Charcot-Marie-Tooth disease (CMT) is a genetic neurological disorder that targets motor and sensory neurons. A mutation in just one gene is enough to cause the disease, but the disease has been associated with mutations in more than 80 genes. Furthermore, while the symptoms caused by any of these mutations are consistent, namely muscle weakness that begins in the legs and feet, the actual beginnings of the disease are not well understood.

Using iPS cells made from CMT patients, Neurologist Haruhisa Inoue reports dynamic changes of a single molecule as the earliest sign to date of CMT development.

"CMT causes demyelination. Myelination is necessary for neurons to transmit electric signals for communication with other cells. Without myelination, the nerves cannot signal to muscles for movement," he said.

Schwann cells are responsible for myelination, and many studies on CMT have focused on these cells. Inoue, however, believed that these cells may already be diseased and that other cell types earlier in development are better candidates for revealing the initial stages of the disease.

"Neural crest cells (NCCs) are the progenitors of Schwann cells. The adult body does not have them, but we can make NCCs from iPS cells, he said."

Inoue prepared NCCs from iPS cells made from three patients with different CMT mutations. All mutant NCCs showed a common difference from NCCs prepared from healthy donors. Specifically, Inoue found irregularities in glutathione S-transferase theta 2 (GSTT2), a gene that encodes an enzyme involved in cell detoxification and is not mutated in CMT. The expression of GSTT2 RNA was significantly higher in patient NCCs, indicating the cells were experiencing undue stress, but there was no difference in GSTT2 RNA expression when comparing healthy and patient iPS cells.

Other research has shown that GSTT2 expression rises with a rise of toxic metabolites in the cell. At this point, Inoue is not clear what toxins are promoting the GSTT2 increase, but if found it could provide a drug target to prevent the initiation of CMT.

"It is very difficult to treat CMT, because the only commonality between patients is symptoms. A molecular marker would allow early diagnosis and maybe give new drug targets," he said.

• doi: 10.1097/WNR.0000000000000831