The role of X-chromosome inactivation in the manifestation of Rett syndrome

X-chromosome inactivation (XCI) is random in the majority of patients with classical Rett syndrome (RTT). Preferential inactivation of the X chromosome with the mutated MECP2 gene is found in mildly symptomatic or asymptomatic carrier females. These findings lead to a hypothesis that random XCI is causally involved in the pathogenesis of RTT in heterozygous females. It is the cluster of functionally defective nerve cells lacking fully functional MeCP2 generated by inactivation of normal MECP2 allele that causes the wide spectrum of RTT symptoms. Thus, RTT is a rare human disease manifestation which is triggered most probably by random XCI.