What is Charcot-Marie-Tooth (CMT) disease type 2?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Patients tend to present with symptoms later in life than patients with CMT1. They may have greater atrophy and distal leg weakness with relatively less hand weakness. Nerve hypertrophy is absent but is variable in CMT1 as well. CMT2 often presents a greater diagnostic dilemma because characteristic features such as enlarged nerves and near-pathognomonic neurophysiologic findings are absent. With later onset, this condition may be very difficult to differentiate from a late-life acquired neuropathy when the family history is unclear. While several disease genes have been identified, not all can be tested for commercially yet, and together they explain as many cases of CMT2 as is the case for disease genes in CMT1. In practice, CMT2 and CMT1 can rarely be differentiated by history and examination findings alone. As with other forms of CMT, phenotypic variation is common between and within families.

In CMT2A, the clinical presentation is typical. Affected members of a large southern Italian pedigree had distal weakness, wasting, hyporeflexia, and mild panmodal sensory loss. Nerve biopsies revealed a loss of large myelinated fibers but no myelin abnormalities.

CMT2B is a predominantly sensory neuropathy to the point that its classification with hereditary motor and sensory neuropathy (HMSN) is unclear. While neurophysiologic findings are established early in life, clinical onset may be much later. CMT2B was mapped to chromosome arm 3q13-q22, and 2 missense mutations (Leu129Phe and Val162Met) in the small guanosine triphosphatase (GTPase) late endosomal protein RAB7 were recently found. [18] RAB7 is ubiquitously expressed, and the authors found expression in sensory and motor neurons.

CMT2C usually starts in the first decade of life. Mild sensory loss is combined with weakness in the limbs, diaphragm, intercostal muscle, and vocal cords, which can lead to early death. Vocal cord dysfunction also occurs occasionally in several other CMT subtypes.

Patients with CMT2D may have worse hand than leg weakness and slow progression. Onset is usually in people aged 16-30 years. Tendon reflexes are usually absent in the arms and decreased in the legs. Progression is slow. It has been linked to chromosome arm 7p14.

CMT2E is characterized by worse leg weakness, slow progression, and onset in the second and third decades of life. Pes cavus was reported in 100% of patients older than 20 years, and some develop hyperkeratosis, although this association remains unclear. Missense mutations (Gln333Pro, protein rod domain and Pro8Arg, head domain) affecting the self-assembly of neurofilament light chain protein were found (chromosome arm 8p21).

Patients with Charcot-Marie-Tooth disease type 2F (CMT2F) have slow progression and worse distal weakness. In 2001, Ismailov et al reported a 6-generation family with autosomal dominant CMT of the axonal type from the Voronezh province of Russia. [19] Disease onset occurred in people aged 15-25 years. Patients had symmetric progressive weakness and atrophy of the lower limb muscles, resulting in foot drop and steppage gait. Wasting of upper limb muscles caused clawing of the hands several years later. Depressed or absent deep tendon reflexes were observed at an early stage. Mild-to-moderate sensory impairments occurred in the feet and hands in all the patients. The course of the disease was slowly progressive, with disability after 15-20 years, but reproductive fitness was conserved and life span not restricted. Linkage to chromosome arm 7q11-q21 was established.

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