Medical professionals have known for a long time that peripheral nerve cell damage plays a major role in Charcot-Marie-Tooth (CMT) disease. A recent study published in Human Molecular Genetics has suggested that nerve damage may not be the only contributing factor. Using mouse models of CMT, a team of researchers discovered that muscle damage led to the characteristic symptoms.

About CMT

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy, is a neurological disorder that affects the peripheral nervous system. It occurs as the result of mutations in various genes (CMT1, CMT2, CMT3), all of which result in the death of peripheral nerves. Depending on which gene is affected, this condition can be inherited in an autosomal dominant or recessive pattern. There is also an X-linked version of the disease, which is passed down through mutations of the GJB1 gene. Regardless of inheritance, affected individuals may experience foot deformities, difficulty with walking and fine motor skills, weakness in the hands and feet, and lower leg deformities. There is currently no cure for this disease, although physical and occupational therapy are used to maintain muscle strength and use. Pain medications may also be prescribed.

About the Study

Using mouse models of dominant-intermediate CMT type B (DI-CMTB), researchers from the Swiss Federal Institute of Technology investigated the disease mechanisms. As this type of CMT is typically the result of a mutated DNM2 gene, the researchers replicated this mutation in the mice.

Compared to the control group, the mice with CMT experienced mild motor and gait impairments, along with slightly decreased body mass. These differences were expected. There were a few details that took researchers by surprise, however. The expected axonal or nerve abnormalities were not present. Instead, the mice presented with muscular abnormalities.

Researchers observed nerve-muscle dysfunction, but there was no major damage to the nerves. This meant that the muscle defects were the cause. When investigating this further, they found damaged muscle fibers and a build-up of immune macrophages. Other findings include:

• Significantly lower muscle weight in the mice with CMT
• Higher levels of genes related to inflammation and the extracellular mix organization were present in CMT mice
• Lower levels of genes related to mitochondria and energy-related metabolism in the CMT mice

In the end, these findings contradict what we know about CMT in humans; nerve damage plays a major role. To explain this, the researchers note that the differences between mice and humans may be the cause. They acknowledge that further research is necessary.

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