Rett Syndrome is most often caused by mutations (structural alterations or defects) in the MECP2 (pronounced meck-pea-two) gene, which is found on the X chromosome. Scientists identified the gene,which is believed to control the functions of several other genes,in 1999. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which acts as one of the many biochemical switches that tell other genes when to turn off and stop producing their own unique proteins. Because the MECP2 gene does not function properly in those with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are formed. The absence or malfunction of the protein is thought to cause other genes to be abnormally expressed, but this hypothesis has not yet been confirmed. Seventy to 80 percent of girls given a diagnosis of Rett syndrome have the MECP2 genetic mutation detected by current diagnostic techniques. Scientists believe the remaining 20 to 30 percent of cases may be caused by partial gene deletions, by mutations in other parts of the gene, or by genes that have not yet been identified; thus, they continue to search for other mutations.
Mutations in another gene known as CDKL5 are believed to cause an atypical form of Rett Syndrome called the early-onset seizure variant. The CDKL5 gene provides instructions for making a protein that appears to be essential for normal brain development. Although the function of this protein is unknown, it may play a role in regulating the activity of other genes. Researchers are working to determine how mutations in the CDKL5 gene lead to seizures and the features of Rett syndrome in affected individuals.
Although Rett Syndrome is a genetic disorder — resulting from faulty gene or genes — less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are sporadic, which means the mutation occurs randomly, mostly during spermatogenesis, and is not inherited.
Rett Syndrome is reported to affect one in every 10,000 to 15,000 live female births, although it is believed to be even more prevalent and often misdiagnosed . It occurs in all racial and ethnic groups worldwide.
Prenatal genetic testing is available for families with an affected child who has an identified gentic mutation. Since the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is believed to be less than 1 percent. Genetic testing is also available for sisters of girls with Rett syndrome and an identified genetic mutation to determine if they are asymptomatic carriers of the disorder, which is an extremely rare possibility. Girls have two X chromosomes, but only one is active in any given cell. This means that in a child with Rett syndrome only about half the cells in the nervous system will use the defective gene. Some of the child’s brain cells use the healthy gene and express normal amounts of the proteins. The story is different for boys who are born with the genetic mutations known to cause Rett syndrome in girls. Because boys have only one X chromosome they lack a back-up copy that could compensate for the defective one, and they have no protection from the harmful effects of the disorder.