The most common hereditary neuropathy is Charcot-Marie-Tooth disease, often called CMT. It affects roughly 1 in 5,600 people worldwide, with a pooled prevalence of about 17.7 per 100,000 based on a recent meta-analysis. CMT damages the peripheral nerves that connect the brain and spinal cord to the rest of the body, gradually weakening the muscles in the feet, legs, hands, and arms over a person’s lifetime.
What CMT Does to the Body
CMT targets both sensory and motor nerves. Motor nerve damage causes progressive muscle weakness and wasting, while sensory nerve damage leads to numbness, tingling, and pain. Symptoms typically start in the feet and lower legs during the teenage years or early adulthood, though they can appear at any age. Over time, weakness can spread upward to the hands, fingers, and arms.
The hallmark early signs include difficulty lifting the foot (called foot drop), a high-stepping gait to compensate, and frequent tripping. Because the muscles in the lower legs waste away while the upper legs remain relatively normal, many people develop a characteristic “inverted champagne bottle” shape to their calves. Foot deformities are common: high arches, curled toes (hammertoes), and chronic tightening of the tendons around joints.
As the disease progresses, you may notice trouble with fine motor tasks like buttoning a shirt or writing. Some people lose the ability to sense vibrations, temperature changes, or the position of their limbs in space, a sense called proprioception. Scoliosis and hip displacement can also develop, particularly in more severe cases. Muscle cramps and nerve pain are frequent complaints throughout the course of the disease.
The Genetic Cause
The most common form, CMT type 1A, results from having an extra copy of a gene called PMP22 on chromosome 17. This gene provides instructions for making a protein that helps form myelin, the insulating sheath that wraps around nerves and speeds up electrical signals. An extra copy means the body overproduces PMP22 protein, and the excess overwhelms the cells responsible for maintaining myelin. The result is a buildup of nonfunctional protein that destabilizes and eventually strips away the myelin coating, slowing nerve signals dramatically.
Interestingly, the opposite problem with the same gene causes a different condition. When one copy of PMP22 is deleted instead of duplicated, the body produces too little of the protein, leading to hereditary neuropathy with liability to pressure palsies (HNPP), a related but distinct disorder where nerves become unusually vulnerable to compression.
Main Subtypes of CMT
CMT is not a single disease but a family of related conditions, classified by which part of the nerve is damaged and how the condition is inherited.
- CMT1 accounts for about 50% of all cases. It damages the myelin sheath (the nerve’s insulation), follows an autosomal dominant inheritance pattern, and tends to appear early. Nerve signals travel significantly slower than normal.
- CMT2 makes up 15% to 30% of cases. Instead of the myelin, it damages the axon itself, the inner cable of the nerve. It typically appears in a person’s twenties or thirties, and nerve conduction speeds remain closer to normal.
- CMTX represents 10% to 15% of cases and is X-linked, meaning it tends to affect males more severely. It damages both the myelin and the axon. Males generally show slower nerve conduction speeds than females with the same mutation.
- CMT3 is uncommon and begins in infancy, causing low muscle tone, feeding difficulties, and severe impairment.
- CMT4 accounts for fewer than 10% of cases and follows an autosomal recessive pattern, meaning both parents must carry the gene for a child to be affected. It causes progressively severe symptoms.
Autosomal dominant inheritance is by far the most common pattern across all subtypes. That means only one copy of the altered gene, inherited from one parent, is enough to cause the disease. Each child of an affected parent has a 50% chance of inheriting it.
How CMT Is Diagnosed
Diagnosis usually begins with a physical exam and family history, since the hereditary pattern is a strong clue. The key diagnostic tool is nerve conduction testing, which measures how fast electrical signals travel through the nerves. Doctors focus on the speed in the motor nerves of the upper arm. Speeds below 38 meters per second point toward CMT1 (the demyelinating type), while speeds above 38 m/s suggest CMT2 (the axonal type). Some people fall into an intermediate zone between 25 and 45 m/s, which helps narrow down the specific genetic subtype.
Genetic testing confirms the diagnosis and identifies the exact mutation. This matters because different subtypes progress differently and carry different inheritance risks for future children. In CMT1A specifically, the PMP22 gene duplication can be identified with a straightforward blood test.
Living With CMT
There is currently no approved drug that slows or reverses CMT. Management focuses on maintaining function and quality of life for as long as possible. The good news: CMT does not shorten life expectancy in the vast majority of people. Only a small percentage experience severe weakness, and life-threatening complications are very rare.
Physical therapy is the cornerstone of care. Home-based exercise programs lasting 12 to 16 weeks have been shown to improve muscle strength and reduce the time needed to perform everyday tasks like getting dressed or preparing food. Programs that target the hip flexors and thigh muscles are particularly helpful because stronger proximal muscles can compensate for weaker feet and ankles. Both strength training and endurance exercises appear to benefit people with CMT.
Bracing plays an important but nuanced role. Ankle-foot orthoses (AFOs) can prevent foot drop and reduce tripping by keeping the ankle in a better position during walking. They also improve hip mechanics during the swing phase of each step. Splinting the hands can improve function in daily activities and work tasks. However, the evidence on night splints for maintaining ankle flexibility is less convincing, and unnecessary bracing in children may do more harm than good.
Pain management is another practical concern. Neuropathic pain, the burning or shooting kind that comes from damaged nerves themselves, is common and can be treated with medications designed specifically for nerve pain. Foot deformities that become severe enough to interfere with walking or cause chronic pain may eventually require orthopedic surgery.
Treatment on the Horizon
Several experimental therapies are in clinical trials, including both traditional drug approaches and gene-based strategies. Two candidates, govorestat and PXT3003, have completed clinical trials, while others, including a class of drugs called HDAC6 inhibitors, are approaching the trial stage. None have received approval yet, but the pipeline is more active than at any point in the disease’s history.