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MIAMI BEACH – Researchers have homed in on a gene that, when mutated, can cause Charcot-Marie-Tooth (CMT) disease, a discovery that may lead to better screening in affected families.

The newly discovered variant is not the first mutation to be linked to this inherited progressive disorder of the distal motor and sensory nerves. But it could be a key player not only in the pathogenesis of CMT, but in other neuropathies as well, investigators said here at the AAN Annual Meeting in April.

On a more clinical basis, testing for the gene that encodes dynamin 2 could help ensure patients aren't wrongly classified based on standard clinical and electrophysiological findings, said Stephan Zuchner, MD, Assistant Research Professor at the Center for Human Genetics at Duke University Medical Center in Durham, NC, who presented the findings.


Although CMT “is genetically heterogeneous, the clinical manifestations can look pretty much the same,” he said. “The classical phenotype includes muscle weakness, usually starting in the feet and later spreading to the hands, and sensory impairment with depressed tendon reflexes and foot deformities.”

Patients are typically classified as having one of two predominant forms of CMT based on histological and electrophysiological studies: CMT type 1, characterized by slow nerve conduction velocities and demyelination, and CMT type 2, with normal nerve conduction velocities and axonal degeneration but no demyelination.

“In the middle is a group with nerve conduction velocities that are a little slow – that is, intermediate CMT – and we've been trying to figure out what these patients actually represent,” said Michael E. Shy, MD, Professor of Neurology and Molecular Medicine and Genetics at Wayne State University in Detroit.

The new discovery “tells us the genetic cause” of some of these cases, said Dr. Shy, who was not involved with the research.


Dr. Zuchner said that clinically, one of the most interesting findings is that some patients with the gene variant for intermediate CMT have normal nerve conduction velocities. Therefore, they would be misclassified as having CMT type 2 based on standard clinical and electrophysiological examinations, he said.

In addition, in two of the families, neutropenia – which had previously not been associated with CMT neuropathies – was inherited along with the disease, he noted.

Since there are currently no targeted treatments for the different forms of CMT, genetic testing is not yet vital for patient outcome, he said. “But as we develop specific therapies, genetic testing will become more important,” Dr. Zuchner said.


Dr. Stephan Zuchner said testing for the gene that encodes dynamin 2 could help ensure patients arent wrongly classified based on standard clinical and electrophysiological findings.

Currently, testing for the mutation is available only on a research basis.

The study, which was presented as a late-breaking poster at the AAN meeting, also appears in the March issue of Nature Genetics (2005;37:289–294). Dr. Zuchner said he wasn't starting from scratch: Geneticists had previously linked three different subtypes of the intermediate form of CMT to three different chromosomal loci.


The new study included three generations of three unrelated families in North America, Australia, and Belgium – about 30 people in all – who were known by linkage analysis to have one of the three subtypes, known as autosomal dominant intermediate CMT B.

Using classical genetic mapping techniques, they first refined the chromosomal locus. “We knew exactly which chromosome – 19 – and exactly where in the chromosome – the short arm – the mutation is,” Dr. Zuchner said.

After screening candidate genes, his group then identified in all families with mutations in dynamin 2, a ubiquitous protein involved in membrane transport.

To explore the effects of the mutations, the researchers performed functional studies, transfecting neuronal cell lines with normal and mutant variants of the gene. The gene products were labeled so that the scientists could follow their actual path.

“Two major things happened, both of which could have implications for axonal transport,” Dr. Zuchner said. “First, the microtubule network was disturbed by the mutant copy,” he said.

Peripheral neurons rely on long – perhaps 1 meter long – axons for transport of proteins, organelles, mitochondria, and all the other stuff needed for metabolism, he explained.

If there is a disruption in the microtubules – the railroad tracks that make up axons, if you will – all these goods may never make it to their destination. “As a result, the distal ends don't have sufficient metabolism, and patients may develop the distal symptoms that define CMT,” Dr. Zuchner said.

Dynamin 2 is also important for endocytosis, the process cells depend on to take in molecules, including nutrition, from the outside and form vesicles for transport.

“If you transfect cells with normal dynamin, there is always an association with vesicles,” Dr. Zuchner said. “But cells transfected with the mutant dynamin 2 did not co-localize with the vesicles anymore.”


Dr. Shy said this is the second discovery made by Dr. Zuchner to show the critical role of the axonal transport system in the normal function of nerve cells.

In 2004, his group showed that a mutation in mitofusin 2 is involved in some cases of CMT (Nature Genet 2004;36:449–451). “Mitofusin 2 allows mitochondria to fuse and therefore be able to be transported along neurons,” Dr. Shy said. “Now [in the current study] we see that a mutation in the gene that encodes dynamin 2 causes other disruptions in axonal transport.”

“There is an increased likelihood that when this transport is disrupted, it causes neurons to degenerate. The implications are likely to go way beyond CMT and involve many other neurodegenerative diseases too. It's extremely interesting,” he said.


  • ✓ Investigators identified a mutation in the gene that encodes dynamin 2, which they think could be a key player not only in the pathogenesis of Charcot-Marie-Tooth disease, but in other neuropathies as well.


• Zuchner S, Noureddine M, Kennerson M, et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature Genet 2005: 37: 289–294.
    • Zuchner S, Mersiyanova IV, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genet 2004; 36:449–451.