11 - 05 - 2006: Very mild cases of Rett syndrome with skewed X inactivation.

Abstract
Rett syndrome, one of the most frequent causes of mental retardation in females, is caused by mutations in the MECP2 gene. Most females with MECP2 mutations fulfill the established clinical criteria for Rett syndrome. However, single cases of asymptomatic carriers have been described. It is therefore very likely that there are individuals in-between these two extreme phenotypes. In this article we describe three of these in-between patients who show only minor symptoms of Rett syndrome. Among these, the patient with the best intellectual ability has predominantly psychiatric problems with episodes of uncontrolled aggression that have not been described previously in individuals with MECP2 mutations. All patients have a normal hand function, they communicate well and they show short spells of hyperventilation only under stress.In order to diagnose these patients one has to look for subtle signs of Rett syndrome in females with a mild mental handicap. Analysis of the MECP2 gene revealed mutations that are found frequently in classical Rett syndrome. In order to explain these very mild phenotypes we analyzed X inactivation and revealed skewing in all three cases. We conclude that due to skewed X inactivation the phenotype of Rett patients can be very mild and hardly recognizable.

Lay Summary
X-inactivation is a process by which one of the two copies of the X chromosome present in females is inactivated. Briefly, X-inactivation occurs so that females, with two X chromosomes, do not have twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome. Interestingly, the choice of which X chromosome will be inactivated is random, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the individual. As MeCP2 gene is found on the X chromosome, Rett girls either the non-mutated copy of MeCP2 or the mutated copy of MeCP2 randomly "turned on" in virtually every cell in their body, at a roughly 50:50 ratio. However, sometimes "skewing" of this ratio can occur. In this paper, the authors describe 3 patients with MeCP2 mutations who display only minor symptomes of Rett syndrome. These very mild patients communicate well, have normal hand functions, and age-appropriate motor skills. Here, in all three girls X inactivation analyses showed skewing with ratios of 84:16, 95:5, and 76:24, all favoring the non-mutated copy of MeCP2. One could say that these patients represent the link between classical Rett syndrome patients and non-symptomatic carriers for mutations in the MeCP2 gene. This report extends the growing clinical spectrum of Rett syndrome, by adding females with a very mild disease form that have skewed X inactivation and do not fulfill the established clinical criteria for Rett syndrome. The authors suggest that subtle signs of Rett syndrome such as hand stereotypies, hyperventilation episodes provoked by stress at some point in childhood may be clues to diagnose future similar cases.