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Scientific Abstract from:
Fred Volkmar, M.D.
Yale University
Neurobiology and Genetics of Autism & Related Conditions

Project I: Molecular Genetics

Project Principal Investigator: Edwin H. Cook, M.D.
Site Principal Investigators: Matthew State, M.D., and Christina CorselloM
Co-Investigators: Catherine Lord, Ph.D., Bennett Leventhal, M.D., Thomas Owley, M.D., Kathleen Koenig, M.S., and Jeff Salt, Psy.D.

Autism is a severe developmental disorder afflicting about 1-2 per 1,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, limited fine mapping strategies will be employed in following up genome-wide linkage findings.

The goals of this project continue to be to localize disease genes in autism through a systematic genome search, fine mapping, and candidate gene analysis. In a multi-site, international collaborative effort, 425 families with affected relative pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype and additional 100 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 100 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this IMGSAC international collaborative effort, susceptibility genes can be identified in approximately 425 pairs. In addition, fine mapping studies will be performed in regions of interest, beginning with typing of thirty SNPs in the serotonin transporter gene (SLC6A4) region of interest from IMGSAC genome-wide scan in 250 trios consisting of a randomly chosen case type I from an IMGSAC family and their parents. The transmission disequilibrium test will then be performed, as well as Decay of Haplotype Sharing analysis. This project will continue to be actively involved in CPEA network-wide association analyses.

Project II: Family Genetics of Autism & Asperger Syndrome Project

Principal Investigator: David Pauls, Ph.D
Site Principal Investigators: Elena Grigorenko, Ph.D., and Edwin Cook, M.D.
Co-Investigators: Tammy Babitz, M.A., Sandra DeJong, Jean Frazier, Daniel Geller, Jeff Salt, Psy.D., and Robert Schultz, Ph.D.

No description available at this time.

Project III: Neuroimaging studies of autism spectrum disorders

Principal Investigator: Robert T. Schultz, Ph.D.
Co-Investigators: Adam Anderson, Ph.D., Lawrence Staib, Ph.D., and Richard Bronen, M.D.

Autism spectrum disorders (ASDs) affect multiple functional systems, including reciprocal social behavior, communication and behavioral regulation. This suggests that multiple brain systems are involved in their pathobiology. This project will use high resolution structural MRI and diffusion tensor imaging (DTI) on participants recruited through the Family Genetics study (Project 2) in order to test several current hypotheses about neural systems affected by ASDs. Our preliminary studies show significant brain volume increases, as well as some regionally specific increases and decreases in ASDs. The literature in these areas is not always consistent, and it seems likely that heterogeneity due to ASD subtypes contributes to uncertainty in this area. By adding to our already large, well characterized sample, we will be in good position to stratify subjects along more informative dimensions, which may involve use of Family Genetics data.

We rely heavily on results from our ongoing fMRI studies to guide our selection of brain regions for morphometric analyses. DTI will be used to test the integrity of cerebral white matter. Recent studies have suggested that white matter abnormalities may figure prominently in the pathobiology of the ASDs. We propose to collect MRI data on 120 persons with an ASD, and 50 controls, yielding a combined total of 95 persons with high functioning autism (HFA), 95 persons with Asperger syndrome (AS) and 30 persons with PDD NOS to test the following hypotheses:

  • Brain volume is increased in persons with an ASD
  • Cerebral white matter volume is increased in persons with an ASD
  • Fractional anisotropy is reduced throughout the cerebral white matter, and at boundaries to key gray matter nodes in our model of the social brain
  • Cross sectional area and fractional anisotropy of the genu and splenium of the corpus callosum is reduced in persons with an ASD, and
  • The gray matter volume of specific areas of the medial prefrontal cortex, fusiform gyrus, superior temporal sulcus and the amygdala are significantly altered in persons with an ASD.

Project IV

Project Principal Investigator: Catherine Lord, Ph.D.
Site Principal Investigator: Katarzyna Chawarska, Ph.D.
Co-Investigators: Edwin Cook, M.D., and Ami Klin, Ph.D.

Longitudinal studies continue research began on two cohorts, from North Carolina and from Chicago, of two year-olds referred for possible autism over 10 years ago. These children, as well as a cohort of children with developmental disabilities but not autism, have been followed with regular comprehensive assessments at ages two, three, five and nine years of age. The focus for the present project is on frequent assessment of behavior problems, puberty and epilepsy status as the children grow from ages 11 to 13 to 16 to 18. After an initial intake interview, including the Vineland Adaptive Behavior Scales and the Social Communication Questionnaire, parents and teachers complete Aberrant Behavior Checklists, measures of pubertal status, medications and descriptions of seizures three times a year. The purpose is to investigate which children, in a sample ascertained independently of epilepsy status, develop seizures and whether there are changes in behavior or adaptive functioning that either precede or follow the development of seizures. To date, 5 out of 151 children with ASD whose parents are participating in the study have developed adolescent onset of seizures in the first year and half of the study. In addition, the plan of the project included detailed maternal interviews around the time of the child's fourteenth birthday to assess the effect of having the child with ASD on the family and the relationship of family functioning to earlier characteristics of the child and family. A third component of the longitudinal study is Yale's follow up of children seen in their early clinic at age two. A paper has been submitted describing the first stage of this follow up with very similar results to follow up of the North Carolina and Chicago samples.

Regression Studies

Principal Investigator: Catherine Lord, Ph.D.
Site Principal Investigators from each CPEA site

The regression studies have focused on three issues: description of the phenomenology of early regression in children with ASD, using regression as a predictor of outcome in diagnosis and ability in ASD, and evaluating the relationship between regression and medical factors, including vaccination status, seizures and optimality of pregnancy and birth. Participants were recruited for phone interviews by identifying all children in any of the CPEA sites whose parents reported a loss of words during the parent interview (ADI-R) conducted at entry into the site's research projects. A sample of children with ASD whose parents had not reported loss of words was recruited from each site to be equivalent in age, gender, race and maternal education. Using data from the detailed phone interview, a clear pattern of regression occurred. This pattern included acquisition of 3 -10 words usually at about 12 months of age, followed by a plateau in word learning for several months, at which time (usually between 16 - 19 months), the child stopped talking completely. Other social -communication behaviors also changed near that time, including loss of eye contact, responsive social smile and failure to respond to speech. About 20 percent of children who did not lose words, showed a pattern of loss of social communication skills very similar to those who did lose words. By age 9 or 10, few characteristics differentiated children with and without regression, though children with regression showed slightly lower verbal IQs, than the other children. Children with regression were more likely to be described by their parents as having a history of diarrhea and were more likely to have a maternal history of thyroid disorder. Parents were generally quite consistent in their reports of regression when early interview data was compared to later telephone interview data, though forward telescoping (remembering events as occurring closer to the present than originally reported) was evident. A paper describing the relationship between regression and vaccinations has been submitted for publication.

Last Updated Date: 11/30/2012
Last Reviewed Date: 11/30/2012
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