Autosomal Recessive Charcot-Marie-Tooth Disease Type 4 (CMT4)

Autosomal recessive Charcot-Marie-Tooth disease type 4 (CMT4) is a group of inherited nerve diseases. It mainly damages the peripheral nerves, which control movement and feeling in the feet, legs, hands and arms. Because it is autosomal recessive, a child usually gets one faulty gene from each parent. The damaged nerves send weak or slow messages, so muscles slowly become thin and weak and feeling in the feet and hands decreases. There is no cure at present, but many treatments can reduce symptoms, protect joints and improve quality of life. Most evidence comes from studies of all types of CMT, not only CMT4, because care principles are very similar.

The term “type 4” is used for Charcot-Marie-Tooth forms that are both autosomal recessive and demyelinating. “Autosomal recessive” means a child must receive one faulty copy of the gene from each parent to get the disease. “Demyelinating” means the myelin coating around the nerve fibers is damaged. Myelin works like the plastic cover around an electric wire. When myelin is damaged, nerve signals travel more slowly and less strongly.PubMed+1

People with CMT4 usually develop symptoms in childhood or early teenage years. They often show weakness? in the feet and legs, foot deformities such as high arches or hammer toes, walking problems, and later sometimes weakness in the hands. The condition usually progresses slowly over many years, and the severity can be very different from person to person, even in the same family.NCBI+2malacards.org+2

Other names and types of autosomal recessive CMT type 4

Doctors and scientists use several different names for this group of diseases. These names often describe the same or very similar conditions. Some commonly used names include:

• Charcot-Marie-Tooth disease type 4 (CMT4)

• Autosomal recessive demyelinating Charcot-Marie-Tooth disease

• Hereditary? motor and sensory neuropathy? type 4 (HMSN type 4)

• Recessive demyelinating CMT

All these terms describe inherited nerve diseases that mainly damage the myelin of the peripheral nerves and follow an autosomal recessive pattern.orpha.net+1

CMT4 is not one single disease but a group of subtypes, each caused by a different gene. The main known autosomal recessive CMT4 subtypes and their usual gene changes are:PubMed+1

• CMT4A – caused by changes in the GDAP1 gene

• CMT4B1 – caused by changes in the MTMR2 gene

• CMT4B2 – caused by changes in the SBF2 gene

• CMT4B3 – caused by changes in the SBF1 gene

• CMT4C – caused by changes in the SH3TC2 gene

• CMT4D – caused by changes in the NDRG1 gene

• CMT4E – caused by changes in the EGR2 gene

• CMT4F – caused by changes in the PRX gene

• CMT4G – often linked to HK1 gene changes

• CMT4H – caused by changes in the FGD4 gene

• CMT4J – caused by changes in the FIG4 gene

Each subtype can have slightly different age of onset?, speed of progression?, and extra features (for example, some may also have scoliosis?, cataracts, or hearing problems), but they all share the basic pattern of a recessive demyelinating neuropathy.PubMed+2malacards.org+2

Causes

CMT4 is a genetic? disease, so the basic cause is a change (mutation) in one of the CMT4-related genes. Below are 20 important causes and contributing mechanisms, explained in simple words.

1. Mutations in the GDAP1 gene (CMT4A)
   Changes in the GDAP1 gene can disturb the normal function of mitochondria in nerve cells. Mitochondria are the “power plants” of the cell. When they do not work well, the long nerve fibers in the arms and legs cannot stay healthy, so they slowly stop working.PubMed+1

2. Mutations in the MTMR2 gene (CMT4B1)
   The MTMR2 gene helps control cell membranes inside Schwann cells, the cells that make myelin. Mutations cause abnormal folding of myelin and lead to “myelin outfoldings” seen on nerve biopsy?, which weakens the nerve signal.PubMed+1

3. Mutations in the SBF2 gene (CMT4B2)
   Changes in SBF2 affect similar pathways as MTMR2 and also produce abnormal myelin structure. This can cause early and sometimes severe? weakness and sensory loss, often starting in childhood.PubMed+1

4. Mutations in the SBF1 gene (CMT4B3)
   Mutations in SBF1 disturb how Schwann cells control their internal membranes. This again leads to demyelination and poor nerve conduction, giving weakness and foot deformities in young people.PubMed

5. Mutations in the SH3TC2 gene (CMT4C)
   The SH3TC2 protein is important for Schwann cell function and myelin maintenance. Pathogenic variants cause demyelination, scoliosis, and a typical CMT picture with early walking problems and sensory loss.ScienceDirect+1

6. Mutations in the NDRG1 gene (CMT4D)
   The NDRG1 gene is expressed in Schwann cells and is needed for stable myelin. Mutations lead to severe demyelination, sometimes with very early onset, and can be more common in certain ethnic groups due to founder mutations.ResearchGate+1

