Certain microRNAs (miRNAs) abundant in the brain and detectable in the blood can serve as potential biomarkers of disease course for people with Rett syndrome, according to a recent study.
Some miRNA combinations were found promising for detecting specific symptoms and signs, such as alterations in cholesterol levels and seizures; others were more accurate at identifying affected individuals, male and female, suggesting they may serve as indicators of disease severity.
The study, “Brain-enriched microRNAs circulating in plasma as novel biomarkers for Rett syndrome,” was published in the journal PLOS ONE.
Rett syndrome is a severe neurodevelopmental disorder mainly caused by mutations in the MECP2 gene, which gives instructions to make the methyl-CpG-binding protein 2, thought to regulate other genes’ activity and key for brain development and function.
The MECP2 gene is located on the X chromosome and given that women have two X chromosomes they normally have one functional copy of the MECP2. Unlike girls, boys only carry one X chromosome, so if they have a MECP2 mutation, they usually do not survive.
This makes Rett almost exclusively present in girls, with first symptoms usually appearing between ages 6–18 months. Cases in boys are rare and when they occur they typically appear earlier and are more severe.
Finding biomarkers of disease progression and response could facilitate screening tests of potential treatments, help define target populations for clinical trials, and improve therapeutic monitoring.
In this study, researchers wanted to understand whether small DNA-related molecules, called microRNAs (miRNAs), could be such markers.
miRNAs play critical roles in regulating the activity of genes, typically blocking their ability to give rise to proteins. There is an apparent link between MECP2, the faulty protein in RTT, and specific miRNAs.
Loss of MECP2 can switch “on” or “off” many genes, including those coding for specific brain miRNAs. This in turn, may change the concentrations of several miRNAs in the blood.
In fact, prior work supports the potential of looking at blood miRNAs for screening and monitoring neurodegenerative diseases. Although nerve cell degeneration is not seen in Rett, changes in miRNA patterns have been reported in the brains of Rett mouse models as well as in bodily fluids of children with autism spectrum disorder (of note, some patients with Rett have autism-like symptoms).
Prompted by this, the researchers investigated whether miRNAs circulating in the blood could be a minimally invasive and reliable way of detecting, monitoring, and evaluating the different aspects of disease, such as liver and muscle complications.
They used four MECP2-mutant mice models to test eight miRNAs, which were known to be enriched in the brain but could still be detected in plasma.
Pairs of miRNAs were used to determine a corrected level between samples. These combinations were able to distinguish between male and female mice with Rett-like disease and healthy animals, with an accuracy superior to 90%.
However, researchers noted that miRNAs were able to more accurately identify affected males, who typically have worse disease. This suggested these biomarkers could be useful for indicating disease severity.
Next, researchers tested these same miRNAs pairs together with additional ones in blood plasma samples of 30 female patients, ages 2–34, comparing them against age-matched subjects. The results showed that selected miRNAs were able to discriminate Rett patients from controls with 85% to 100% sensitivity.
Moreover, comparisons across age groups revealed that certain miRNAs could reflect disease progression and the presence of particular symptoms and signs.
For instance, patients with seizures, walking problems, or cholesterol levels higher or lower than normal, were distinguished from patients without these problems based on the levels of specific miRNAs.
An important observation was that the same miRNAs could be used to detect Rett in both mice and humans, suggesting both share common mechanisms of disease.
“The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here,” the researchers concluded.