Rett Syndrome in Males

Rett syndrome is a genetic neurodevelopmental disorder that almost exclusively affects females and is very rare in males.

The syndrome is mainly caused by mutations in the MECP2 gene located on the X chromosome and whose function includes regulating the activity of many other genes. Because males have only one X chromosome, this means that a mutation in the MECP2 gene cannot be compensated by a healthy gene copy. Therefore, they do not usually survive infancy.

There are, however, reported cases of males with MECP2 mutations. These patients have more severe symptoms that develop early in life, with the first signs of the disease seen at birth or shortly thereafter.

In males, most changes in the MECP2 are due to spontaneous mutations that occur during the division and formation of sperm, the male germ cell. As the diagnosis of Rett syndrome is based on clinical criteria and presentation, mutations in the MECP2 gene are not sufficient to make a diagnosis of Rett. People with such mutations who do not meet the clinical criteria for Rett are given the designation of MECP2-related disorders.

There are some circumstances that explain the occurrence of Rett syndrome in males. They are:

Klinefelter syndrome

Klinefelter syndrome is a genetic condition where males have two X chromosomes in addition to their Y chromosome. This condition affects around 1 in 500 to 1,000 males.

There is a small chance that a boy with Klinefelter syndrome may have a mutation in the MECP2 gene in one of his X chromosomes that leads to a clinical presentation consistent with Rett. In addition to Rett symptoms, affected males also have symptoms of Klinefelter syndrome, such as underdeveloped genitalia and low production of sex hormones.

Mosaicism

Mosaicism describes the presence of two different populations of cells in the body. Every person originates from one cell, a fertilized egg cell. Because every cell in the body arose from the same original cell, all cells are genetically identical. This is true unless a genetic modification or a mutation occurs during development.

In males with Rett syndrome and mosaicism, some cells have a mutated MECP2 gene while other cells carry a healthy copy.

The clinical presentation, and whether symptoms are similar to those seen in females, depend on the percentage of affected cells.

MECP2-related severe neonatal encephalopathy

Some MECP2 mutations can cause neonatal encephalopathy, a condition characterized by brain dysfunction during infancy.

Males with Rett-causing mutations usually have earlier onset and more severe symptoms than females, as all the cells in the male have the mutated gene. These patients often have severe breathing problems, feeding difficulties, and seizures. They may survive to late childhood with aggressive medical intervention.

Less severe MECP2 mutations

Some MECP2 mutations do not significantly affect the function of the MeCP2 protein, for which this gene codes. Females with one such mutation usually have no symptoms or only very mild ones. In males, these mutations may cause learning difficulties or behavioral problems, but not the typical symptoms of Rett syndrome.

 

Last updated: Feb. 7, 2022, by Teresa Carvalho MS

 


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