These resources include the best available evidence about the course of Rett syndrome and its management as well as practical information about family associations, specialist clinical centres and links to relevant websites.
Archer H, Evans J, Leonard H, Colvin L, Ravine D, Christodoulou J, Williamson S, Charman T, Bailey ME, Sampson J, de Klerk N, Clarke A. Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. Journal of Medical Genetics. 2007;44(2):148-52. Download snapshot, see article abstract.
Girls and women with Rett syndrome can be quite different from one another even though they might be the same age and have the same type of mutation. It is believed that this might be due to inactivation of one of the X-chromosomes in each cell.
X-chromosome inactivation (henceforth referred to as X-inactivation) occurs in females during embryonic development. X-inactivation occurs so that only one X-chromosome is active in each cell at a time. If there were two active X-chromosomes there would be twice the number of genes being expressed in females than there would be in males. X-inactivation is mostly a random process and therefore each female will have a unique pattern of active and inactivate X-chromosomes, even if she is a twin.
Sometimes the process of inactivation is not random, and one of the copies may be active in higher proportions than the other. This is called skewed X-inactivation. For example if one of the X-chromosomes has a mutation, as occurs in Rett syndrome, the X-chromosome with the mutation may be active at a higher or lower proportion.
For this study, we examined how Rett syndrome characteristics can be affected by X-inactivation for 2 of the common types of mutation - p.R168X and p.T158M.
What we did
For this study, we combined information provided by families in Australia and the UK. The laboratory scientists analysed blood samples and determined which X-chromosome was active. The relationship between clinical severity (using the Pineda and Kerr scoring system) and the X-inactivation pattern of girls and woman was then analysed.
What we found
For girls with either a p.R168X or p.T158M mutation, a higher proportion of their active X-chromosome with the mutation was associated with greater clinical severity.
What does it mean
Our results indicate that X-inactivation may explain some of the differences in the characteristics of girls and women with Rett syndrome. Milder characteristics are more likely in those who have fewer active copies of the X-chromosome which carry the mutation.