Charcot-Marie-Tooth disease (CMT) is a diverse group of inherited disorders affecting the peripheral nervous system (nerves outside the brain and spinal cord). Also known as Hereditary Motor and Sensory Neuropathy (HMSN), CMT progressively damages both motor nerves controlling movement and sensory nerves responsible for sensation. This nerve dysfunction typically leads to muscle weakness and atrophy, primarily in the lower legs and feet, along with sensory loss in the extremities. Diagnosing CMT is a multi-step process combining clinical observations, electrophysiological studies, and genetic testing to identify the specific subtype.
Initial Clinical and Neurological Evaluation
The diagnostic process begins with a detailed patient interview and a thorough physical examination conducted by a neurologist. Since CMT is an inherited condition, a comprehensive review of the family history is an important first step to identify familial patterns of neuropathy. The physician looks for physical signs of the disease, which often manifest in the feet.
Classic symptoms include foot drop (difficulty lifting the front part of the foot) and significant foot deformities, such as high arches (pes cavus) and hammer toes. The neurological exam assesses muscle strength, particularly in the distal limbs, checks for diminished or absent deep tendon reflexes, and tests for sensory changes like numbness or tingling. This initial evaluation provides the clinical suspicion necessary to warrant further, more definitive testing of nerve function.
Measuring Nerve Function with NCS and EMG
Following the clinical assessment, Nerve Conduction Studies (NCS) and Electromyography (EMG) are performed to objectively measure the health and function of the peripheral nerves and muscles. NCS is the most informative procedure, directly measuring how quickly electrical signals travel along the nerves. By stimulating a nerve with a mild electrical impulse and recording the response, the test determines the nerve conduction velocity (NCV) and the amplitude of the signal.
NCS results classify the neuropathy into two primary physiological types: demyelinating or axonal. In demyelinating CMT (Type 1), damage to the myelin sheath (the protective insulation) causes a significant and uniform slowing of the NCV, often to less than 38 meters per second. Conversely, in axonal CMT (Type 2), the nerve fiber itself is primarily affected. Here, the NCV remains relatively normal or only slightly slowed, but the signal’s amplitude is markedly reduced, indicating a loss of functional nerve fibers.
The second part of this evaluation, EMG, involves inserting a fine needle electrode into various muscles to record their electrical activity at rest and during contraction. This procedure assesses the muscle’s response to nerve signals and can reveal signs of chronic denervation, which is indicative of long-term nerve damage. Together, the NCS and EMG findings provide the necessary electrodiagnostic evidence to confirm peripheral neuropathy and establish the physiological subtype, setting the stage for genetic confirmation.
Identifying the Specific CMT Type Through Genetic Testing
Genetic testing is the definitive step, moving beyond the physiological classification to identify the specific gene mutation causing the disease. This testing is critical because CMT is caused by mutations in over 100 different genes, and identifying the exact gene provides the most accurate subtyping (e.g., CMT1A or CMTX). A simple blood or saliva sample is collected and sent for DNA sequencing and analysis.
The most common cause, accounting for up to 50% of all CMT cases, is a duplication of the PMP22 gene, resulting in the CMT1A subtype. Other common genes tested include GJB1 (associated with X-linked CMT, or CMTX), MPZ, and MFN2. While a positive result conclusively confirms the diagnosis and subtype, a negative result does not rule out CMT, as many causative genes remain undiscovered or rarely tested. Genetic testing is important for genetic counseling, understanding prognosis, and informing family planning decisions.
Differential Diagnosis and Confirmation
The final phase involves ruling out other conditions that mimic CMT symptoms, a process known as differential diagnosis. Many acquired neuropathies share clinical features with CMT, requiring exclusion to confirm the hereditary nature of the disorder. Examples include chronic inflammatory demyelinating polyneuropathy (CIDP), and neuropathies caused by diabetes, vitamin deficiencies, or heavy metal exposure.
Specialized blood tests are performed to check for markers of these treatable acquired causes, such as vitamin B12 levels or signs of autoimmune disease. In rare and diagnostically challenging cases where clinical, electrophysiological, and genetic tests are inconclusive, a nerve biopsy may be performed. This procedure involves removing a small piece of peripheral nerve tissue for microscopic examination. The biopsy can reveal characteristic physical changes, such as the “onion bulb” formations seen in demyelinating CMT, confirming the diagnosis by exclusion. This comprehensive diagnostic journey ensures the correct identification of CMT for creating an appropriate, long-term management plan.