Sharing Ella's journey on rare disease day 2021

Rett Syndrome and the Iceberg Effect

Why males rarely have Rett syndrome

During conception if all goes well with the fertilization process the cells in a human carry the DNA instructions (genes) on 23 pairs of chromosomes. The mother gives the fetus 23 chromosomes and the father gives the fetus 23 chromosomes creating 46 chromosomes in each person. The special pairs of chromosomes that determine fetal sex are called the X & Y chromosomes.

Females typically have two X chromosomes whereas males typically have an X and a Y chromosome. Over the years, we have learned that Rett syndrome (RTT) is caused by loss of the MECP2 gene function which is located on the X chromosome. This gene provides instructions for making a protein called MeCP2 that helps regulate how and when our cells use different genes. If the MECP2 gene is mutated this causes the protein to not function properly, causing signs of RTT to appear.

In females, classical RTT occurs when one MECP2 gene is mutated and the other copy of the gene (on the other X chromosome) functions normally. The healthy copy of MECP2 acts as a vital crutch to support development and growth.

RTT in males is very rare due to the fact that most males only have one X chromosome, and if a mutation occurs in their only copy of MECP2, the fetus usually doesn't survive, or is very sick at birth and may not live very long. Some males defy the odds and can survive without a normal copy of MECP2; however they are usually quite severely delayed from birth and are severely disabled. Some boys have RTT in addition to another condition which provides a second X chromosome with a working copy of MECP2. These boys typically look very similar to girls with RTT. The first condition is known as Klinefelter syndrome, where males have two X chromosomes and one Y chromosome. The second is when the fetus is mosaic for the MECP2 mutation; there is a mix of two different population of cells (one of which has a normal MECP2 gene). These conditions allow one functioning copy of the MECP2 gene to support development and growth.

For more information about genetics and the MECP2 gene you may refer to "The Rett Syndrome Handbook" written by Kathy Hunter.