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1.  Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders 
Structural neuroimaging studies in autism report atypical volume in deep brain structures which are related to symptomatology. Little is known about metabolic changes in these regions, and how they vary with age and sex, and/or relate to clinical behaviors. Using magnetic resonance spectroscopy we measured N-acetylaspartate, choline, creatine, myoinositol and glutamate in the caudate, putamen, and thalamus of 20 children with autism and 16 typically developing controls (7–18 years). Relative to controls, individuals with autism had elevated glutamate/creatine in the putamen. In addition, both groups showed age-related increases in glutamate in this region. Boys, relative to girls had increased choline/creatine in the thalamus. Lastly, there were correlations between glutamate, choline, and myoinositol in all three regions, and behavioral scores in the ASD group. These findings suggest changes in deep gray matter neurochemistry, which are sensitive to diagnosis, age and sex, and are associated with behavioral differences.
PMCID: PMC3897261  PMID: 24459534
Magnetic resonance spectroscopy; Autism spectrum disorders; Deep gray matter; Caudate nucleus; Putamen; Thalamus and social cognition
2.  Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency 
Molecular Autism  2013;4:18.
22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.
A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.
Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.
This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.
PMCID: PMC3707861  PMID: 23758760
22q13 deletion syndrome; Autism; Microarrays; Mutation; Phelan-McDermid syndrome; SHANK3
3.  Effects of age and symptomatology on cortical thickness in autism spectrum disorders 
Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with ASD, between the ages of 7 and 39 years in comparison to typically developing controls. Additionally, we examined differences in cortical thickness in relation to symptomatology in the ASD group, and their association with age. Analyses were conducted using a general linear model, controlling for sex. Social and communication scores from the Autism Diagnostic Interview-Revised (ADI-R) were correlated with the thickness of regions implicated in those functions. Controls showed widespread cortical thinning relative to the ASD group. Within regions-of-interest, increased thickness in the rostral anterior cingulate cortex was associated with poorer social scores. Additionally, a significant interaction between age and social impairment was found in the orbitofrontal cortex, with more impaired younger children having decreased thickness in this region. These results suggest that differential neurodevelopmental trajectories are present in individuals with ASD and some differences are associated with diagnostic behaviours.
PMCID: PMC3652338  PMID: 23678367
Autism spectrum disorders; Structural MRI; Cortical thickness; Social impairment; Developmental changes
4.  Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial 
Molecular Autism  2012;3:16.
There are no effective medications for the treatment of social cognition/function deficits in autism spectrum disorder (ASD), and adult intervention literature in this area is sparse. Emerging data from animal models and genetic association studies as well as early, single-dose intervention studies suggest that the oxytocin system may be a potential therapeutic target for social cognition/function deficits in ASD. The primary aim of this study was to examine the safety/therapeutic effects of intranasal oxytocin versus placebo in adults with ASD, with respect to the two core symptom domains of social cognition/functioning and repetitive behaviors.
This was a pilot, randomized, double-blind, placebo-controlled, parallel design trial of intranasal oxytocin versus placebo in 19 adults with ASD (16 males; 33.20 ± 13.29 years). Subjects were randomized to 24 IU intranasal oxytocin or placebo in the morning and afternoon for 6 weeks. Measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised) were administered. Secondary measures included the Social Responsiveness Scale, Reading-the-Mind-in-the-Eyes Test and the Yale Brown Obsessive Compulsive Scale – compulsion subscale and quality of life (World Health Organization Quality of Life Questionnaire – emotional/social subscales). Full-information maximum-likelihood parameter estimates were obtained and tested using mixed-effects regression analyses.
Although no significant changes were detected in the primary outcome measures after correcting for baseline differences, results suggested improvements after 6 weeks in measures of social cognition (Reading-the-Mind-in-the-Eyes Test, p = 0.002, d = 1.2), and quality of life (World Health Organization Quality of Life Questionnaire – emotion, p = 0.031, d = 0.84), both secondary measures. Oxytocin was well tolerated and no serious adverse effects were reported.
