Dominant Intermediate Charcot-Marie-Tooth Disease (DI-CMT)

Dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) is a rare type of CMT, known for its symptoms of muscle weakness and wasting, that is characterized by intermediate nerve conduction velocity (NCV). NCV is the speed at which an electrical impulse moves through a nerve fiber, measured in meter per second, or m/s.

Intermediate NCV lies between the velocities observed in CMT type 1 (CMT1) and type 2 (CMT2). The NCV in CMT1 — caused by loss of myelin, the insulating layer of nerve fibers — is significantly slow, typically about 20 m/s and usually less than 40 m/s. Meanwhile, in CMT2, which is caused by nerve fiber degeneration, NCV is nearer the normal range, usually above 38 m/s.

Individuals in a family with intermediate CMT may have motor conduction velocities in both the CMT1 and CMT2 ranges, or specifically, above and below 38 m/s. This may be due to abnormalities in both nerve fibers and myelin, which may be observed in nerve biopsies.

Symptoms

Symptoms of DI-CMT range from mild to moderately severe, and typically include slowly progressive muscle weakness and atrophy, or wasting, of the distal extremities — the muscles in the limbs farthest from the center of the body. Sensory loss in the extremities, reduced or absent deep tendon reflexes, and feet deformities all are common. Other signs include neutropenia, or unusually low numbers of a type of white blood cells called neutrophils, and early-onset cataracts, which refers to the clouding of the eye lens.

Some patients may experience tremors in the arms, as well as neuropathic pain, or a pain that comes from the spinal cord, the brain, and the peripheral nerves. The peripheral nerves are those located outside the spinal cord and brain, which comprise the central nervous system.

Inheritance

DI-CMT is inherited in an autosomal dominant manner. That means the disease develops even if there is a mutation in just one of the two copies of a gene inherited from the biological parents. An affected individual has a 50% chance of passing the faulty gene to his or her children.

Causes and types

There are five subtypes of this CMT form: DI-CMTB, DI-CMTC, DI-CMTD, DI-CMTE, and DI-CMTF. Each has its own characteristics.

Understanding the differences between these subtypes is important for both prognosis and treatment.

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.

Mutations in DNM2 impair the activity of the dynamin 2 protein and may disrupt endocytosis and cellular organization. Researchers suggest that DNM2 mutations also may cause dysfunction of Schwann cells — cells that produce myelin.

Of note, mutations in the DNM2 gene also may cause CMT2 subtype M.

DI-CMTC

DI-CMTC results from mutations in the YARS gene, which provides instructions for making an enzyme called tyrosyl-tRNA synthetase that plays an important role in protein production. Specifically, this type of enzyme is responsible for linking amino acids, the building blocks of proteins, to their corresponding tRNA molecule.

DI-CMTD

Defects in the MPZ gene cause DI-CMTD. This gene codes for myelin protein zero, which is required for the proper formation and maintenance of myelin.

Notably, mutations in MPZ may also cause CMT1 subtype B, as well as CMT2 (subtypes I and J).

DI-CMTE

DI-CMTE is caused by mutations in the INF2 gene, which codes for the protein inverted formin-2. Important in cell structure, this protein also is involved in responses to DNA damage, cellular stress, and low oxygen.

These mutations may affect the structure of Schwann cells and therefore disrupt myelin production.

This subtype of CMT is related to a condition called focal segmental glomerulosclerosis, which causes elevated protein in the urine (proteinuria) and may progress to end-stage renal disease.

DI-CMTF

Normally manifesting in adolescence, DI-CMTF is caused by mutations in one of two genes: GNB4 and NEFL. GNB4 codes for guanine nucleotide-binding protein subunit beta-4, which has been reported to play a role in peripheral nerve regeneration and functioning. The NEFL gene codes for neurofilament light polypeptide, which has an important role in neuronal structure.

Defective NEFL gene also is a cause of CMT1 subtype F and CMT2 subtype E.

 

Last updated: Feb. 3, 2022, by Teresa Carvalho MS

 


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