Charcot-Marie-Tooth (CMT) disease is a group of inherited neurological disorders affecting the peripheral nerves. These nerves transmit sensory information and motor commands between the central nervous system and the body. CMT typically causes progressive muscle weakness and sensory loss, most notably in the feet, legs, hands, and arms. A definitive diagnosis requires a structured, multi-step process combining clinical observation with specialized laboratory and genetic testing.
Starting the Diagnostic Process
The diagnostic process for Charcot-Marie-Tooth disease begins with a comprehensive clinical evaluation by a neurologist. This focuses on patient history to understand the onset and progression of symptoms, such as difficulty walking, frequent tripping, and numbness or tingling. The doctor looks for common physical signs, including foot deformities like high arches (pes cavus) or hammertoes, and sensory loss.
A thorough neurological examination assesses the extent of nerve damage. The physician tests muscle strength, checking for weakness, especially in the lower legs and feet, and evaluates deep tendon reflexes, which are typically reduced or absent. Gait assessment is performed, as foot muscle weakness often causes foot drop. This initial clinical picture helps determine if specialized testing for peripheral neuropathy is warranted.
A detailed family history is important because CMT is often passed down through generations. Knowing if other family members have similar symptoms strongly suggests a hereditary neuropathy. A lack of family history does not rule out CMT, however, as new mutations can occur. This initial process aims to rule out other causes of peripheral neuropathy, such as diabetes or vitamin deficiencies, before specialized tests are performed.
Assessing Nerve Function
If clinical evaluation suggests CMT, the next step involves electrodiagnostic studies: Nerve Conduction Studies (NCS) and Electromyography (EMG). These tests provide a physiological snapshot of the peripheral nerves and muscles. NCS measures the strength and speed of electrical signals traveling through motor and sensory nerves.
During NCS, electrodes stimulate the nerve with a mild electrical shock. Delayed or slowed responses indicate a problem with the myelin sheath (demyelinating CMT, or Type 1). If the speed is near normal but the strength (amplitude) is reduced, it suggests damage to the central nerve fiber (axonal CMT, or Type 2).
This distinction between demyelinating and axonal neuropathy guides subsequent, targeted genetic testing. For instance, a motor nerve conduction velocity below 38 meters per second in the median nerve often classifies a neuropathy as demyelinating.
Electromyography (EMG) is typically performed alongside NCS, involving a fine needle electrode inserted into various muscles. This test measures the electrical activity within the muscle at rest and during voluntary contraction. EMG helps determine if muscle weakness results from nerve damage, seen as abnormal electrical activity, or if the problem lies within the muscle itself.
EMG can reveal signs of chronic denervation, supporting the diagnosis of a progressive neuropathy. While NCS is more informative for distinguishing between CMT types, EMG assesses the extent of muscle involvement and rules out other conditions. These studies provide the physiological evidence necessary to confirm the presence of a peripheral neuropathy and classify its subtype.
Identifying the Genetic Cause
Genetic analysis is the most definitive method for confirming Charcot-Marie-Tooth disease, identifying the specific gene mutation responsible. CMT is caused by mutations in over 130 different genes, making genetic testing essential for precise diagnosis and classification. Identifying the exact mutation, such as the PMP22 gene duplication in CMT1A, is crucial.
Genetic testing is usually performed on a blood or saliva sample, utilizing strategies based on NCS and EMG results. If electrodiagnostic results point toward a specific subtype, the initial test may target only the common PMP22 duplication. If targeted testing is negative, a broader multi-gene panel is often used to simultaneously sequence many known CMT-causing genes.
If clinical and physiological evidence strongly suggests CMT but the gene panel is negative, the physician may recommend whole exome sequencing. This advanced method examines all protein-coding regions of the DNA to search for less common or newly discovered mutations. Finding the specific gene mutation provides a confirmed diagnosis, invaluable for genetic counseling and predicting disease progression. A positive genetic test confirms the diagnosis, but a negative result does not completely rule out CMT.
Confirming the CMT Diagnosis
A confirmed diagnosis of Charcot-Marie-Tooth disease relies on the convergence of three distinct lines of evidence. The first is the clinical picture, including characteristic symptoms like muscle weakness, sensory loss, and foot deformities identified during the physical examination. The patient’s history and family inheritance patterns strengthen this initial suspicion.
The second line of evidence is the physiological data provided by electrodiagnostic studies (NCS and EMG). These tests objectively confirm the presence of a peripheral neuropathy and classify it as demyelinating (Type 1), axonal (Type 2), or an intermediate form. The third evidence is the identification of a pathogenic gene mutation through genetic testing.
When all three components—clinical symptoms, abnormal nerve function, and a causative gene mutation—align, the diagnosis is confirmed. If clinical and physiological tests are positive for CMT but genetic testing fails to find a mutation, the diagnosis is still considered CMT. This situation highlights the complexity of these disorders, as the specific genetic subtype remains undiagnosed.