What is DI-CMT?

Dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) is a rare, dominantly inherited type of CMT that is characterized by intermediate nerve conduction velocity (NCV). That means the NCV in patients with DI-CMT lies in between the NCVs observed in demyelinating CMT (CMT caused by loss of myelin) and axonal CMT (CMT caused by axonal degeneration).

The NCV in demyelinating CMT is significantly slow, typically about 20 m/sec and usually less than 40 m/sec. The NCV in axonal CMT also is slow, but nearer the normal range, usually more than 38 m/sec. (The normal range of NCV is 50-60 m/sec).

The NCV in DI-CMT overlaps the NCVs of axonal and demyelinating NCVs. The affected individuals in a family with intermediate CMT have motor conduction velocities in both the axonal CMT and demyelinating CMT ranges, i.e., above and below 38 m/sec. This may be due to abnormalities in both axons and the myelin sheath since nerve biopsies from patients with DI-CMT have shown axonal degeneration as well as demyelination.

Inheritance

DI-CMT is inherited in an autosomal dominant manner, which means the disease develops even if there is a defect (mutation) in just one of the two copies of a gene. Thus, an individual develops DI-CMT if he/she inherits the defective gene from just one parent. The defective copy of the gene dominates the effect of the normal copy, so the parent carrying the faulty gene also has the condition. An affected individual has a 50 percent chance of passing the faulty gene to his or her children.

Causes

There are three types of DI-CMT — DI-CMTB, DI-CMTD, and DI-CMTC, depending on which genes are mutated.

DI-CMTB

DI-CMTB is caused by mutations in the DNM2 gene. This gene encodes for a protein called dynamin 2, which is involved in endocytosis (the process by which the cell takes in substances) and the organization of cell structure.

Researchers have identified a few DNM2 gene mutations that cause DI-CMTB. The mutations impair the activity of the dynamin 2 protein and may disrupt endocytosis and cellular organization. Researchers suggest that the mutations also may cause dysfunction of the Schwann cells (cells that produce myelin). It is unclear how DNM2 gene mutations cause the signs and symptoms of CMT.

DI-CMTD

DI-CMTD is caused by mutations in the MPZ gene. This gene encodes for myelin protein zero, which is required for the proper formation and maintenance of myelin.

Several mutations in the MPZ gene can cause DI-CMTD, although the exact mechanism is not known. DI-CMTD often does not become evident until adulthood.

DI-CMTC

DI-CMTC is caused by mutations in the YARS gene. This gene provides instructions for making an enzyme called tyrosyl-tRNA synthetase, which plays an important role in production synthesis.

Three mutations in the YARS gene have been associated with DI-CMTC. These mutations probably reduce the activity of tyrosyl-tRNA synthetase, which could affect the synthesis of any protein that contains tyrosine. It is unclear exactly how these mutations lead to DI-CMTC.

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