Charcot-Marie-Tooth Disease Type 4 (CMT4)

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

✅ Fact-checked by José Lopes, PhD 

Charcot-Marie-Tooth disease type 4 (CMT4) is a rare type of CMT that causes damage to the myelin sheath, an insulating fat-rich layer surrounding nerve fibers that connect the brain and spinal cord to the motor and sensory muscles. The resulting muscle weakness is the hallmark of CMT4.

Symptoms typically begin in childhood, and people with this disease type may progressively lose the ability to walk.


CMT4 causes muscle weakness, mostly in muscles farther from the center of the body, called distal muscles, but sometimes also in those closer to the trunk, called proximal muscles. Changes in sensations — touch, pain, sound, or temperature — also may occur.

Patients also may develop other symptoms such as cataracts, a clouding of the eye lens, or deafness. The symptoms vary from mild to severe. Some subtypes of CMT4 cause severe symptoms with early onset.

In general, people with CMT4 have more severe symptoms than do those with CMT1 or CMT2.


There are 10 subtypes of CMT4, each caused by different genetic mutations. Each has its own characteristic symptoms.

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


CMT4 subtype A (CMT4A) is caused by recessively inherited mutations in the GDAP1 gene. Recessive inheritance means that for the disease to develop, a patient must have mutations in both gene copies — one from each biological parent.

About 75% of people with mutations in the GDAP1 gene have CMT4A.

GDAP1 codes for a protein called ganglioside-induced differentiation-associated protein 1 found in mitochondria, which are the energy-producing centers in the cell.

CMT4A patients usually experience symptom onset by age 20, and most before age 10. Symptoms include muscle wasting and contractures, or permanent shortening of the muscles, that affect both lower and upper limbs. Patients also may have delayed milestones, such as in sitting and walking. Most need walking assistance by age 30, and about 75% need a wheelchair later in life.

As the disease progresses, a hoarse voice can develop and vocal cord weakness also has been reported. Life expectancy and intelligence are normal.


CMT4B is caused by defects in the genes MTMR2 (CMT4B1) or SBF2/MTMR13 (CMT4B2), found on chromosome 11.

The MTMR2 gene codes for an enzyme called myotubularin-related protein 2, which modifies chemical messengers within the cell. Researchers have identified 17 MTMR2 gene mutations that cause CMT4B1.

The SBF2 gene, also called MTMR13, encodes for a protein called SET binding factor 2. As many as 24 SBF2 gene mutations have been identified in people with CMT4B2. It is thought that myelin folding is disrupted due to these mutations.

CMT4B patients usually become symptomatic early in life, with an average age of onset at 34 months, or by age 3. In contrast with most types of CMT, patients often experience both proximal and distal weakness.

Individuals with this disorder type also may experience glaucoma, a buildup of pressure within the eye that damages the optic nerve.


CMT4C is caused by mutations in the SH3TC2 gene, which is required for healthy myelin. Researchers have identified more than 70 SH3TC2 gene mutations associated with CMT4C.  

This form of CMT is characterized by early-onset severe spine deformities. Most affected children have scoliosis, a sideways curvature of the spine, that occurs by age 20. Progressive CMT symptoms such as muscle weakness usually manifest in the first 10 years of life, or during adolescence. Foot deformities — high-arched or flat feet — also are common. Patients often have mild difficulty with walking, and some may need a wheelchair. It is common to have lower and upper limb weakness, beginning in the hands and feet, and sometimes extending above the elbows and knees.

Hearing loss, vocal cord involvement, and facial weakness have been reported. Nerve conduction velocity, or the speed at which signals travel across nerve cells, is slow and usually ranges between 15 and 36 m/s in the arms.


Defects in the NDRG1 gene, located on chromosome 8, cause CMT4D.

This form of the disease was first described as a separate disorder in a Romani population. Symptoms include distal weakness, muscle wasting, sensory loss, foot and hand deformities, and loss of deep tendon reflexes — nerve reflexes that determine muscle contraction upon tapping.

CMT4D patients always develop deafness, which usually occurs between ages 15 and 30. Nerve conduction is severely reduced in younger patients.


CMT4E is caused by defects in the EGR2 gene, located on chromosome 10, which codes for a DNA-binding protein called early growth response 2. This protein induces the activity of several other genes involved in the formation of myelin. Mutations in EGR2 result in the loss of myelin.

Symptoms in this disease type are severe, and include delayed motor milestones, potential respiratory impairment, and slow nerve conduction velocities.


Also severe is CMT4F, a type of CMT caused by mutations in the PRX gene. PRX is located on chromosome 19 and codes for periaxin, a protein required to maintain myelin. Disrupted myelin structure can lead to loss of myelin, called demyelination, and to the impaired transmission of nerve impulses.

Nerve conduction studies show marked slowness, and onion bulb formations — layers of myelin-forming Schwann cells and the buildup of collagen around nerve fibers — are observed in nerve biopsies.

Mutations in the DRP2 gene also have been found to contribute to nerve damage in CMT4F. This gene codes for a protein called dystrophin-related protein 2 that forms a complex with periaxin. This complex aids in the formation of structures called Cajal bands, which are important in myelin assembly.


CMT4G is caused by mutations in the HK1 gene, which codes for a hexokinase enzyme that is important in sugar breakdown in cells.

In this subtype, symptoms start in early childhood, and include progressive distal muscle weakness and wasting, as well as delays in acquiring motor skills.

Patients also experience altered sensation and absent tendon reflexes, called areflexia. The speed at which electrical signals travel along nerve fibers is moderately reduced.

Deformities in the hands and feet have been reported in Romani in the Balkans.


CMT4H results from defects in the FGD4 gene, which codes for a protein called FRABIN. FRABIN has been suggested to play a key role in the proliferation and survival of Schwann cells.

This CMT form may result in mild to severe spine deformity and loss of myelin. Symptoms begin early in life and can vary from person to person.


Mutations in the FIG4 gene, located on chromosome 6, cause CMT4J.

Symptoms and age of onset vary, with some patients having rapidly progressive muscle weakness in childhood, while others experience a slow development of symptoms. Often a specific muscle will be affected on one side of the body but not the other. In some cases, moreover, only part of a limb is impacted, such as only one portion of the leg.

In adulthood, the disease typically progresses with more severe changes.

CMT4J causes intermediate-to-slow nerve conductions due to changes in myelin.


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