Rett syndrome is a rare neurological and developmental disorder that impacts brain development, primarily affecting girls. It leads to a progressive loss of motor skills, communication abilities, and cognitive function after a period of typical early development, usually starting around 6 to 18 months of age. While children with Rett syndrome require lifelong care, it is not a degenerative disorder, and individuals can live into adulthood.
The MECP2 Gene and Its Role
Rett syndrome is caused by mutations in the MECP2 gene, which is located on the X chromosome. This gene provides instructions for creating the methyl CpG binding protein 2 (MeCP2), a protein found throughout the body with high levels in the brain. MeCP2 is a transcriptional regulator, meaning it helps control the activity of other genes.
The MeCP2 protein plays a significant role in normal brain development and function, regulating gene expression and maintaining connections between nerve cells, known as synapses. When a mutation occurs in the MECP2 gene, it disrupts the proper function of this protein, leading to the widespread neurological deficits seen in Rett syndrome.
Understanding Rett Syndrome Inheritance
Rett syndrome follows an X-linked dominant inheritance pattern, as the MECP2 gene resides on the X chromosome. In most cases, approximately 99% of Rett syndrome diagnoses result from a de novo mutation, a genetic change that is new and not inherited from either parent. These spontaneous mutations often originate in the paternal germline cells and are then passed to a female offspring.
While less common, some cases of Rett syndrome are inherited from a carrier mother. Girls are predominantly affected because they have two X chromosomes, allowing for X-inactivation where one X chromosome is randomly “turned off” in each cell during embryonic development. This inactivation ensures balanced gene expression between sexes and can lead to a milder presentation in females if the X chromosome with the mutated MECP2 gene is largely inactivated.
Boys, having only one X chromosome, typically experience more severe symptoms if they inherit a mutated MECP2 gene, often leading to miscarriage or death in early infancy. In rare instances where males survive with MECP2 mutations, they may have a condition called MECP2-related severe neonatal encephalopathy. Survival in males can occur due to mosaicism, where some cells have the mutation and others do not.
Genetic Diagnosis and Family Planning
Genetic testing for MECP2 mutations is available and is a common method to confirm a clinical diagnosis of Rett syndrome. This testing identifies the specific genetic alteration, which can guide access to targeted resources and care options. While newborn screening for Rett syndrome is possible, its direct benefit for asymptomatic infants is currently limited.
For families, understanding the genetic basis has implications for family planning and genetic counseling. Since most cases are de novo, the recurrence risk for future pregnancies is generally low, estimated to be less than 1%. However, if a mother is identified as a carrier, the recurrence risk for each subsequent pregnancy can be as high as 50%. Genetic counseling can help families assess these risks and explore options like prenatal testing when applicable.