7. Mutations in the EGR2 gene (CMT4E)
   EGR2 is a transcription factor that controls the expression of many myelin genes. When EGR2 is changed, the whole myelin program in Schwann cells is disturbed, leading to severe peripheral neuropathy? and sometimes overlap with Dejerine–Sottas disease.NCBI+1

8. Mutations in the PRX gene (CMT4F)
   The PRX gene encodes periaxin, a structural protein that keeps myelin attached to the axon. Mutations cause extremely unstable myelin and can lead to very low nerve conduction speeds and early walking problems.malacards.org+1

9. Mutations in the HK1 gene (CMT4G)
   HK1 is involved in glucose metabolism inside cells. Changes in this gene can damage energy supply in Schwann cells, which then fail to maintain normal myelin, giving a recessive demyelinating neuropathy.PubMed+1

10. Mutations in the FGD4 gene (CMT4H)
    FGD4 plays a role in actin cytoskeleton regulation, which helps cells keep their shape and internal traffic. Defects in FGD4 damage Schwann cell structure, causing very early-onset demyelinating CMT with delay in walking and sometimes cranial nerve signs.NCBI+1

11. Mutations in the FIG4 gene (CMT4J)
    The FIG4 gene is important in phosphoinositide metabolism, which controls membranes in neurons and Schwann cells. Mutations can cause a mixed axonal and demyelinating neuropathy, sometimes with sudden worsening after infections or other stress.PubMed+1

12. Autosomal recessive inheritance and carrier parents
    In CMT4, both parents usually carry one faulty copy of the gene but are healthy. When a child receives the faulty copy from both parents, the child has no healthy copy left, so the disease appears. This inheritance pattern is the basic cause of all CMT4 subtypes.CMT Research Foundation+1

13. Consanguinity (parents related by blood)
    When parents are related (for example, cousins), they have a higher chance of carrying the same rare mutation. This increases the chance that a child receives two copies of the same faulty gene and develops autosomal recessive CMT4.ScienceDirect+1

14. Founder mutations in specific populations
    In some regions or ethnic groups, a specific mutation appeared many generations ago and has been passed down many times. This is called a founder mutation. It explains why certain CMT4 subtypes are more common in specific countries or groups.ScienceDirect+1

15. Primary demyelination of peripheral nerves
    A direct cause of symptoms is loss of myelin from the nerve fibers. This demyelination slows or blocks the electrical signals traveling along the nerves and is a key feature of CMT4 on nerve conduction studies and nerve biopsy.NCBI+1

16. Secondary axonal damage
    When myelin is damaged for a long time, the underlying axon can also degenerate. This axonal loss makes weakness and sensory loss more permanent and harder to recover from, even if myelin could be partly repaired.NCBI+1

17. Schwann cell dysfunction
    Many CMT4 genes are expressed in Schwann cells. When these cells do not function normally, they cannot wrap the axon properly with myelin or maintain that myelin over time. This Schwann cell failure is a direct biological cause of the neuropathy.PubMed+1

18. Impaired cellular trafficking and membrane recycling
    Genes like MTMR2, SBF2, and FIG4 are involved in how cells recycle membranes and control vesicles. When these pathways are disturbed, Schwann cells develop abnormal myelin structures, leading to nerve conduction problems.PubMed+1

19. Mitochondrial energy failure in nerves
    Some genes (for example GDAP1) affect mitochondrial function. If mitochondria cannot provide enough energy, long peripheral nerves, which require high energy to maintain their length, slowly fail, contributing to weakness and muscle wasting.ResearchGate+1

20. Gene–environment interaction (modifiers)
    The main cause is genetic, but other health problems (such as diabetes? or vitamin deficiencies) can add extra stress to already fragile nerves. These factors do not cause CMT4 by themselves but can make symptoms appear earlier or become more severe in someone who already has the gene mutations.Mayo Clinic+1

Symptoms

CMT4 mainly affects the feet, legs, and later the hands and arms. Symptoms usually start in childhood or early teens and progress slowly.

