Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders that damage the peripheral nerves, which transmit signals between the brain, spinal cord, and the rest of the body. This damage leads to progressive muscle weakness, typically starting in the feet and lower legs, and can spread to the hands and arms over time. Symptoms include sensory and motor issues like numbness, tingling, and muscle atrophy. CMT is the most common inherited neuropathy, affecting an estimated one in 2,500 people globally.
Current Status of a Cure
Currently, there is no approved treatment that can fully cure Charcot-Marie-Tooth disease. CMT is a diverse group of disorders caused by over 100 different genetic mutations, making the development of one universal cure exceptionally challenging. The current focus of medical care is entirely on managing the symptoms, slowing the progression of physical disability, and maintaining the best possible quality of life.
The goal of present-day treatment is to prevent further complications and help individuals remain mobile and independent. While rehabilitation, orthotics, and surgery are available to ameliorate symptoms, they do not address the underlying genetic cause or reverse the existing nerve damage. Research efforts are focused on developing disease-modifying therapies, but these are still in the experimental stages.
Genetic Basis and Nerve Damage
The complexity of CMT stems from the fact that different genetic errors lead to damage in different parts of the peripheral nerve. A peripheral nerve functions much like an electrical cable, consisting of the axon, which transmits electrical signals, and the myelin sheath, the insulating layer. Gene mutations in CMT disrupt the proteins that maintain the structure or function of either the axon or the myelin.
CMT is broadly categorized into types based on which part of the nerve is primarily affected. Type 1 (CMT1) is the demyelinating form, where faulty genes cause the myelin sheath to break down. The most common subtype, CMT1A, is caused by a duplication of the PMP22 gene, resulting in the overproduction of a protein essential for myelin structure. This excess protein impairs the insulating layer, causing signals to slow down and weaken.
Type 2 (CMT2) is the axonal form, where the genetic fault directly affects the axon itself. In this case, nerve signal transmission is weakened, failing to reach the muscles and sensory receptors with sufficient strength. A frequent cause of CMT2 is a mutation in the MFN2 gene, which is involved in the function of the nerve cell’s energy-producing mitochondria. This extensive genetic heterogeneity means that a therapy effective for one type, such as CMT1A, may be ineffective for an axonal form like CMT2A.
Managing Symptoms and Mobility
The primary approach to CMT involves comprehensive management to maintain mobility and reduce the impact of the disease on daily life. Physical therapy and occupational therapy are cornerstones of this management, helping to maintain muscle strength, flexibility, and range of motion. Low-impact exercises, such as swimming or cycling, are recommended to keep muscles active without unduly stressing joints.
Assistive devices play a major role in preserving functional independence. Ankle-foot orthoses (AFOs) are commonly prescribed to compensate for foot drop, a weakness in the muscles that lift the front of the foot. AFOs stabilize the ankle, prevent tripping, and restore a smoother gait, which can also reduce muscle fatigue. Modern AFOs are often made of lightweight, custom-molded plastic or carbon fiber.
Pain is a frequent symptom of CMT, resulting from muscle cramps, skeletal deformities, and neuropathic pain. Managing this pain requires a combination of physical therapy, proper bracing, and sometimes prescription medications specifically for neuropathic discomfort. For foot deformities like high arches, hammer toes, or joint instability, orthopedic surgery may be necessary. These procedures aim to correct the physical structure of the foot to improve balance, reduce pain, and enhance the function of orthotic devices.
Experimental Therapies and Research
Despite the lack of a current cure, a significant amount of research is focused on developing disease-modifying treatments that target the genetic root of the condition. One promising area is gene therapy, which aims to correct the underlying genetic error. Strategies include gene replacement for conditions caused by a lack of a functional protein, and gene silencing for conditions, like CMT1A, caused by the overproduction of a protein.
Antisense Oligonucleotides (ASOs) represent a targeted approach to gene silencing, particularly for CMT1A. ASOs are small synthetic molecules designed to bind to the messenger RNA (mRNA) produced by the faulty gene, preventing the harmful protein from being made. Preclinical studies using ASOs to reduce the expression of the overactive PMP22 gene in animal models of CMT1A have shown potential for reversing some disease features. Researchers are now working on developing improved delivery vehicles, such as specialized nanoparticles, to ensure the ASOs can effectively reach the peripheral nerves without causing systemic toxicity.
Another active research direction involves drug repurposing and the development of small-molecule drugs. For instance, a small-molecule drug called govorestat is currently in Phase 3 clinical trials for a specific type of CMT caused by a mutation in the SORD gene. Other gene-mediated therapies are also being explored, including the use of plasmids to deliver growth factors that support nerve health and improve function, showing encouraging results in early-phase clinical trials for CMT1A. These studies represent a shift from purely supportive care toward therapies designed to modify the disease process itself.