Charcot-Marie-Tooth (CMT) disease type 1
Incidence
CMT disease is the most common peripheral neuropathy, having an estimated prevalence of 1:2500 individuals. Families with CMT phenotype appeared to segregate in a Mendelian fashion, with autosomal dominant transmission most commonly observed.
Clinical Characteristics
Charcot-Marie-Tooth (CMT) disease, also known as "peroneal muscular atrophy," is characterized by a progressive muscular atrophy with initial involvement of feet and legs. Symptoms start in the first or second decade of life. Muscle weakness is usually detected as an abnormality of gait (typically steppage or equine gait) or clumsiness in running. Cramps are frequently reported. Physical examination often reveals foot deformities, including pes cavus or equinovarus, and an "inverted champagne bottle" appearance of lower limbs. Deep tendon reflexes are usually absent. Sensory symptoms are very mild, and the patients report them as diminished sensation over the feet. This results in calluses, and less often ulcers, which develop over pressure points. Later in life, patients may experience weakness of intrinsic hand muscle, which may lead to a "claw hand" appearance. Both interfamilial and intrafamilial variability of phenotypic expression has been described in CMT. Families with CMT phenotype appeared to segregate in a Mendelian fashion, with autosomal dominant transmission most commonly observed. CMT1 families with X-linked dominant (CMTX1) and with X-linked recessive (CMTX2) inheritance patterns have been reported. It is now clear from electrophysiological and genetic studies, that the term CMT generally refers to phenotypically similar conditions caused by mutations at distinct genetic loci. On the basis of the electrophysiological data, CMT patients can be divided into two major categories: CMT type 1 disease (CMT1) patients showing decreased motor-nerve conduction velocity (MNCV) and CMT2 patients with normal MNCV. Electrophysiology represents an important diagnostic tool for CMT disease. The conduction velocities of peroneal and ulnar nerves in the patients are, on average, less than half the values of normal individuals. There is a general agreement that 38 m/sec is considered to be the threshold MNCV value for defining CMT1. However, some patients with values slightly above 38 m/sec have been described in families with CMT1. Therefore, it has been recommended that mean values of MNCV of all affected members in the kindred be used for CMT1 diagnosis. Although not practical for screening purposes, sensory-nerve conduction velocity (SNCV) measurements are also abnormal in CMT1, and it has been suggested that they may provide a better discrimination between CMT1 and CMT2. Little information is available on the age at which MNCV abnormalities first appear; patients with CMT1 have normal MNCV at birth, and they clearly show MNCV abnormalities by 4 to 5 years of age. There is no correlation between the degree of MNCV abnormalities and the severity of the phenotype. Since there is no pharmacological treatment available for CMT, the therapy is symptomatic. Patients are advised to maintain normal body weight, to have good foot care, and to enroll in physical fitness programs. More severely affected individuals should undergo proper physical therapy.
Precipitants
no
Provocation Tests
no
Diagnostic Procedures
DB-W. Electrophysiology represents an important diagnostic tool for CMT disease. The conduction velocities of peroneal and ulnar nerves in the patients are, on average, less than half the values of normal individuals. DNA duplication is the most common defect in CMT1 and is seen in approximately 70 percent of the patients. The duplication is stably transmitted through both meiosis and mitosis, and there is a high frequency of de novo duplication events. The majority of patients with CMT type 1A (CMT1A) have a submicroscopic duplication involving the short arm of chromosome 17 (17p11.2). The region of chromosome 17 spanning the duplication (17p11.2-p12) has been characterized in detail. The finding of a duplication in the majority (>65 percent) of patients with CMT1 greatly facilitates diagnosis. Presymptomatic and prenatal diagnosis can be offered to families with CMT1A. Molecular diagnosis can now be performed also in sporadic CMT1 cases to differentiate between CMT1A and other types of CMT1. The duplication can be identified by the following methods: RFLP analysis by Southern blotting, PCR analysis using short tandem repeats (STR), PFGE analysis and FISH analysis. RFLP analysis seems to be the most efficient method so in most cases RFLP analysis should be performed first and PFGE analysis may be used in uninformative cases, and as an independent molecular method to confirm the RFLP results. The pathology findings in CMT patients have been extensively described. These include spinal cord and peripheral nerve abnormalities. Demyelination and gliosis, often associated with enlargement of the peripheral nerves, are the most frequent findings. Onion bulb structures, consisting of circumferentially directed Schwann cells and their processes, can be observed at internodes under phase and electron microscopy.