This pilot study suggests that there is therapeutic potential to daily administration of intranasal oxytocin in adults with ASD and that larger and longer studies are warranted.
Trial registration
PMCID: PMC3539865  PMID: 23216716
Autism; Adults; Oxytocin; Clinical trial; Social cognition
5.  Functional deficits of the attentional networks in autism 
Brain and Behavior  2012;2(5):647-660.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
PMCID: PMC3489817  PMID: 23139910
Alerting; anterior cingulate cortex; attentional networks; autism; executive control
6.  Endocrine Disruptors and Childhood Social Impairment 
Neurotoxicology  2010;32(2):261-267.
Prenatal exposure to endocrine disruptors has the potential to impact early brain development. Neurodevelopmental toxicity in utero may manifest as psychosocial deficits later in childhood. This study investigates prenatal exposure to two ubiquitous endocrine disruptors, the phthalate esters and bisphenol A (BPA), and social behavior in a sample of adolescent inner-city children. Third trimester urines of women enrolled in the Mount Sinai Children's Environmental Health Study between 1998 and 2002 (n = 404) were analyzed for phthalate metabolites and BPA. Mother-child pairs were asked to return for a follow-up assessment when the child was between the ages of 7 to 9 years. At this visit, mothers completed the Social Responsiveness Scale (SRS) (n = 137), a quantitative scale for measuring the severity of social impairment related to Autistic Spectrum Disorders (ASD) in the general population. In adjusted general linear models increasing log-transformed low molecular weight phthalate (LMW) metabolite concentrations were associated with greater social deficits (β = 1.53, 95% CI 0.25-2.8). Among the subscales, LMWP were also associated with poorer Social Cognition (β = 1.40, 95% CI 0.1-2.7); Social Communication (β = 1.86, 95% CI 0.5-3.2) and Social Awareness (β = 1.25, 95% CI 0.1-2.4), but not for Autistic Mannerisms or Social Motivation. No significant association with BPA was found (β = 1.18, 95% CI: -0.75, 3.11). Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. Even mild degrees of impaired social functioning in otherwise healthy individuals can have very important adverse effects over a child's lifetime. These results extend our previous finding of atypical neonatal and early childhood behaviors in relation to prenatal phthalate exposure.
PMCID: PMC3057338  PMID: 21182865
Endocrine Disruptors; Phthalates; BPA; SRS; Autism Spectrum Disorder; Environmental Exposure
7.  Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study 
PLoS ONE  2011;6(11):e28044.
Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.
Methods/Principal Findings
DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.
Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.
PMCID: PMC3223195  PMID: 22132206
8.  Divalproex Sodium vs Placebo for the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorders 
Neuropsychopharmacology  2009;35(4):990-998.
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46±2.46, mean nonverbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.
PMCID: PMC2846602  PMID: 20010551
ASD; irritability; divalproex; children; adolescents; Development/Developmental Disorders; Psychiatry & Behavioral Sciences; Psychopharmacology; Clinical Pharmacology/Trials; autism; adolescents; children; EEG; divalproex
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and repetitive behaviors and interests. Irritability/aggression is a significant co-morbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability / aggression in children and adolescents with ASD.
This was a 12 week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. Fifty five subjects signed consent and 27 were randomized in a 1:1 fashion (mean age 9.46±2.46, mean non verbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study due to either lack of efficacy or side effects (increased irritability).
The primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, focused on irritability. 62.5% of divalproex subjects vs. 9% of placebo subjects were responders (CGI-irritability OR:16.7, Fisher’s exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for the responders to have higher valproate blood levels than the non-responders.
This study suggests efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.
PMCID: PMC2846602  PMID: 20010551
ASD; irritability; divalproex; children; adolescents
10.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. 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.
PMCID: PMC2925224  PMID: 19404257
11.  Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT 
BMC Medical Genomics  2008;1:50.
It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.
In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.
MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).
MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.
PMCID: PMC2588447  PMID: 18925931

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