Rett syndrome is a rare genetic neurodevelopmental disorder that primarily affects brain development and function. It is characterized by a period of apparently typical early development followed by a loss of previously acquired skills, including speech, purposeful hand movements, and motor abilities. It occurs predominantly in females and is most commonly associated with changes in the MECP2 gene located on the X chromosome.

Role of the MECP2 gene
The MECP2 gene provides instructions for producing methyl-CpG-binding protein 2 (MeCP2). This protein plays an important role in regulating gene expression, particularly in the brain. It helps control the activity of numerous other genes involved in the development, maintenance, and functioning of nerve cells.
Brain cells, called neurons, communicate with one another through specialized connections known as synapses. MeCP2 contributes to the regulation of neuronal maturation, synaptic function, and the maintenance of healthy neural networks.
When the MECP2 gene contains a disease-causing variant, the protein may be absent, produced in insufficient amounts, or unable to function properly. This disrupts the regulation of genes necessary for normal brain function.
As a result, the development and functioning of neural networks may be affected, leading to the characteristic features of Rett syndrome.

How do genetic changes cause the condition?
Most cases of classic Rett syndrome are associated with pathogenic variants in the MECP2 gene. These variants may include:
– Missense variants: A change in one DNA nucleotide alters an amino acid in the protein.
– Nonsense variants: A DNA change introduces a premature stop signal, potentially resulting in a shortened protein.
– Frameshift variants: Insertions or deletions alter the reading frame of the gene.
– Splice-site variants: Changes affect the processing of RNA, potentially altering the final protein.
– Deletions: Part or, occasionally, all of the gene may be missing.
Different variants can affect protein function in different ways. However, the relationship between a particular variant and the severity of symptoms is not always straightforward.

Is Rett syndrome always caused by an MECP2 variant?
No. Although MECP2 is the principal gene associated with classic Rett syndrome, not every person with Rett-like features has an identifiable pathogenic variant in this gene.
Some individuals have Rett-like disorders caused by changes in other genes, including CDKL5 and FOXG1. These conditions have distinct clinical and genetic characteristics and are often classified separately from classic Rett syndrome.
Genetic testing helps distinguish these conditions and supports an accurate diagnosis.

Why does Rett syndrome usually occur spontaneously?
In most affected individuals, the pathogenic variant arises de novo, meaning it occurs for the first time in the affected child rather than being inherited from a parent.
A de novo variant may arise during the formation of an egg or sperm or very early after fertilization. Consequently, parents can have no symptoms and no known family history of the condition.
Rarely, a variant may be inherited from a mother who carries it, including a mother who has few or no obvious symptoms.

Can Rett syndrome be prevented?
There is currently no established method to prevent the spontaneous genetic changes that cause Rett syndrome. However, genetic counselling can help families understand the diagnosis, inheritance pattern, recurrence risk, and reproductive options.