More Genes Implicated In CMT

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More Genes Implicated In CMT

http://www.mdausa.org/research/060420cmt_more_genes.html

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 , 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? " has

some ideas, but, he says, " The story is not finished. "

In another study, published in the February issue of ls 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 Timmerman and Albena

Jordanova (see above), both at the University of Antwerp (Belgium),

and 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. "