Good News for CMT-2A Patients
Researchers Discover Elusive CMT-2A Gene

This April, researchers discovered the gene responsible for Charcot-Marie-Tooth Disease-2A (CMT-2A), the second most common form of CMT. In the April issue of Nature Genetics, an International group led by Stephan Züchner, MD and Jeffery Vance MD, reported promising findings about Type 2A. Up until now, the mutated gene that causes CMT-2A had remained elusive; this is the last major gene causing Charcot-Marie-Tooth Disease to be discovered. Now that the mutated gene and the protein it codes for have been determined, not only will genetic testing for CMT-2A be available but an understanding of the underlying basis of the disease will open new research pathways that can lead to potential treatments.
“Our results indicate that mitofusin 2 is a major gene underlying CMT type 2A, and probably one of the major genes that cause all hereditary forms of the axonal neuropathy, CMT type 2," said senior author Jeffery Vance, M.D., associate director of the Center for Human Genetics and professor of medicine at Duke. Dr. Vance and his team traveled around the country collecting tissue and histories of CMT2 families and had previously linked the defective gene to a small region on chromosome 1. In this study, the researchers also used genes from large families in Russia, Italy, Turkey and Japan.

When the researchers sequenced this region in seven large CMT-2A families of diverse ethnic backgrounds, the individuals with CMT had a mutation in the gene sequence encoding the mitochondrial fusion gene, while unaffected family members did not. A mutation in the same region of chromosome 1, found in a Japanese family, had earlier been indicated to be associated with CMT-2A, but this could not be confirmed in other CMT-2 families. Dr Vance added, "This marks the first time that mitochondrial fusion has been implicated in a human disease and opens up a whole new area of exploration for the basis of peripheral neuropathies in general."

If you remember mitochondria from biology class, they are known as the powerhouse of the cell. Mitochondria convert the energy in sugar to energy stored as ATP, which is used by the body to power cellular functions, but they have other critical function as well. They are sausage-shaped organelles, in the cytoplasm of the cell, with an outer membrane and a highly folded inner membrane. The defective gene that the researchers identified codes for the mitochondrial fusion protein mitofusin 2 (MFN2). It is interesting that this MFN2 gene is expressed not only in nerve cells but in other cells as well. The stretch of the gene where the mutations occur is “highly conserved,” meaning that the DNA and the amino acids it codes for have remained essentially unchanged throughout evolution. Scientists regard these cross species similarities (the authors note the round worm, C. elegans, and the fruit fly) as evidence that the gene and the protein it makes are involved in an essential function. Mitochondria also contain their own DNA (all of which comes from the mother), which is a separate entity from the genes of the cell where MFN2 is located.

Mitochondria are pictured as stand-alone structures, however recent research indicates that they are connected by their outer membranes into a dynamic system. “Mitochondria must link into constantly shifting networks through fusion and fission in order to provide the energy required for neurons to fire and stimulate muscles to move," said lead author of the study Stephan Züchner, M.D., of the Duke Center for Human Genetics and the Department of Neuropathology at the University Hospital Aachen in Germany. "Mitofusin 2 is critical to that process."

The authors conclude, “The mutations in MFN2 gene are the primary cause underlying CMT2A. The present study demonstrates a new mechanism for axonal neuropathies and should provide insight into the pathophysiology of neuropathic disease, both hereditary and acquired.”

What does this mean for CMT patients?

Charcot-Marie-Tooth Disease is divided into two primary groups; CMT type 1 characterized by demyelination (loss of myelin sheath surrounding the nerve cell or axon) with resulting slowed nerve conduction velocity and CMT type 2 distinguished by axon loss and normal or near normal nerve conduction rates.

The genetic defect (a duplication of the gene for PMP22) on chromosome 17 that causes the most common CMT type, CMT-1A, has been known for some time and the mutations for most of other CMT types have been identified and therefore genetic testing for these types is available. Now that the mutated gene and the protein that it codes for have been determined, genetic testing, hopefully, will be available for CMT-2A in the near future.

Also, because the gene, the protein it codes for and the function of the protein are known, the disease is now open for intervention and potential cures, not tomorrow, but at some point in the future. “Know thine enemy and he is yours,” eventually. For example, other researchers, using a virus, introduced a normal gene for mitofusin 2 into Mfn2 deficient mice and “rescued” them.
The authors conclude that, ‘this raises the possibility that CMT2A may be amenable to some similar type of intervention in the future.”

JD Griffith, M.S.
CMT Foundation



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