Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease

Updated: Jan 07, 2016
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Robert H Meier, III, MD  more...
  • Print
Overview

Background

Charcot-Marie-Tooth disease (CMT) is the most common inherited neurologic disorder. CMT is characterized by inherited neuropathies without known metabolic derangements. In 1886, Professor Jean Martin Charcot of France (1825-1893) and his student Pierre Marie (1853-1940) published the first description of distal muscle weakness and wasting beginning in the legs, calling it peroneal muscular atrophy.

Howard Henry Tooth (1856-1926) described the same disease in his Cambridge dissertation in 1886, calling the condition peroneal progressive muscular atrophy. Tooth was the first to correctly attribute the disorder's symptoms to neuropathy rather than to myelopathy, as physicians had done before him. In 1912, Hoffman identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease and later was known as Charcot-Marie-Tooth-Hoffman disease.

In 1968, CMT was subdivided into 2 types, CMT-1 and CMT-2, based on pathologic and physiologic criteria. [1, 2] CMT has been further subdivided, based on the genetic cause of the disease. With the advent of genetic testing, all of the different diseases that fall under the heading of CMT syndrome eventually are likely to become distinguishable.

Next:

Pathophysiology

Charcot-Marie-Tooth disease (CMT) is actually a heterogeneous group of genetically distinct disorders with a similar clinical presentation. CMT-1A is a disorder of peripheral myelination resulting from a duplication in the peripheral myelin protein-22 (PMP22) gene. [3, 4] PMP22 -related neuropathies should be viewed as the consequence of impaired neuron–Schwann cell interactions that are likely to be operative during fetal development. [5]

Mutation in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ), [6, 7] causes CMT-1b and it accounts for 5% of patients with CMT. The mutation results in abnormal myelin that is unstable and spontaneously breaks down. This process results in demyelination, leading to uniform slowing of conduction velocity. Autosomal dominant hereditary motor and sensory neuropathies (HMSNs), CMT neuropathy) account for 60-70% of families with CMT. [8]

Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. A study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A are caused by loss or damage to large-diameter motor and sensory axons. [9] Pain and temperature sensations usually are not affected, because they are carried by unmyelinated (type C) nerve fibers.

In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance.

CMT-2 is primarily a neuronal (ie, axonal) disorder, not a demyelinating disorder. Type 2 results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT-2 is likely to display much more genetic heterogeneity than CMT-1. [10] Some cases of CMT-2 have also been linked to mutations in the MPZ gene. [11] CMT-3 (also known as Dejerine-Sottas disease) is characterized by infantile onset.

Type 3 results in severe demyelination with delayed motor skills and is a much more severe form than type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.

CMT-X (X-linked CMT) and CMT-4 are also demyelinating neuropathies.

Previous
Next:

Epidemiology

Frequency

United States

The prevalence of Charcot-Marie-Tooth disease (CMT) is 1 person per 2500 population. CMT is the most common inherited disorder that involves the peripheral nerves, affecting an estimated 150,000 people in the United States. [12] CMT-1 incidence is 15 persons per 100,000 population. CMT-1A incidence is 10.5 persons per 100,000 population, or 70% of CMT-1 cases. CMT-2 incidence is 7 persons per 100,000 population. CMT-X represents at least 10-20% of persons with the CMT syndrome.

International

In Japan, the prevalence of CMT is reportedly 10.8 cases per 100,000 population. [13] In Italy, the prevalence is reported to be 17.5 cases per 100,000 population, [14] and in Spain, it is 28.2 cases per 100,000 population. In Norway, estimated prevalence of CMT is 1 in 1214 and the prevalence of PMP22 duplication and of mutations in Cx32, MPZ, and MFN2 is 19.6%, 4.8%, 1.1%, and 3.2%, respectively. [15]

Mortality/Morbidity

Morbidity in Charcot-Marie-Tooth disease (CMT) is mainly secondary to distal muscle weakness and foot deformities. [16, 17] Neuropathic pain is also one of the reasons for significant morbidity. [18] In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.

Race

No race predilection is recognized in Charcot-Marie-Tooth disease.

Sex

There is no known sex predilection in Charcot-Marie-Tooth disease.

Age

The age of presentation for Charcot-Marie-Tooth disease (CMT) varies depending on the type of CMT. Please refer to the table under Causes.

Previous