A comprehensive metabolic analysis uncovered significantly different levels of 66 molecules in people with Rett syndrome compared to their non-affected siblings, potentially providing a foundation to help better understand and treat the disease.
The study, “Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings,” was published in the journal Frontiers in Integrative Neuroscience.
Rett syndrome is caused primarily by a mutation in the MECP2 gene, which is located on the X-chromosome. Current treatments are designed to manage symptoms, but clinical trials have shown promising results.
Still, a key challenge of these trials is the lack of specific biomarkers for Rett syndrome. Identifying biomarkers might help clinicians better understand disease processes and evaluate treatment effectiveness.
Several studies have linked Rett syndrome to specific changes in biological metabolites, suggesting that a detailed metabolic analysis could uncover new biomarkers.
A team from the U.S. used data from the RTT Natural History Study (NCT00299312), a study under the umbrella of the National Institutes of Health (NIH) that collected comprehensive data from people with Rett syndrome to better characterize the disease.
Data were collected from 34 Rett syndrome patients (average age 11.3, range 3–25), matched by age and gender to their 37 siblings. Blood samples were then analyzed by Metabolon.
In their study, the researchers used an emerging technique called metabolomics, which uses statistics-based algorithms to identify any large scale changes to products of the body’s metabolism.
Results showed 66 unique metabolites with significantly different levels in those with Rett syndrome compared to their siblings; 29 were higher and 37 were lower in patients than in controls.
Researchers then grouped the metabolites based on their functions, looking specifically at the top 25 most significant differences. They found that a number of these top results were involved with the metabolism of amino acids (the building blocks of proteins) and of caffeine.
For the amino acids, some of the differences were in the levels of the amino acids themselves, such as aspartate and glutamate. However, other changes were found in the products of amino acids breakdown.
The team then looked at metabolic pathways more broadly, and discovered differences in the products of the urea cycle, which breaks down protein and other nitrogen-containing compounds for excretion.
The largest difference between Rett syndrome patients and their siblings was the 3,4-hydroxyphenyl lactate/creatine ratio, which was lower in patients and could be used accurately to distinguish them from controls. These two molecules are involved in muscular metabolism and energy production.
Notably, the researchers said that although different levels of caffeine and other metabolites could reflect dietary differences, other changes comparing Rett syndrome patients to their siblings likely have other explanations.
Overall, the metabolites identified in the study suggest abnormalities to mitochondria (the cells’ powerhouses) and to gut microbiota — the community of microorganisms living in the intestines. While these observations will require additional examination, the metabolomics data may help provide a foundation for future studies.
“We identified sixty-six significantly altered metabolites that cluster broadly into amino acid, nitrogen handling, and exogenous substance [caffeine] pathways,” the researchers wrote. “These observed changes provide insight into underlying pathological mechanisms and the foundation for biomarker discovery of disease severity biomarkers.”
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