From Duke University Medical Center
Duke study finds link between patients with autistic disorder and patients with Rett syndrome mutations
DURHAM, N.C. – A new genetic study, conducted by Duke University Medical Center researchers, has shown that two similar neurodevelopmental disorders – Rett disorder (RD) and autism – once considered to be clinically distinct, may not be as different as previously believed.
The researchers' findings suggest that female patients who have been diagnosed with autism should be considered for genetic screening to detect the presence of a mutation in the MeCP2 gene, which is known to cause RD.
Both disorders are considered pervasive developmental disorders and, while both share many clinical similarities, RD is characterized by an smaller-than-normal head size (microcephaly) and loss of ability to control ones' hands. Generally, RD, which overwhelmingly strikes girls, is a progressive disease that ultimately leads to severe mental retardation by early adulthood; autism's symptoms tend to be more diffuse and not as progressive.
"Screening patients with autistic disorder for the MeCP2 gene, especially the girls, could help us better classify the patients and may give clues to long-term prognosis in the disease," said Margaret Pericak-Vance, director of Duke's Center for Human Genetics (CHG) who together with John Gilbert and Dr. Jeffery M. Vance are the lead researchers on the project. With its collaborators, the CHG runs one of the largest programs aimed at unlocking the genetic basis of autism.
This finding will help genetic researchers better understand the underlying causes of autism or RD, which, over time, could lead to new insights into both disorders.
While it is known that there are many complex genetic roots to autism, the genetics of RD are comparatively simpler – more than 80 percent of patients diagnosed with RD have a specific mutation in the MeCP2 gene on the X chromosome. This mutation is not inherited, but occurs after conception.
In their study, the Duke researchers analyzed 69 girls who had been diagnosed with autism, but who showed none of the classical clinical signs of RD. They found that two had mutations in the MeCP2 gene.
The results of the team's study were presented Friday at the International Congress of Human Genetics in Vienna.
In 1999, a team of researchers from Baylor College of Medicine demonstrated that a mutation in the MeCP2 (methyl-CpG-binding protein 2) gene on the X chromosome caused RD. This explains why RD almost always affects only females. Females have two copies of the X chromosome, but only one normally remains functional in each cell. Which copy remains working is random, the researchers say, so in RD females enough normal X chromosomes remain working to support life, but the presence of the abnormal RD containing X chromosome in the rest of the cells causes the disease.
Males, on the other hand, have only one copy of the X chromosome. Therefore, boys with the RD-containing X chromosome have no normal chromosome present and die before or shortly after birth, they said.
While the role of the MeCP2 gene is still seen as crucial to the development of RD, and maybe autism, new findings have muddied the scientific waters.
"In the past year or so, milder cases of RD have been found as well as males with a mutation in the MeCP2gene," Pericak-Vance said. "This leads us to the question of what exactly is Rett disorder?
"Based on clinical descriptions, we find patients who look like they have RD, but don't have MeCP2 mutations; and we can find patients without the classical clinical signs of RD who do have MeCP2 mutations," she continued. "However, we're finding this occurs more and more as we get in to the genetic roots of different diseases – what we see clinically isn't always as straightforward once we understand the underlying genetics of a disorder."
RD is the most common cause of mental retardation in females, with an incidence of about 1 in every 10,000 to 15,000. Children usually appear normal through the ages of 6 to18 months, then start exhibiting such behaviors as repetitive hand movements, body rocking, prolonged toe walking and sleep disorders.
Autism is a complex disease that affects two to 10 per 10,000 people, making it the third most common developmental disability – almost as common as Down syndrome. But because of the broad differences in severity of the disease, doctors have difficulty diagnosing it with certainty. Some children simply talk later than normal, while others have severe withdrawal and self-destructive patterns of repetitive head banging and difficulty sleeping or other manifestations.
Joining CHG investigators in the study were researchers from the CHG; University of New Mexico; University of Helsinki, Finland; University of South Carolina; and Baylor College of Medicine.
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