Most cases of Rett syndrome are caused by a change (also called a mutation) in a single gene. In 1999, NICHD-supported scientists discovered that most classic Rett syndrome cases are caused by a mutation within the Methylcytosine-binding protein 2 (MECP2) gene. The MECP2 gene is located on the X chromosome. Between 90% and 95% of girls with Rett syndrome have a mutation in the MECP2 gene.1,2,3 Among families with a child affected by Rett syndrome the chance of having a second child with the syndrome is less than 1%.4
Eight mutations in the MECP2 gene represent the most prevalent causes of Rett syndrome. The development and severity of Rett syndrome symptoms depend on the location and type of the mutation on the MECP2 gene.5
The MECP2 gene makes a protein that is necessary for the development of the nervous system, especially the brain. The mutation causes the gene to either make insufficient amounts of this protein or to make a damaged protein that the body cannot use. In either case, if there is not enough of the working protein for the brain to develop normally, Rett syndrome develops.
Researchers are still trying to understand exactly how the brain uses this protein, called MeCP2, and how problems with this protein cause the typical features of Rett syndrome.
Mutations on two other genes can cause some of the atypical variants of Rett syndrome: Congenital Rett syndrome (Rolando variant) is associated with mutations of the FOXG1 gene, and CDKL5 mutations are linked with the early-onset, or Hanefeld, variant.6,7 Males affected by these types of mutations can survive infancy. Males can also have a duplication of a normal MECP2 gene and survive, but are severely affected. Too much MeCP2 protein is as bad for development as too little.
In 99.9% of cases, the genetic change that causes Rett syndrome is spontaneous, meaning it happens randomly. Such random mutations are usually not inherited or passed from one generation to the next. However, in a very small percentage of families—about 1 %—Rett mutations are inherited and passed on by female carriers.2,8
Two types of chromosomes determine the sex of an embryo: the X and the Y chromosomes. Girls have two X chromosomes, and boys have one X and one Y chromosome.
Because the mutated gene that causes Rett syndrome is located on the X chromosome, females have twice the opportunity to develop a mutation in one of their X chromosomes. Females with Rett syndrome usually have one mutated X chromosome and one normal X chromosome. Only one X chromosome in a given cell remains active throughout life and cells randomly determine which X chromosome will remain active. If the cells have an active mutated gene more often than the normal gene, the symptoms of Rett syndrome will be more severe. This random process allows most females with Rett syndrome to survive infancy.
Because most boys have only one X chromosome, when this gene is mutated to cause Rett syndrome the detrimental effects are not softened by the presence of a second, normal X chromosome. As a result, many males with Rett syndrome are stillborn or do not live past infancy.6,9
Some boys with Rett syndrome, however, do live past infancy, likely for one of three reasons:
Duplication of the MECP2 gene can occur in boys and affects intellectual and physical function.
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