Charcot-Marie-Tooth disease (CMT) is caused primarily by genetic mutations that affect the peripheral nerves, which are the nerves outside the brain and spinal cord responsible for movement and sensation in the limbs. These mutations disrupt the normal function and structure of either the myelin sheath—the protective covering around nerve fibers—or the nerve axons themselves, leading to the progressive weakening and loss of muscle control and sensation.
At the core of CMT’s cause are mutations in specific genes that play crucial roles in the health and maintenance of peripheral nerves. The most common form, known as CMT1, is a demyelinating type caused mainly by duplication or mutation of the PMP22 gene. PMP22 encodes a protein essential for the formation and stability of the myelin sheath produced by Schwann cells, which wrap around nerve fibers to insulate them and speed up electrical signals. When PMP22 is duplicated, the excess protein disrupts myelin production, causing the sheath to become thin or damaged, which slows nerve conduction and leads to symptoms of weakness and sensory loss.
Other genes involved in CMT1 include MPZ, which encodes myelin protein zero, another critical component of the myelin sheath. Mutations in MPZ can cause a similar demyelinating effect but often with different severity or progression rates. These genetic changes impair the Schwann cells’ ability to maintain the myelin, leading to nerve damage over time.
There is also an axonal form of CMT, called CMT2, where the primary problem lies in the nerve axons themselves rather than the myelin. In these cases, mutations affect genes responsible for the structure, transport, or metabolism within the nerve fibers. This leads to degeneration of the axons, which are the long projections of nerve cells that transmit signals to muscles and sensory organs. Because the axons are damaged, the nerve signals weaken, causing muscle wasting and sensory deficits.
Some rarer forms of CMT involve mutations in genes related to cellular stress responses, such as small heat shock proteins (HSPB1 and HSPB8). These proteins help protect nerve cells from damage by assisting in the proper folding and maintenance of other proteins. Mutations here can impair autophagy, a process that removes damaged cellular components, leading to accumulation of toxic materials and nerve cell dysfunction.
The genetic mutations causing CMT can be inherited in different patterns, including autosomal dominant, autosomal recessive, or X-linked inheritance, depending on the specific gene involved. This means the disease can be passed down from one or both parents or linked to the sex chromosomes, influencing who is affected and how severely.
In summary, Charcot-Marie-Tooth disease arises from genetic mutations that disrupt the normal biology of peripheral nerves, either by damaging the myelin sheath that insulates nerve fibers or by directly harming the nerve axons. These disruptions impair nerve signal transmission, leading to the characteristic muscle weakness, atrophy, and sensory loss seen in affected individuals. The complexity of the disease reflects the variety of genes and cellular processes involved in maintaining healthy peripheral nerves.
