Rett syndrome twins hint at hidden genetics in disease severity
Study of identical twin sisters finds symptoms vary despite same mutation
Researchers in Italy described a rare case of 27-year-old identical twin sisters with Rett syndrome who, despite sharing the same disease-causing mutation, developed symptoms of different severity.
Identical (monozygotic) twins develop from a single fertilized egg that divides into two embryos, so they are genetically identical.
“The clinical differences described in our paper could thus be explained by other genetic mechanisms,” the researchers wrote, adding that “more detailed genetic investigations are necessary.”
The study, “Clinical differences in monozygotic twins with Rett syndrome: case report and systematic review,” was published in the Orphanet Journal of Rare Diseases.
What to know about Rett syndrome and its genetic cause
Rett syndrome is a rare disorder that mainly affects girls, occurring in about one in 10,000 female births. Rett syndrome is most often caused by mutations in MECP2, a gene that provides the instructions needed to produce a protein of the same name that’s key for normal brain development.
Early in infancy, children with Rett syndrome may develop normally, but later, they begin to lose some of the skills they had learned — a process called developmental regression.
As it progresses, common Rett symptoms include loss of speech, repetitive hand movements, problems with walking and coordination, seizures, and breathing difficulties.
Although Rett syndrome itself is rare, even rarer cases have been reported in identical twins.
In this study, researchers in Italy — together with a collaborator in the U.S. — described a pair of twin sisters who both carried the same MECP2 mutation (called p.Thr158Met) but developed different clinical features.
The girls were born at 32 weeks of gestation by normal delivery to healthy, unrelated parents. Both had low muscle tone at birth.
Twin A never developed the ability to speak and had greater social impairment, with poor eye contact and less communicative intent. She lost all purposeful hand use and developed pronounced lower-limb spasticity. Over time, she also experienced teeth grinding (bruxism), constipation that required laxatives, difficulty swallowing (dysphagia), mild scoliosis (a sideways curvature of the spine), and significant sleep and breathing problems.
Twin B learned a single word in early development but later lost it. She retained more social skills, maintained minimal hand use, and had milder teeth grinding and spasticity, with only rare episodes of difficulty swallowing. She also experienced constipation, and her scoliosis was more pronounced, requiring a rigid corset. Sleep and breathing problems were present but milder than her sister.
Both sisters developed epilepsy at age 4. Twin A’s seizures became resistant to anti-seizure therapies, leading to multiple daily episodes only partly controlled with two medications. Twin B’s seizures were well managed with a single medication (carbamazepine). After puberty, Twin A continued to have seizures about once a week, while Twin B experienced them only once every month or two.
EEG tests, which measure electrical activity in the brain, reflected this difference: Twin A’s recordings showed severe abnormalities, while Twin B’s pattern remained more stable.
Genetic testing at age 6 showed both sisters had the exact same MECP2 mutation.
Researchers explore why the twins developed symptoms so differently
To understand why the twins’ symptoms differed, the researchers examined which X chromosome was active in their cells. The MECP2 gene is located on the X chromosome, and because females have two Xs, each cell naturally shuts one down — either the mother’s or the father’s. This process, called X-chromosome inactivation (XCI), determines whether each cell uses the healthy or the mutated copy of MECP2.
In both twins, most blood cells had inactivated the same X chromosome, and in those cells the healthy MECP2 copy was mainly switched on, rather than the faulty one.
However, when the scientists created stem cell samples from each twin’s blood, they found the more severely affected twin had a higher proportion of cells using the faulty copy of the gene. This could help explain her more severe symptoms, according to the researchers.
The researchers noted that if future studies confirm that more blood cells from the severely affected twin express the faulty MECP2 copy, it could suggest tissue mosaicism — a condition in which the mutated copy is active only in certain tissues.
A review of other Rett twin cases confirmed that this kind of variability is not unique. Some identical twins develop very similar symptoms, while others differ widely — with only a few cases explained by XCI.
Taken together, the findings suggest that other genetic mechanisms are likely involved in shaping disease severity.
“We believe that this work, along with the review of the cases described so far, allows us to deepen our knowledge of the clinical aspects of twins with [Rett] syndrome, particularly with regard to epilepsy, and to focus attention on the variability of [which MECP2 copy is expressed] in patients with a very severe [form of the disease], which needs, however, further, and more in depth genetic investigations,” the researchers wrote.
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