Gender & Rett Syndrome

Most individuals with Rett syndrome are female. One explanation given for this was that the genetic defect that caused Rett syndrome in females caused embryonic lethality in males (that is, males with pathogenic MECP2 mutations died before they were born). While a plausible hypothesis, more recent research has contradicted this explanation.

Most males with a pathogenic MECP2 mutation suffer from neonatal encephalopathy and die within a year or so of birth. Males who have two X chromosomes and a Y chromosome (often called Klinefelter's syndrome), one with a mutated MECP2 gene, follow a similar development path to females with Rett syndrome. Males who have somatic mosaicism also have symptoms like females with Rett syndrome.

Some researchers (for example Masuyama et al 2005) have reported cases of males with Rett syndrome who have a pathogenic MECP2 mutation but do not have a somatic mosaicism or an extra chromosome.

Unlike most genetic diseases, many cases of Rett syndrome involve spontaneous mutations in one of the parent’s gonads. It has been argued that one cause of the majority of Rett syndrome individuals being female is that mutations to MECP2 are possibly more common in male gonads than female gonads, and only females can inherit a mutated MECP2 gene from fathers (males inherit a Y chromosome from fathers, which does not contain a copy of MECP2).