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When things go wrong in the Peripheral Nervous System.

Charcot Marie Tooth (CMT) is a group of inherited diseases representing the most common neuromuscular disorders. Patients gradually lose strength of their peripheral muscles, first affecting feet and lower legs, later also the hands. The disorders result from errors in making or maintaining myelin in the peripheral nervous system (PNS). Myelin is vitally important to a healthy nervous system. It is an insulating material wrapped around the axons of nerve cells, whose major role is to accelerate transmission of nerve impulses along the axon. The production, assembly and maintenance of myelin is a highly complex process and animal models carrying mutations in the many proteins involved are being used to clarify the roles of the major players in CMT disorders.

Mistakes made in making, assembling or maintaining myelin result in neural disorders (neuropathies). The Charcot Marie Tooth (CMT) neuropathies are characterised by neuromuscular failure. The three main CMT disorders arise from errors (mutations) in the DNA coding for myelin proteins. However, as yet, there are no known treatments for these diseases. Mimicking the diseases in animal models should give us a better idea of what has gone wrong and may lead to strategies for treatment of the symptoms. Because the business of myelinating a nerve fibre is a complex one, there are many steps where errors can occur. When the protein involved in a disorder is known, we can mimic the disease in animal models (usually rodents, fish or flies). Researchers can modify the DNA of the animals in such a way, that they switch off a gene, or express the mutated gene. By carefully studying these mutant animals, the disease can be investigated in the kind of detail that would be impossible in humans. A different approach is to try to identify proteins that are not yet known to be involved in neuropathies. This can be done by creating random mutations in animal models and looking for the animals that display symptoms of the disease: neuromuscular failure in the case of CMT. Sophisticated modern genomic technology now allows us to quickly identify which gene mutation has lead to the disease.

Research in animal models has given us valuable information about the myelination of peripheral nerves. In addition, the onset and progress of neuropathies can be much better characterised in an animal than in humans. This may help with early detection of human neuropathies and more successful intervention. Finally, it is possible to assess the influence of environmental factors and different genetic backgrounds on the severity of symptoms. This helps to identify risk factors which might exacerbate the disease symptoms.

You may now appreciate how the use of model animals offers the prospect of successful therapies in the future not only for CMT disorders but also for other neuropathies which result from neural defects in processes other than myelination.