Autism and Rett Syndrome
Introduction
Autism and Rett Syndrome are devastating, lifelong neurological disorders that are classified as pervasive developmental disorders (sometimes abbreviated PDD). Autism and Rett Syndrome are characterized clinically by severe, pervasive impairment in communication skills and in reciprocal social interaction skills. Stereotyped behavior and interests are typical. In many cases, autism and Rett Syndrome are accompanied by mental retardation as well as seizures. These disorders cause significant hardships for the affected children and adults, as well as their families, schools and communities.
Today, the diagnosis of autism and related pervasive developmental disorders such as Asperger's Syndrome is based upon clinical criteria. There are no known biological causes. There are very few proven neurochemical, genetic, neuroanatomical, neurophysiological, structural, metabolic, or other molecular differences between these patients and the normal population.
Autism: what is known
Autism was first described in the 1940s by Leo Kanner of Johns Hopkins. It is characterized by a triad of deficits: (1) an individual's failure to have normal reciprocal social interactions, (2) impaired language or communication skills, and (3) restricted, stereotyped patterns of interests and activities. Some autistic children appear to develop normally but then undergo a period of regression in language skills between 18 and 24 months of age. 75% of autistic individuals have mental retardation. The prevalence of autism has been estimated to be from 1:500 to 1:2,000 individuals.
The cause of autism is unknown, but the disorder is clearly genetic. The concordance between monozygotic twins is 60%, and >90% if coaffected twins are defined as having classically defined autism or more generalized impairments in social skills, language, and cognition. Most genetic linkage studies have not resulted in the identification of genes that are significantly associated with autism, although the long arm of chromosome 15 has been implicated.
Some autism web links:
National Alliance for Autism Research (NAAR)
National Autistic Society (NAS)(includes many autism-related links)
Rett Syndrome: Background
Rett Syndrome affects girls almost exclusively. The diagnosis is based upon clinical criteria including deceleration of head growth during development, loss of purposeful hand movements, development of severely impaired language, and sterotyped movements. Twin studies suggest that the cause is genetic, and linkage studies implicated the X chromosome.
In October 1999, Huda Zoghbi and colleagues discovered that mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) cause some cases of Rett Syndrome. MeCP2 is a transcriptional repressor, and mutations in this gene could allow many other genes to be inappropriately overexpressed.
Some Rett Syndrome web links:
International Rett Syndrome Association (IRSA)
Rett Syndrome 101 (by J. Pevsner) at IRSA's site
Rett Syndrome Research Foundation (RSRF)
The Great Mississippi River Race for Rett Syndrome
Our lab's approaches to Autism and Rett Syndrome
We focus our studies on postmortem human brains to study autism, Rett Syndrome, and control brains. Unfortunately, sometimes people die (for example in a car accident or from an illness), and the brains are donated to science. We obtain brain samples from brain banks, including diseased samples and controls that are matched for gender, age, and brain region. We then ask the question "what is different between the autistic and Rett Syndrome brains relative to controls?" We measure changes in gene expression using the technique of high density cDNA microarrays.
There are thought to be about 35,000 human genes, and they are expressed in specific regions of the body and at specific times in development. Many genes are dynamically regulated in response to changes in the environment. Thus, the postmortem brain samples contain a complex mixture of tens of thousands of distinct mRNAs (expressed genes). We are identifying genes that are consistently up- or down-regulated in autistic and/or Rett Syndrome brains.
Once abnormally regulated genes are identified, we confirm these changes with a variety of tests. The identification of regulated genes may be useful in two ways. (1) We may develop a diagnostic test for autism. (2) The genes that are abnormally regulated may indicate a biochemical pathway that has been perturbed, suggesting an approach for therapeutic intervention.