Classification Of Charcot Marie Tooth Disease

Charcot Marie Tooth (CMT) disease is a hereditary neuropathy that is classified as a genetically heterogeneous group of disease affecting the peripheral nervous system. It is the most common hereditary neuropathy and is also known as hereditary motor and sensory neuropathy (HMSN). Since it was first described by Charcot, Marie, and Tooth in 1886, it is coined by their names. Approximately 10-30 cases per 100,000 populations are affected by Charcot Marie Tooth, depending on the geographical area of origin.(1)

Classification Of Charcot Marie Tooth Disease

Classification Of Charcot Marie Tooth Disease

The classification of the disease is based on inheritance pattern and clinical, electrophysiological and pathological features. Dyck and Lambert in 1968 introduced the terminology ‘hereditary motor and sensory neuropathy’. They also classified HMSN type I (or Charcot Marie Tooth 1) as the autosomal dominant form with low conduction velocities and HMSN type II (or Charcot Marie Tooth 2) as the autosomal dominant form with preserved conduction velocities. In 1980 Harding and Thomas found out that the motor nerve conduction velocities have a bimodal distribution, so they set a threshold for median nerve conduction velocities (NCV) at 38 m/s between demyelinating HMSN type I (motor NCV <38 m/s) and the axonal HMSN type II (motor NCV >38 m/s).(1)

The most common classification of Charcot Marie Tooth includes the inheritance pattern (autosomal dominant, autosomal recessive, X-linked) and clinical findings along with either electrophysiological or anatomical pathology findings (demyelinating or axonal). The demyelinating form mainly affects the myelin sheath, which surrounds the axons of peripheral nerves. Since, myelin sheath protects and increases the nerve conduction velocities, when there is myelin loss, it results in low NCV. In the axonal form of the disease, the axon is affected and the NCV is preserved; however, the amplitude of the motor and sensory potentials is reduced. There are disease types in which both the axon and the myelin sheath are affected and they have intermediate conduction speeds; these are mostly X-linked diseases.(1)

The combination and interpretation of this data help in identifying different types of Charcot Marie Tooth and classifying them. The majority of the cases fall under Charcot Marie Tooth type 1, which is mainly autosomal dominant and is the demyelinating (loss of myelin sheath) form with reduced NCV. Additionally, Charcot Marie Tooth type 2 has autosomal dominant inheritance and is the axonal type; Charcot Marie Tooth type 4 has autosomal recessive inheritance pattern and is the most severe form. These types are further subdivided into subcategories.(1)

Charcot Marie Tooth 1 (HMSN I) is a peripheral myelination disorder that occurs due to a mutation in peripheral myelin protein-22 (PMP22) gene. The subtypes of CMT 1 include CMT 1A (most common) and CMT 1B, which are both autosomal dominant inheritance, CMT 1C (unknown autosome), CMT X1 (X-linked dominant), CMT X2 (X-linked recessive), CMT X3 (X-linked recessive) and autosomal recessive CMT 1.(2)

Charcot Marie Tooth 2 (HMSN II) is the axonal type that is caused due to axonal death and Wallerian degeneration and mutation in the ATP1A1 gene is noted. Its subtypes include CMT 2A, CMT 2B, CMT 2C, CMT 2D, which have all autosomal dominant inheritance and there is another CMT 2 that is autosomal recessive.(2)

Charcot Marie Tooth 3 (HMSN III) is also known as Dejerine-Sottas disease and has infantile-onset that results in severe myelin loss and delayed motor skills, it is more severe than Charcot Marie Tooth 1. It is inherited as an autosomal recessive pattern.(2)

Charcot Marie Tooth X and CMT 4, both are associated with myelin sheath loss and mutations in the PRPS1 gene is noted in CMT X, which is an X-linked inheritance.(2)
HMSN IV is also known as Refsum syndrome and is characterized by phytanic acid excess. It has an autosomal recessive inheritance pattern and there is tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increase in CSF protein.(2)

HMSN V is also known as spastic paraplegia in which there is an absence of sensory symptoms, but normal upper limbs.(2)

HMSN VI is characterized by optic atrophy.(2)

HMSN VII is associated with retinitis pigmentosa.(2)

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