Lay abstracts

Male Predominance in Autism: Neuroendocrine Influences on Arousal and Social Anxiety

Donald W. Pfaff, Isabelle Rapin, and Sylvie Goldman


The fact that there are so many more boys than girls with autism spectrum disorders (autism for short) is well documented but not well understood. We propose that a reason for this sex-linked difference is that higher levels of the male hormone testosterone boost brain arousal in boys. The amygdala is a brain nucleus concerned with responding most effectively to perceived dangers. Perceived dangers arouse fear or anxiety and in animals bring about “flight or fight” responses. When male mice pups are exposed before birth or soon thereafter to a variety of stresses, this sensitizes testosterone-responsive neurons in their brainstem responsible for brain arousal. The consequence is increased excitation of the amygdala and intensification of anxiety and social avoidance. Female pups are not exposed to high levels of testosterone and, further, the neuropeptide oxytocin and female estrogenic hormones protect them better than males from stress-induced excessive excitation of the amygdala and brainstem arousal neurons. We anticipate that similar neuroendocrine mechanisms to those in mice will contribute to explaining the male predominance and core social deficits of the autism spectrum disorders. We propose that parallel behavioral, neurologic, and endocrine studies in young children and animals will help determine whether this sex-linked theory attempting to explain the social avoidance and anxiety characteristic of the autism spectrum is correct. If it is, it will help our understanding of why so many more boys than girls have autism, and may open up some new avenues for treatment. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 163–176. DOI: 10.1002/aur.191

Phonology and Vocal Behavior in Toddlers with Autism Spectrum Disorders

Elizabeth Schoen, Rhea Paul, and Katarzyna Chawarska


The acquisition of spoken language is a strong predictor of the ability to function independently. The ability to vocalize, more specifically produce consonants, is an important step preceding spoken language. This study examined the vocal production of toddlers, 18–36 months, with autism spectrum disorder (ASD) and compared their vocalizations to those of children with typical development. Speech samples were collected during play sessions from 30 toddlers with ASD, 11 typically developing toddlers who were similar in age and 23 typically developing toddlers who had similar expressive language skills. Vocalizations were examined for consonants, consonant-vowel combinations, whines, cries, screams and yells. Toddlers with ASD produced consonants and consonant-vowel combinations similar to those of toddlers with similar spoken language skills, but produced significantly more screams when compared to both typically developing groups. The findings of this study suggest that toddlers with ASD show speech-like sound production (e.g., consonant production) that is linked to their language level, in a manner similar to that seen in typical development. The main area of difference in vocal development in this population is in the production of screams. These findings suggest that toddlers with ASD continue to produce screams even when they have consonants and other speech-like vocalizations within their vocalization repertoire. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 177–188. DOI: 10.1002/aur.183

Contactin 4 as an Autism Susceptibility Locus

Catherine E. Cottrell, Natalie Bir, Elizabeth Varga, Carlos E. Alvarez, Samuel Bouyain, Randall Zernzach, Devon L. Thrush, Johnna Evans, Michael Trimarchi, Eric M. Butter, David Cunningham, Julie M. Gastier-Foster, Kim McBride, and Gail E. Herman


We found a small piece of missing genetic material located at chromosome position 3p26.3 in a boy with autism. The missing material included the beginning of a gene called contactin 4 (CNTN4). Other members of this gene family may be involved in causing autism or related disorders. To try to gather more evidence whether CNTN4 may also be a contributing cause of autism, we sequenced coding portions of the gene in 75 autism families and 107 adult controls and compared the results. We found 4 changes in the gene and protein sequence in the autism families and a single different change in one control. Additional, larger studies will be needed to confirm whether the CNTN4 protein contributes to the genetic causes of autism in a small number of families. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 189–199. DOI: 10.1002/aur.184

Altered Posterior Cingulate Cortical Cyctoarchitecture, But Normal Density of Neurons and Interneurons in the Posterior Cingulate Cortex and Fusiform Gyrus in Autism

Adrian L. Oblak, Douglas L. Rosene, Thomas L. Kemper, Margaret L. Bauman, and Gene J. Blatt


Autism is a behaviorally defined disorder with increasing prevalence rates globally. The disorder is characterized by deficits in several domains including social behaviors, restricted and repetitive behaviors, and deficits in communication. Two regions thought to contribute to deficits in social behavior are the posterior cingulate cortex (PCC) and fusiform gyrus (FFG). The PCC is involved in processing emotionally salient stimuli, and also has a role in processing faces. The FFG is the area responsible for object and face recognition. A potential imbalance between excitatory and inhibitory processing in the brain may contribute to some of the abnormal social behaviors observed in autism. This is supported by previous work suggesting reduced GABA receptors in the autistic brain. The present study used thionin stained section to qualitatively assess cortical patterning and quantitatively assess the density of neurons. Furthermore, immunohistochemistry was used to determine the density of a subset of GABAergic interneurons. In the autistic brain, the PCC displayed several abnormal cortical patterns including irregularly distributed neurons in specific cortical layers, and the presence of increased white matter neurons. In marked contrast, the FFG appeared normal and there were no significant differences in the density of neurons or interneurons in either region. The present study highlights the presence of abnormal findings in the PCC, which appear to have developmental origins and could affect local processing of social-emotional behaviors as well as the function of interrelated cortical areas. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 200–211. DOI: 10.1002/aur.188

