CMT Type 1
With the exception of Type 1X, which is inherited through the X Chromosome, CMT Type 1 is inherited in an autosomal dominant pattern. CMT Type 1 accounts for more than two-thirds of all cases of CMT.
This is the most common form of CMT, comprising at least 60 percent of all patients with CMT Type 1. The disorder is caused by a duplication of the PMP22 gene on Chromosome 17. Instead of having two copies of the gene (one of each paired chromosome), there are three copies, two on one chromosome and one on the other. PMP22 is a peripheral myelin protein, but its exact function in causing CMT is still not known. It is inherited in an autosomal dominant fashion.
CMT1A usually presents with a typical CMT phenotype (clinical presentation). Patients are slow runners in childhood, develop high arches, hammertoes and often require orthotics (braces) for ankle support. Varying degrees of hand weakness occur, often appearing as much as ten years after foot and leg problems. Problems with balance because of ankle weakness and loss of proprioception are common. Most patients remain ambulatory throughout life and life expectancy is normal.
This type is caused by a defect of the MPZ gene on chromosome 1. Again, MPZ is peripheral myelin protein, but its role is not known. Type 1B is an autosomal dominant disorder. Patients with 1B have a somewhat typical phenotype, but often with more pronounced calf wasting. There is a wide range of severity within Type 1B, from very severe forms such as Dejerine-Sottas (infantile onset) to milder cases with onset much later in life. (More than one type of CMT may be referred to as Dejerine-Sottas since the term refers to an age of onset of less than three years rather than to a unique genetic defect.)
Researchers at the University of Washington have recently identified the locus of Type 1C as Chromosome 16, the LITAF/SIMPLE gene. Type 1C is also autosomal dominant in inheritance. There is limited clinical information on patients with 1C, but they develop distal weakness, atrophy, and sensory loss and have slow nerve conduction velocity scores.
This type is caused by an early growth response protein 2, known as ERG2, found on Chromosome 10. Inheritance is autosomal dominant. Most cases of 1D are severe, such as Dejerine-Sottas, while a few have milder phenotypes presenting later in life.
Type 1F accounts for a very small percentage of cases. It is an autosomal dominant form of CMT in which the defect is on Chromosome 8 and the neurofilament light chain protein.
This second most common of form of CMT, accounting for 10-16 percent of all cases is found on the X Chromosome, one of sex chromosomes. The flaw is caused by a gap junction beta 1 protein connected to connexin 32. Typically, this form has onset in adolescence or childhood and often affects males more severely than females. An affected male with CMT1X cannot pass the defect to his son, but will pass it to all his daughters. An affected female has a 50% chance of passing the mutation to either her sons or her daughters.
CMT Type 2
CMT Type 2 represents axonal forms that are dominantly inherited and make up about one-third of all dominant CMT cases. The clinical presentation is similar to Type 1: distal weakness, muscle atrophy, sensory loss and foot deformities. Patients with Type 2 have a wider age range for onset of the disorder and more variation in degree of disability. They are slightly more likely to maintain their deep tendon reflexes.
The defect causing CMT 2A is found on chromosome 1p36 at the MFN2 gene. This gene is mutated and is involved in the fusion of mitochondria, the metabolic engines of the cells. This type of CMT is often severe and can include optic atrophy.
Type 2B is characterized by severe ulceration problems and the defect is located on chromosome 3, the RAB 7 protein. CMT 2B is predominantly a sensory disorder and there is some thought that it is not really CMT, but a pure sensory neuropathy.
This type is a very rare form in which patients may have diaphragm or vocal cord paresis in addition to the other problems of CMT. Linkage to chromosome 12 has been found.
The CMT 2D locus is on chromosome 7p14 and the genetic cause has been identified as mutations in the glycyl RNA synthetase gene. CMT 2D is a confusing disorder because some patients have sensorimotor neuropathies, while others have only motor symptoms.
CMT type 2E has been established with linkage to chromosome 8p21 and studies have identified mutations in the neurofilament light gene.