Molecular Abnormalities Suggest Charcot–Marie–Tooth Starts During Embryonic Development

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by Magdalena Kegel |

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Charcot-Marie-Tooth genetic mutations

Researchers have identified molecular abnormalities in cells found during embryonic nerve development that are common to patients with demyelinating Charcot–Marie–Tooth (CMT) disease caused by three different mutations.

The findings advance the understanding of how the disease develops, and “further studies focusing on the common molecular signature in demyelinating CMT could reveal a therapeutic target for future translational medicine,” the research team from Kyoto University in Japan said.

Embryonic neural crest cells later develop into Schwann cells, which wrap neurons outside the brain and spinal cord with myelin — a fatty protective substance lacking in the majority of people with CMT.

While researchers have known that CMT can be caused by several different genes, they had been unable to identify any molecular abnormalities that are common to patients with various mutations causing demyelinating CMT — the most common form of the disease.

While earlier studies have focused on Schwann cells, the study, “Analysis of neural crest cells from Charcot–Marie–Tooth disease patients demonstrates disease-relevant molecular signature,” instead set out to explore their precursors. The study appeared in the scientific journal NeuroReport.

Using cells from healthy people and patients with demyelinating CMT, the team produced neural crest cells from so-called induced pluripotent stem cells (iPSCs). iPSCs are cells that are forced back in development in the lab and then pushed to become the cell type researchers are interested in studying.

This allows researchers to create difficult-to-obtain cells that have the genetic flaws of patients, and compare those cells to healthy cells.

The team found that CMT patients with mutations in the PMP22, MPZ, or EGR2 genes all had an abnormal enzyme. The enzyme, called GSTT2, is part of a detoxification pathway, protecting the body from so-called reactive oxygen species (molecules that can damage tissues by reacting with numerous compounds).

Patients also had higher levels of these reactive oxygen species, and researchers figured that the higher than normal levels of the GSTT2 enzyme might reflect a protective process, where the cells try to protect themselves from increased oxidative processes.

This indicates that the disease might strike at very early stages of development, researchers said, affecting not only the myelination process, but the development of Schwann cells, necessitating further research into the early stages of the disease.