Rare Rett-causing Mosaic Mutation Found for 1st Time in Male Patient

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A mosaic mutation — one that is present in only some body cells — causing Rett syndrome was found in a 2-year-old boy in India, a report says.

According to researchers, this is the first time this specific mutation has been reported in a male patient.

The report, “A rare case of a male child with post-zygotic de novo mosaic variant c.538C > T in MECP2 gene: a case report of Rett syndrome,” was published in BMC Neurology.

In most cases, Rett syndrome is caused by a mutation in MECP2, a gene in the X chromosome that is needed for brain development. The disorder occurs almost only in girls and affects brain function after an initial six months after birth of normal development. Girls typically have two X chromosomes (XX), and may have one healthy copy of MECP2 even if the other copy is defective.

In turn, boys typically have one X and one Y chromosome (XY), and will likely not survive early infancy if there is a mutation in MECP2. Boys who survive beyond the age of 2 have either an extra X chromosome or a somatic mosaic mutation.

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A somatic mutation is a spontaneous change in DNA that occurs after conception in any of the body’s cells except the reproductive (germ) cells. If the change occurs in only some of the body cells, they will differ from their neighboring cells. This phenomenon is known as mosaicism because the cells appear to form a mosaic pattern.

Now, a team of investigators reported the case of a boy from western India, age 2 years and 7 months, with a mosaic mutation occurring anew in MECP2. The report adds to the 11 other cases of boys with Rett syndrome due to a mosaic mutation described until now. Of note, this specific mutation has only been reported to date in females.

The boy was born prematurely at 32 weeks (about eight months gestation) by cesarean section, or C-section. As a very young child, he showed delays in gross motor skills — he was able to hold his head up straight at age 7 months, sit at 1 year, and stand alone at 2 years 5 months, yet for no longer than 10 minutes. About two months later, he was able to walk with support.

At age 1 year 9 months, he had a seizure induced by fever and was started on antiepileptic therapy to prevent further seizures.

He also had polydactyly, or one extra finger, and a simian crease — a single crease across the hand’s palm — in the right hand. The boy communicated by babbling, and autism spectrum disorder was suspected.

To look for a genetic basis for the boy’s symptoms, the investigators performed genetic testing on a sample of blood. Using a technique called sequencing to “read” the information carried in DNA, they identified a mutation in MECP2. The mutation, called c.538C > T (p.R180*), results in a shorter protein and has been reported previously. It was present in about one-third of the sequencing reads, suggesting mosaicism.

“To the best of our knowledge, no male has ever been reported with the same mutation,” the investigators wrote, noting this was “an ultra-rare case.”

“This variant has previously been observed exclusively in females,” they noted.

The boy’s parents did not carry the mutation, indicating it occurred de novo — meaning, a mutation present for the first time — after conception.

A look at the various cases of boys with Rett syndrome due to a mosaic mutation revealed that all survived beyond the age of 2 and most were diagnosed with the classical type of Rett syndrome. Five of the boys experienced seizures.

This child is one of the youngest boys to be diagnosed with a mosaic mutation. According to the researchers, for the other patients, “the age at the time of evaluation ranged from 2 years 5 months to 14 years.”

The team noted that the severity of symptoms may vary with the type of mutation, its position along the gene, and the fraction of body cells carrying the mutation.