Abnormal Breakdown of Certain Lipids May Underlie Rett Syndrome Development, Study Suggests

Abnormal breakdown of lipid (fat) molecules known as sphingolipids may be involved in the development of Rett syndrome, and their levels could be used as a biomarker for the disorder, a pilot study reports.

The research, “Sphingolipid Metabolism Perturbations in Rett Syndrome,” was published in the journal Metabolites.

Metabolic analyses can be used to diagnose inborn errors of metabolism in children, but are also increasingly used to detect metabolic impairments in different diseases.

Nearly all cases of Rett syndrome are caused by a mutation in the MECP2 gene, which codes for a protein that controls expression of a wide range of other genes and regulates metabolic balance.

Studies in a mouse model of Rett syndrome have identified several metabolic alterations, mostly involving cholesterol. However, no studies have investigated the metabolic imbalances of Rett syndrome in humans.

In the study, researchers from Italy and the U.S. used an analytical technique known as liquid chromatography-tandem mass spectrometry to detect altered metabolic components in blood samples from 14 girls and women with Rett syndrome (mean age was 14.4 years, age range was 3 to 29).

More than 900 metabolites were analyzed, including amino acids (the building blocks of proteins), organic acids, fatty acids, neurotransmitters (which enable communication between nerve cells), nucleotides (components of DNA and RNA), vitamins, and bile acids.

Sphingolipids — a type of lipid found in cell membranes, particularly nerve cells and brain tissues — are important in signal transmission and cell recognition, and are believed to protect the cell surface from harmful environmental factors.

Results of the study showed that Rett syndrome patients had increased levels of sphingolipid metabolites of the sphinganine/sphingosine pathway compared with controls. These molecules included sphinganine, sphinganine 1-phosphate, sphingosine, and sphingosine 1-phosphate.

Besides providing a protective role in cell membranes, sphingolipids such as sphinganine and sphingosine perform a neurotrophic role, which means that they support the growth, survival, and maturation of nerve cells.

Previous studies have shown a trend towards increased levels of these sphingolipids in neurons of people with Rett syndrome, suggesting their link to neurological symptoms.

Also, higher levels of sphingosine 1-phosphate were reported in individuals with autism spectrum disorder. Research has shown that Fingolimod, a multiple sclerosis treatment (brand name Gilenya) that acts via the sphingosine 1-phosphate receptor, improved motor function and prolonged survival of mice with Rett syndrome.

“In conclusion, by an untargeted metabolic analysis, this pilot study unraveled changes in sphingolipid and sphinganine/sphingosine metabolites in plasma [blood] of Rett syndrome subjects,” the researchers wrote.

“[T]his study suggests that alterations in sphingolipid metabolism might play a role in Rett syndrome pathogenesis and it may pave the way toward the development of disease-specific biomarkers,” they added.

However, the researchers said that these changes need to be confirmed in a larger group of patients, and that the processes underlying these alterations and their consequences still need to be established.