Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

The most common cause of CMT (70-80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein. Cells contain separate sets of genes in their nucleus and in their mitochondria. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning.

CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. Another cell involved in CMT is the Schwann cell, which creates the myelin sheath, by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a Swiss roll.

Neurons, Schwann cells, and fibroblasts work together to create a working nerve. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.

Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.

The myelin sheath allows nerve cells to conduct signals faster. When the myelin sheath is damaged, nerve signals are slower, and this can be measured by a common neurological test, electromyography. When the axon is damaged, on the other hand, this results in a reduced compound muscle action potential (CMAP).