Charcot-Marie-Tooth (CMT) disease is the most common inherited neurological disorder, affecting the peripheral nerves responsible for sensation and muscle movement in the limbs. This progressive disease damages the nerves connecting the brain and spinal cord to the rest of the body, causing symptoms that usually begin in the feet and lower legs. Because CMT encompasses over 130 genes and numerous subtypes, a definitive diagnosis requires a multi-step process combining clinical observation with specialized electrophysiological and genetic testing. The diagnostic journey confirms the presence of neuropathy, classifies the type of nerve damage, and pinpoints the specific genetic cause.
Clinical Assessment and Physical Examination
The diagnostic process begins with a detailed clinical assessment, where a physician gathers a thorough patient and family history. Since CMT is an inherited disorder, a family history of similar symptoms strongly suggests the condition. The doctor inquires about the onset and progression of symptoms, such as difficulty walking, frequent tripping, or clumsiness in childhood.
The physical examination focuses on identifying characteristic signs of peripheral nerve damage, particularly in the lower extremities. The physician looks for muscle weakness and atrophy, which typically appear first in the feet and lower legs, often leading to foot drop. Deep tendon reflexes, such as the knee-jerk reflex, are usually diminished or entirely absent.
Specific foot deformities are a hallmark of the disease, including high arches (pes cavus) and curled toes (hammer toes). Sensory nerves are also affected, and testing may reveal reduced sensation or numbness, often starting in the feet. These initial clinical findings confirm the presence of a hereditary motor and sensory neuropathy and guide the next steps.
Measuring Nerve Function
Once a hereditary neuropathy is suspected, the next step involves electrodiagnostic tests, primarily Nerve Conduction Studies (NCS) and Electromyography (EMG). These tests confirm nerve damage and help classify the physiological type of CMT. NCS measures the speed and strength of electrical signals traveling through the motor and sensory nerves in the arms and legs.
The results from the NCS are crucial for distinguishing between demyelinating and axonal types of CMT. In demyelinating CMT (Type 1), damage to the protective myelin sheath causes the electrical signal to slow significantly, often to less than 38 meters per second. Conversely, in axonal CMT (Type 2), the nerve fiber itself is primarily affected, resulting in a relatively normal or mildly slowed conduction velocity but a reduced signal amplitude, indicating fewer working nerve fibers.
Electromyography (EMG) is often performed alongside NCS, involving the insertion of a fine needle electrode into various muscles. The EMG evaluates the electrical activity within the muscle both at rest and during gentle contraction. This helps assess nerve-muscle communication, determine the extent of muscle involvement, and differentiate CMT from other conditions that might present with similar muscle weakness.
Pinpointing the Cause Through Genetic Testing
Genetic testing is the most definitive step in CMT diagnosis, confirming the condition and identifying the specific subtype. CMT is caused by mutations in over 130 different genes, making precise genetic identification essential for accurate prognosis and counseling. A simple blood or saliva sample is collected for DNA analysis, which is sequenced to look for known genetic mutations.
The most common CMT subtype, CMT1A, is caused by a duplication of the PMP22 gene, accounting for up to 70-80% of all CMT Type 1 cases. Genetic testing identifies this and other common mutations, such as those in GJB1 (CMTX) and MFN2 (CMT2A), which account for the majority of genetically defined cases. Identifying the specific mutation clarifies the inheritance pattern, which can be autosomal dominant, autosomal recessive, or X-linked.
A positive genetic test provides a precise classification (e.g., CMT1A or CMT2A), which is valuable for family planning and determining eligibility for future clinical trials. However, a negative result does not rule out the disease, as some genetic mutations remain undiscovered or are not included in standard testing panels. In these cases, a clinical diagnosis is still made based on the physical exam and electrodiagnostic findings.
The Role of Nerve Biopsy
A nerve biopsy, involving surgically removing a small piece of peripheral nerve tissue, is an invasive procedure rarely used for CMT diagnosis today. Advancements in genetic testing have largely made this technique unnecessary for most patients. The tissue is typically taken from the sural nerve in the calf and examined under a microscope.
The primary use of a nerve biopsy is reserved for specific diagnostic dilemmas. This includes cases where genetic testing is inconclusive, or when the physician needs to rule out other acquired neuropathies, such as vasculitis or chronic inflammatory demyelinating polyneuropathy (CIDP), which can mimic CMT symptoms. For example, a biopsy in demyelinating CMT can reveal characteristic “onion bulb” formations (rings of Schwann cells surrounding the nerve fiber).
In modern practice, the biopsy serves as a last resort. It provides morphological evidence of nerve damage and its pattern when other less invasive methods fail to provide a definitive answer. It can also provide a functional association when genetic tests detect a “variant of uncertain significance.”