Rare Case of Brothers with Rett Suggests Multiple Factors in Disease Course

Two brothers with Rett syndrome carrying the same MECP2 mutation display distinct disease courses, a case study reports, highlighting that additional factors can modify disease severity.

Researchers believe that mutations in other genes, or individual differences in the levels of the MECP2 protein in various tissues may account for the differences in symptoms and patient outcomes.

The report, “Rett Syndrome in Males: The Different Clinical Course in Two Brothers with the Same Microduplication MECP2 Xq28,” was published in the International Journal of Environmental Research and Public Health.

Rett is a rare, neurodevelopmental disorder characterized by normal early development, followed by slower growth and a loss of motor control. As the disease progresses, patients often develop difficulties in motor skills and possibly intellectual abilities, and multi-organ dysfunction, with symptoms such as repetitive motions, problems walking, loss of speech, and seizures.

Almost all cases of Rett syndrome are caused by mutations in the MECP2 (methyl CpG binding protein 2) gene. This gene provides instructions for making the MECP2 protein, involved in regulating the activity of other genes.

MECP2 protein is present across various cells and organs in the body, but it plays a particularly important role in the brain, where it is thought to help maintain the connections between nerve cells.

Rett almost exclusively affects females, because the MECP2 gene is located on the X chromosome. Females have two copies of the X-chromosome, so girls with one faulty copy of the MECP2 gene survive because of a second and healthy gene copy. Males, who only have one copy of the X chromosome, normally die of this disease before birth or in early infancy.

Despite being rare, a few reported cases of male patients exist, who display a wide variety of symptoms, including congenital encephalopathy (brain malfunction), severe intellectual disability, and classical Rett manifestations.

Researchers describe the case of an 11-year-old boy with Rett whose disease was caused by a microduplication of MECP2 Xq28. (The MECP2 gene is located on the long arm, or q, of the X chromosome; more precisely, it’s in the Xq28 region.)

Beginning at an early age, he had a history of multi-organ dysfunction, seizures, encephalopathy, and motor and intellectual disability.

In contrast, his older brother died at the age of 9 due to paralytic ileus (obstruction of the bowel). He was a carrier of the same microduplication of the MECP2 gene at the Xq28 region.

In light of the recent scientific updates about MECP2, researchers put forward possible explanations for the different clinical courses in these brothers.

MECP2 protein is present in many organs, which can explain the problems affecting multiple organs in both boys.

Among potential reasons for their distinct disease courses can be the presence of mutations at genes other than MECP2 that might modify disease severity.

Mutations in genes such as SCN1A and ATP2A2 have been detected in tissues outside the brain in one sibling in a pair of identical twins. This correlated with only one of the twins showing disease symptoms.

Within the same individual, different tissues may also carry different mutations.

The two brothers presented here were not identical twins. As such, “there is a high probability that the differences in their genomes account for the differing lifespans regardless of the role of MECP2,” the researchers wrote. (The genome is the entire genetic composition of an individual.)

The amount of MECP2 protein produced in cells could also differ between the brothers, and this may play an important part as well.

“In further studies, it would be useful to know the relative levels of MECP2 expression from the patient samples. In our patients it is possible that MECP2 levels were higher in the older brother accounting for the shortened lifespan,” the researchers wrote.

“Given the limited case history of [Rett] in males, further studies are needed to better characterize this syndrome in males and consequently improve the currently available therapeutic strategies,” they concluded.