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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 Foundation (IRSF)
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.