Basal Ganglia Morphometry and Repetitive Behavior in Young Children with Autism Spectrum Disorder

Annette Estes, Dennis W.W. Shaw, Bobbi F. Sparks, Seth Friedman, Jay N. Giedd, Geraldine Dawson, Matthew Bryan, and Stephen R. Dager


We investigated repetitive and stereotyped behavior (RSB) in 3–4 year old children with autism spectrum disorder (ASD; n=77) and developmental delay without autism (DD; n=34). We then asked whether RSB was associated with the volume of brain regions called the basal ganglia and thalami. Children were assessed for RSB through clinical evaluation and parent report using RSB-specific scales extracted from the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview, and the Aberrant Behavior Checklist. A subset of children with ASD (n=45), DD (n=14) and a group of children with typical development (TD; n=25) were also assessed by magnetic resonance imaging (MRI) to measure brain volumes. Children with ASD demonstrated elevated RSB compared to children with DD. They also demonstrated enlargement of some of the brain regions of interest relative to the TD group. However, these regions were not significantly enlarged after taking into account overall cerebral volume. The DD group tended to demonstrate smaller thalami and basal ganglia regions even when accounting for cerebral volume. Elevated RSB, as measured by the ADOS, was associated with decreased volumes in several of the brain regions we measured within the ASD group. These results confirm earlier reports that RSB is common early in the clinical course of ASD and, furthermore, demonstrate that such behaviors may be associated with decreased volumes of the basal ganglia and thalamus. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 212–220. DOI: 10.1002/aur.193

A De Novo 1.5 Mb Microdeletion on Chromosome 14q23.2–23.3 in a Patient with Autism and Spherocytosis

Anthony J. Griswold, Deqiong Ma, Stephanie J. Sacharow, Joycelyn L. Robinson, James M. Jaworski, Harry H. Wright, Ruth K. Abramson, Helle Lybæk, Nina Øyen, Michael L. Cuccaro, John R. Gilbert, and Margaret A. Pericak-Vance


Previous research has suggested that genetics play an important role in leading to autism. For several reasons, it has been difficult to determine which specific genes are involved. Recent advances in technology have allowed us to examine DNA at a much better resolution, revealing new potential genetic regions, that may be involved in various diseases. One type of genetic change, which contributes to the genetic basis for the disorder including, is deletion or addition of extra genetic material, known as copy number variation. Our study has identified a large deletion of about 1.5 million DNA base pairs on chromosome 14 in a boy with autism. The region contains 15 genes and among these are at least three could contribute to autism risk based on their role in brain function. This study demonstrates the importance of identifying copy number variations in autism and identifies a new region and at least three specific genes that might contribute to the genetic cause of autism. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 221–227. DOI: 10.1002/aur.186

Fine Mapping of Xq11.1–q21.33 and Mutation Screening of RPS6KA6, ZNF711, ACSL4, DLG3 and IL1RAPL2 for Autism Spectrum Disorders (ASD)

Katri Kantojärvi, Ilona Kotala, Karola Rehnström, Tero Ylisaukko-oja, Raija Vanhala, Taina Nieminen von Wendt, Lennart von Wendt, and Irma Järvelä


The prevalence of autism spectrum disorders (ASD) and X-linked mental retardation both show higher prevalence in males compared to females. About 80% of cases in autism express intellectual disability. To date, some common genes for ASD and X-linked mental retardation (XLMR) without autism have been identified suggesting a common genetic background. In the genome wide scan of Finnish ASD families suggestive evidence for a predisposing locus was found residing close to marker DXS7132 at Xq11.1, in the vicinity of the neuroligin 3 (NLGN3) gene, mutated in ASD. Further analysis of the region flanking NLGN3 showed that the region of interest is located somewhat distally nearby DXS7117. Fine-mapping of the region in 99 Finnish families with ASD using 11 microsatellite markers confirmed the previous results and assigned the most likely locus to DXS1225 on Xq21.1. The region contains many candidate genes for ASD. Of them we sequenced the coding regions and the splice sites of five relevant candidate genes: RPS6KA6 and ZNF711 residing at the peak region as well as ACSL4 and DLG3 previously known to cause XLMR and IL1RAPL2, a homologous gene for IL1RAPL1 that causes XLMR and autism. Six novel and 11 known SNPs were identified; none of them functionally significant. © 2011 INSAR/Wiley Periodicals, Inc.

Article Citation:Autism Res2011, 4: 228–233. DOI: 10.1002/aur.187