What Causes Rett Syndrome?
Most cases of Rett syndrome are caused by a mutation. A mutation is a defect or structural alteration. In most cases of Rett syndrome, this change is in the MECP2 gene, which is located on the X chromosome. Chromosomes contain the genes that dictate how we look, grow and function. The X chromosome is one of two chromosomes that establish a person’s gender. Researchers identified the MECP2 gene in 1999. It is one of the genes responsible for making a protein needed for normal brain development.
The progression and severity of the disorder depends on the type, location and severity of the genetic mutation and balance of “X-inactivation.” In girls, every cell in the body has two X chromosomes but in each of the body’s cells one of the X chromosomes is inactivated and one remains active. Depending on the randomly determined balance of which X chromosome is inactivated (i.e. the one with our without the MECP2 mutation) the severity of the girls condition may vary. Which means two girls who are the same age and have the same mutation can have very different disabilities.
Boys only have one X chromosome (the match in the pair being the Y chromosome) so if they have a full MECP2 mutation; it is active in all cells resulting in early miscarriage or a severe clinical picture. However, as more is learned about the genetics of this condition, a variety of rare clinical presentations and genetic mechanisms have been described in boys.
Rett Syndrome without MECP2 Mutation
95% of girls with classical Rett syndrome will have a mutation of the MECP2 gene if extensive testing is done. Some patients are noted to have “variant forms” of Rett syndrome because of unique features (e.g. congenital onset, infantile seizures). Many of these “variant forms” are now know to be caused by mutations in other genes.
Is Rett Syndrome Inherited?
Although Rett syndrome is a genetic disorder – meaning that it’s caused by a faulty gene or genes – less than five percent of recorded cases are inherited or passed from one generation to the next. Typically the mutation is new having occurred during the replication/division of the chromosomes during formation of most commonly the sperm and less commonly the egg. Thus most Rett syndromes occur randomly, rather than being inherited. Still, there appear to be some cases in which the parent is a carrier and clusters of Rett syndrome cases within families are found in specific geographic regions – such as Sweden, Norway, and northern Italy. It is now recommended that mothers of children with Rett syndrome have carrier testing done (fathers are unlikely to be assymtomatic carriers given the relative severity of classic Rett syndrome in males). If the mother is a carrier, recurrence risk is 50%. If not a carrier, recurrence risk is very low (<0.1%) with the low rate of recurrence related to gonadal mosaicism (i.e. carriage of the abnormal gene in some cells within the ovaries or testes). In the case of variant Rett syndrome since these are often due to mutations in other genes, genetic counseling regarding recurrence risk will vary.
What Are the Risk Factors for Rett Syndrome?
With the exception of being female or known maternal assymtomatic carrier, there are no other known risk factors for Rett syndrome. The genetic mutation that causes the syndrome appears randomly in most cases.
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National Institute of Neurological Disorders and Stroke