Rethinking the fate of males with mutations in the gene that causes Rett syndrome

Abstract

Rett syndrome (RTT) is usually described as an X-linked dominant disorder that is lethal prenatally to males. While this hypothesis stemmed from the nearly exclusive recognition of the classical features in females and the scarcity of similarly affected or severely affected brothers of girls manifesting the classic phenotype, there are actually no pedigree data to support it. The identification of methyl-CpG-binding protein 2 gene ( MECP2) as the causative gene for most cases of RTT allows us to examine the fate of males with a mutation in the gene. Although the number of cases is small, mutations in MECP2 that lead to the classical phenotype in females do not appear to result in prenatal lethality of affected hemizygous males. It is likely that sporadic cases are not ascertained because of the relative non-specific congenital onset encephalopathy. Males who have MECP2 mutations and Klinefelter syndrome or who are mosaic for the mutation are more likely to present with a RTT-like phenotype.