The Genetics of Rett Syndrome
To understand the rarity of Rett Syndrome in boys, you must first remember what you learned in high school about human genetics. Most people are familiar with the X and Y chromosomes. They are the chromosomes that determine gender, or sex chromosomes as they are often referred. Females have two X chromosomes, while males have an X and a Y chromosome. These chromosomes play a huge role in Rett Syndrome.
Rett Syndrome is caused by a genetic mutation in one X chromosome. A gene known as MECP2 (pronounced meck-pee-two) found on the X chromosome, not only supplies essential MeCP2 proteins to the brain necessary for proper development, but also regulates other genes. The MECP2 gene signals other genes to turn on or off as needed. In girls with Rett Syndrome, the MECP2 gene suffers an unexplained mutation, affecting the production of MeCP2 proteins. The resulting drop in MeCP2 proteins accounts for the characteristic symptoms and stages of Rett Syndrome. It is believed that only one of the two X chromosomes in affected females has such mutations.
Rett Syndrome in Boys
Rett Syndrome is considered a dominant genetic mutation. That means that only one X chromosome needs the mutation in order for the disorder to present. In females, the remaining normal X chromosome produces enough normal MeCP2 proteins to compensate for the mutated gene. That is, at least enough for the child to survive and develop, albeit with disabilities.
Unfortunately, boys do not have another X chromosome to compensate for the lack of MeCP2 protein. The mutation and lack of MeCP2 proteins drastically affects brain development at some time after conception. Therefore, seldom does a male child with such a mutated gene survive beyond birth. In fact, most male babies born with such a mutation are never diagnosed, nor do they show signs of Rett Syndrome. Instead, they are born with severe problems, commonly resulting in death shortly after their birth.
Klinefelter’s and Rett Syndromes
One genetic abnormality exists that allows a male child with Rett Syndrome mutations to survive past birth. Boys born with Klinefelter’s Syndrome, or an extra X chromosome, can have Rett Syndrome. Since they have two X chromosomes and one Y chromosome, these boys can potentially have the MECP2 mutation but still produce enough MeCP2 proteins to survive. Nearly all cases involving Rett Syndrome in boys involve a child who also has Klinefelter’s Syndrome. Klinefelter’s Syndrome is equally rare, with some variants affecting as few as 1 in 50,000 male children.
There are few anecdotal cases involving male children with symptoms similar to Rett Syndrome who do not have Klinefelter's Syndrome. However, while some of these children may indeed have mutations in the MeCP2 protein-producing genes, most experts do not believe these children to have true Rett Syndrome as the mutation is different. Rather, these boys often have intellectual disabilities or developmental delays unrelated to their gene mutation. They do not present the clinical criteria necessary for a Rett Syndrome diagnosis.
References and Resources
National Institute of Neurological Disorders and Stroke: https://www.ninds.nih.gov/disorders/rett/detail_rett.htm#164573277
Mayo Clinic: https://www.mayoclinic.com/health/rett-syndrome/DS00716/DSECTION=causes
National Institute of Health, Genetics Home Reference: https://ghr.nlm.nih.gov/condition/rett-syndrome
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