twin study of autism spectrum disorders.

INTRODUCTION: Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently. METHODS: Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed. RESULTS: Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74). CONCLUSIONS: Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

Head circumferences in twins with and without Autism Spectrum Disorders.

To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20 % of males and 27 % of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16 % of males and 22 % of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.

Genetic heritability and shared environmental factors among twin pairs with autism.

CONTEXT: Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. OBJECTIVE: To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. DESIGN, SETTING, AND PARTICIPANTS: Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services. MAIN OUTCOME MEASURES: Structured diagnostic assessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD). RESULTS: For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD). CONCLUSION: Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

Similar white matter aberrations in children with autism and their unaffected siblings: a diffusion tensor imaging study using tract-based spatial statistics.

CONTEXT: Autism is a neurobiological condition with a strong genetic component. Recent diffusion tensor imaging (DTI) studies have indicated that white matter structure is aberrant in autism. To date, white matter structure has not been assessed in family members of children with autism. OBJECTIVE: To determine whether white matter structure is aberrant in children with autism and their unaffected siblings compared with controls, and to test the hypothesis that white matter structure in autism is correlated with autism spectrum symptomatology. DESIGN: Cross-sectional, case-control, voxel-based, whole-brain DTI analysis using Tract-Based Spatial Statistics. SETTING: University research center. Patients  A sample of 37 children: 13 subjects with autism, 13 of their unaffected siblings, and 11 controls. Controls were age- and intelligence quotient-matched to the unaffected siblings; all groups were age matched. Main Outcome Measure  Fractional anisotropy (FA) and axial and radial diffusivities. In addition, behavioral correlation analyses were conducted using the Autism Diagnostic Interview and Autism Diagnostic Observation Schedule subscales and FA values, as well as axial diffusivity values in the autism group. RESULTS: Compared with the control group, both the autism and sibling groups had widespread, significantly reduced white matter FA values (P ≤ .05, corrected) in the frontal parietal and temporal lobes and included, but were not restricted to, regions known to be important for social cognition. Within regions of reduced FA, significant reductions in axial diffusivity, but not radial diffusivity, were observed. There were no significant differences in white matter structure between the autism and sibling groups. There were no significant correlations between autism symptomatology and white matter FA or axial diffusivity. CONCLUSIONS: Our findings suggest that white matter structure may represent a marker of genetic risk for autism or vulnerability to development of this disorder.

A comparison of health care utilization and costs of children with and without autism spectrum disorders in a large group-model health plan.

OBJECTIVE: Data on the current costs of medical services for children with autism spectrum disorders are lacking. Our purpose for this study was to compare health care utilization and costs of children with and without autism spectrum disorders in the same health plan. PATIENTS AND METHODS: Participants included all 2- to 18-year-old children with autism spectrum disorders (n = 3053) and a random sample of children without autism spectrum disorders (n = 30529) who were continuously enrolled in the Kaiser Permanente Medical Care Program in northern California between July 1, 2003, and June 30, 2004. Data on health care utilization and costs were derived from health plan administrative databases. MAIN OUTCOME MEASURES: Outcome measures included mean annual utilization and costs of health services per child. RESULTS: Children with autism spectrum disorders had a higher annual mean number of total clinic (5.6 vs 2.8), pediatric (2.3 vs 1.6), and psychiatric (2.2 vs 0.3) outpatient visits. A higher percentage of children with autism spectrum disorders experienced inpatient (3% vs 1%) and outpatient (5% vs 2%) hospitalizations. Children with autism spectrum disorders were nearly 9 times more likely to use psychotherapeutic medications and twice as likely to use gastrointestinal agents than children without autism spectrum disorders. Mean annual member costs for hospitalizations (550 dollars vs 208 dollars), clinic visits (1373 dollars vs 540 dollars), and prescription medications (724 dollars vs 96 dollars) were more than double for children with autism spectrum disorders compared with children without autism spectrum disorders. The mean annual age- and gender-adjusted total cost per member was more than threefold higher for children with autism spectrum disorders (2757 dollars vs 892 dollars). Among the subgroup of children with other psychiatric conditions, total mean annual costs were 45% higher for children with autism spectrum disorders compared with children without autism spectrum disorders; excess costs were largely explained by the increased use of psychotherapeutic medications. CONCLUSIONS: The utilization and costs of health care are substantially higher for children with autism spectrum disorders compared with children without autism spectrum disorders. Research is needed to evaluate the impact of improvements in the management of children with autism spectrum disorders on health care utilization and costs.

Voxel-based morphometry elucidates structural neuroanatomy of high-functioning autism and Asperger syndrome.

Efforts to examine the structural neuroanatomy of autism by using traditional methods of imaging analysis have led to variable findings, often based on methodological differences in image acquisition and analysis. A voxel-based computational method of whole-brain anatomy allows examination of small patterns of tissue differences between groups. High-resolution structural magnetic resonance images were acquired for nine males with high-functioning autism (HFA; mean age 14y [SD3y 4mo]), 11 with Asperger syndrome (ASP; mean age 13y 6mo [SD2y 5mo]), and 13 comparison (COM) participants (mean age 13y 7mo [SD 3y 1mo]). Using statistical parametric mapping, we examined contrasts of gray matter differences between the groups. Males with HFA and ASP had a pattern of decreased gray matter density in the ventromedial regions of the temporal cortex in comparison with males from an age-matched comparison group. Examining contrasts revealed that the COM group had increased gray matter density compared with the ASP or combined HFA and ASP group in the right inferior temporal gyrus, entorhinal cortex, and rostral fusiform gyrus. The ASP group had less gray matter density in the body of the cingulate gyrus in comparison with either the COM or HFA group. The findings of decreased gray matter density in ventromedial aspects of the temporal cortex in individuals with HFA and ASP lends support to theories suggesting an involvement of these areas in the pathophysiology of autism, particularly in the integration of visual stimuli and affective information.

Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.

Autism is a pervasive neurodevelopmental disorder characterized by deficits in language development and social interaction, as well as stereotypical, repetitive behaviors. The etiology of autism is largely unknown. Family and twin studies have provided compelling evidence for a strong genetic component in most idiopathic cases. Several recent candidate gene studies have suggested that alleles of WNT2 and the reelin gene (RELN), two genes involved in distinct aspects of neurodevelopment, confer greater susceptibility to autism. We screened WNT2 for DNA polymorphisms by sequencing all exons and adjacent intronic regions in 24 autistic patients, and identified not only the WNT2 variants reported previously (two common single-nucleotide polymorphisms (SNPs) in the 5' upstream region and the 3' untranslated region (UTR), respectively), but also two new SNPs in its 3' UTR. We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT). Our results revealed no deviation from the null hypothesis of no association. Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism.