Rett syndrome

Rett syndrome is a brain disorder that occurs almost exclusively in girls. The most common form of the condition is known as classic Rett syndrome. After birth, girls with classic Rett syndrome have 6 to 18 months of apparently normal development before developing severe problems with communication and language, learning, coordination, and other brain functions. Early in childhood, affected girls lose purposeful use of their hands and begin making repeated hand wringing, washing, or clapping motions. They tend to grow more slowly than other children and have a small head size (microcephaly). Other signs and symptoms can include breathing abnormalities, seizures, an abnormal side-to-side curvature of the spine (scoliosis), and sleep disturbances.

Researchers have described several variants of Rett syndrome with overlapping signs and symptoms. The atypical forms of this disorder include a very severe type known as the congenital variant, which has no period of normal development, and an early-onset seizure variant characterized by seizures that begin in infancy.

This condition affects an estimated 1 in 10,000 females.

The vast majority of cases of classic Rett syndrome are caused by mutations in the MECP2 gene. This gene provides instructions for making a protein (MeCP2) that is critical for normal brain function. Although the exact function of the MeCP2 protein is unknown, it likely plays a role in maintaining connections (synapses) between nerve cells. Researchers believe that this protein has several functions, including regulating other genes in the brain by switching them off when they are not needed. The MeCP2 protein may also control the production of different versions of certain proteins in nerve cells. Although mutations in the MECP2 gene disrupt the normal function of nerve cells, it is unclear how these mutations lead to the signs and symptoms of classic Rett syndrome.

The congenital variant of Rett syndrome results from mutations in the FOXG1 gene. The protein produced from this gene regulates several other genes involved in brain development. If the FOXG1 gene is altered or missing, it disrupts early brain development and leads to intellectual disability, absent language, and other features of the congenital variant.

Mutations in the CDKL5 gene cause the early-onset seizure variant of Rett syndrome. The CDKL5 gene provides instructions for making a protein that appears to be essential for normal brain function. Although little is known about this protein's function, it has been found to interact with the MeCP2 protein. Researchers are working to determine how mutations in the CDKL5 gene lead to seizures and the other signs and symptoms of the early-onset seizure variant of Rett syndrome.

Read more about the CDKL5, FOXG1, and MECP2 genes.

More than 99 percent of people with classic Rett syndrome have no history of the disorder in their family. Many of these cases result from new mutations in the MECP2 gene.

A few families with more than one affected family member have been described. These cases helped researchers determine that classic Rett syndrome has an X-linked dominant pattern of inheritance. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition.

Males with mutations in the MECP2 gene often die in infancy. However, a small number of males with a genetic change involving MECP2 have developed signs and symptoms similar to those of Rett syndrome, including intellectual disability, seizures, and movement problems.