More Genes Implicated In CMT

Charcot-Marie-Tooth (CMT) disease, a disorder of the peripheral nerves, which run between the spinal cord and the periphery of the body and allow movement and sensation, is associated with mutations in dozens of genes. More genetic causes have been implicated nearly every year since the early 1990s, and two new disease-causing genes have recently been identified.

Broadly speaking, CMT is divided into type 1, which results primarily from defects in the insulating coating known as myelin that surrounds nerve fibers (axons); and type 2, which results primarily from defects in the axons themselves. Intermediate types are a mixture of axonal and myelin degeneration.

Since myelin itself contains multiple proteins, and nerve fibers have many proteins of their own, it’s not surprising that so many different genetic flaws can lead to CMT. The disease is characterized by weakness and loss of sensation, particularly in the feet, hands, lower legs and forearms, with other parts of the body affected in some forms.

In the February issue of Nature Genetics, Albena Jordanova of the University of Antwerp (Belgium) and Sofia (Bulgaria) Medical University and colleagues describe three different genetic mutations in the gene for a protein known as YARS in three unrelated families with an intermediate form of CMT known as DI-CMTC. Jordanova has had MDA support for CMT research.

YARS belongs to a family of proteins that are instrumental in the translation of final genetic instructions into protein molecules. It may play a special role in nerve fibers.

“What is fascinating about the genetic results, is that the disease is caused by a ‘housekeeping’ gene,” says Florian Thomas, professor of neurology, virology, and microbiology and immunology at Saint Louis (Mo.) University and a member of the study team. “That term is used to describe genes that ‘keep house’ and that have as wide a use in the body as, for instance, Ajax does in the household. So the scientific question is, why does this CMT gene cause only a peripheral neuropathy and not total body dysfunction?” Thomas has some ideas, but, he says, “The story is not finished.”

In another study, published in the February issue of Annals of Neurology, Stephan Zuchner of Duke University in Durham, N.C., and colleagues identified mutations in the gene for a protein known as mitofusin 2 as a cause of a form of CMT that involves degeneration of the optic nerves as well as the usual losses in movement and sensation.

This type of CMT, known as hereditary sensory and motor neuropathy type 6, causes a severe, early-onset peripheral nerve disorder, with vision impairment later in life. (In this study, six out of 10 patients with vision loss ultimately recovered their vision to normal or nearly normal levels. The researchers attribute this recovery to nerve fiber regeneration.)

The research team, which included Vincent Timmerman and Albena Jordanova (see above), both at the University of Antwerp (Belgium), and Michael Shy at Wayne State University in Detroit, all of whom have current or recent MDA funding for CMT research, studied six families and identified six different CMT-causing mutations in the mitofusin 2 gene.

Mitofusin 2, which has previously been found to be a cause of CMT2A, an axonal form of CMT that only rarely affects the optic nerves, is thought to affect the behavior of the mitochondria, the energy-producing parts of cells.

Shy, a neurologist and a professor of molecular medicine and genetics, sees rare and common forms of peripheral nerve disease at the CMT clinic he directs at Wayne State, where he’s equally interested in the genetics and in patient care. He has MDA funding to develop gene therapy for CMT.

“My interest came from the genetic and biological side,” he says “but you learn [about daily care issues] as you go, by seeing people.”