What is CMT?

Charcot-Marie-Tooth disease (CMT) is a rare inheritable peripheral neuropathy affecting about 1 in 2500 people, or an estimated three million individuals worldwide. More broadly, CMT is a heterogeneous group of inheritable sensory and motor peripheral neuropathies, axonopathies, myelinopathies, and neuronopathies. Clinically, CMT is a multisystem neuromuscular disease. Medically, it is one of the most complex diseases to understand. For those who have CMT, the disease is intrusive, unrelenting, often debilitating, unforgiving, and, albeit very rare, can sometimes be fatal.

CMT gets its name from the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England. In its infancy, CMT was described as a disease that causes lower-leg muscle weakness and atrophy, known as peroneal muscle atrophy. Over time, CMT revealed itself to be profoundly more diverse, with effects far beyond the lower legs. Today, CMT refers to any peripheral neuropathy that has a genetic cause, even if the specific genetic cause is unknown.

Although first described in 1886, the cause of CMT remained elusive for more than 100 years. Scientists knew CMT was inheritable and clearly ran in families, but they did not know why. Finally, published on January 1, 1991, researchers identified a cause: a duplication of a tiny segment of chromosome 17 (17p11.2). This marked the beginning of modern CMT genetic discovery.

What was once just one known cause in 1991 quickly became several. The original chromosome duplication was refined to a PMP22 gene duplication in 1992. By the end of the decade, scientists had identified CMT-causing mutations in six genes, defining ten different CMT subtypes. By the end of 2001, which marked the first decade of genetic discovery, another seven genes had been identified, adding ten more subtypes to the list, although four of those were formally classified later.

Today, scientists have identified CMT-causing mutations in more than 140 genes that account for more than 170 individual subtypes. These subtypes fall into 13 type classifications, such as dHMN (Distal Hereditary Motor Neuropathy), GAN (Giant Axonal Neuropathy), and HSAN (Hereditary Sensory and Autonomic Neuropathy).

Despite this disease diversity, there is no single symptom or feature that belongs uniquely to any one subtype, with the exception of CMT-SORD. Anyone with CMT can experience any symptom associated with the disease, regardless of subtype. Age at onset, rate of progression, symptom severity, and overall disease course vary widely. Even within the same family, experiences can differ significantly. One thing is certain: CMT is progressive over a lifetime. The progression, however, can look very different from one person to the next.

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