1. Weakness in the feet and lower legs
   One of the earliest signs is weakness in the muscles that lift the feet and toes. Children may trip often or have trouble running. Over time, the muscles in the calves can become thin and wasted, giving a “stork-like” appearance to the legs.Mayo Clinic+1

2. Foot drop and steppage gait
   Because the ankle muscles are weak, the person may not lift the front of the foot properly. The toes drag on the ground, so the person lifts the knees high to avoid tripping. This is called a steppage gait and is very common in CMT.malacards.org+1

3. High-arched feet (pes cavus)
   Many people with CMT4 develop very high arches. This deformity happens because some foot muscles are weak and others are relatively stronger, pulling the foot into an abnormal shape. Over time, walking and shoe fitting can become more difficult.malacards.org+1

4. Hammer toes and other toe deformities
   Toes may curl downwards (hammer toes) or become fixed in abnormal positions. This is also caused by imbalance between weak and relatively strong muscles. These deformities can cause pain?, calluses, and difficulty wearing normal shoes.Mayo Clinic+1

5. Loss of reflexes (areflexia)
   Tendon? reflexes at the ankles and knees are often reduced or absent. This happens because nerve signals do not travel properly in the damaged nerves. Loss of reflexes is a common finding on the neurologic exam in CMT.NCBI+1

6. Reduced feeling in feet and hands
   Sensory nerves are affected, so people may feel numbness?, tingling?, or “pins and needles,” especially in the toes and feet. Later, this can also affect the fingers. It may be hard to feel small injuries, temperature changes, or the position of the joints.Mayo Clinic+1

7. Balance problems and unsteady walking
   Because of muscle weakness? and loss of joint position sense, people with CMT4 can have trouble keeping balance, especially in the dark or on uneven ground. They may sway or appear clumsy when walking or standing still.Mayo Clinic+1

8. Hand weakness and difficulty with fine tasks
   As the disease progresses, weakness and wasting can spread to the hands. People may have trouble writing, buttoning clothes, using zippers, or holding small objects. Grip strength often becomes weaker over time.Mayo Clinic+1

9. Muscle cramps and pain
   Some patients experience cramps, aching muscles, or neuropathic pain (burning, shooting pain) in the feet and legs. This happens because damaged nerves send abnormal signals to the brain and muscles.Mayo Clinic+1

10. Fatigue? in legs during activity
    Walking long distances or standing for a long time can cause strong tiredness in the legs. The weak muscles have to work harder, and the damaged nerves cannot support sustained activity, so people may need frequent rest breaks.Mayo Clinic

11. Scoliosis and other spine deformities
    In some CMT4 subtypes, the muscles that support the spine are affected, leading to abnormal curvature of the spine (scoliosis). This can cause back pain? and may sometimes need bracing or surgery in severe cases.malacards.org+1

12. Delayed walking in early childhood
    In severe or very early-onset CMT4, children may sit and walk later than expected. Parents may notice that the child is slower to reach motor milestones compared with siblings or peers.malacards.org+1

13. Clumsiness and frequent falls
    Weak ankles, poor balance, and reduced feeling in the feet make it easy to trip over small obstacles. Children may be described as clumsy or poor at sports, and adults may have repeated ankle sprains or falls.Mayo Clinic+1

14. Cold, pale, or discolored feet
    Because of poor muscle activity and nerve damage, blood flow in the feet can be reduced. The feet may feel cold, look pale, or change color, especially in cold temperatures.Mayo Clinic+1

15. Possible hearing or vision-related issues in some subtypes
    A few CMT4 subtypes can have extra features such as hearing loss or eye problems (like cataracts) because the same gene is also important in nerves or tissues in these organs. Not everyone has these problems, and they depend on the specific subtype.Charcot-Marie-Tooth Association+1

Diagnostic tests

Doctors use a combination of clinical? examination, electrodiagnostic tests, genetic tests, and sometimes imaging or biopsy studies to diagnose CMT4 and to separate it from other kinds of neuropathy.

Physical exam–based tests

1. Complete neurologic examination
   The neurologist checks muscle strength, reflexes, muscle size, and different kinds of sensation (touch, vibration, pain, temperature). In CMT4, they often find distal weakness, muscle wasting, absent ankle reflexes, and reduced sensation in a “stocking-and-glove” pattern.NCBI+1

2. Gait and posture assessment?
   The doctor watches how the person walks, turns, and stands. A steppage gait, frequent tripping, and difficulty walking on heels are typical signs. The examiner also looks for scoliosis and abnormal posture, which can appear in some CMT4 subtypes.malacards.org+1

3. Foot and skeletal examination
   The feet are carefully inspected for high arches, flat feet, hammer toes, calluses, and ankle instability. The doctor may also check the shape of the spine and the alignment of the knees and hips. These findings support the diagnosis? of a long-standing neuropathy like CMT4.malacards.org+1

4. Family history? and pedigree analysis
   A detailed family history helps identify an autosomal recessive pattern. In CMT4, both parents may be healthy, but several siblings can be affected. Drawing a family tree helps doctors suspect a recessive neuropathy and guides genetic testing.CMT Research Foundation+1

Manual bedside tests

5. Manual muscle testing (MRC scale)
   The doctor tests each major muscle group by hand and scores the strength from 0 to 5. In CMT4, distal muscles (for example, ankle dorsiflexors and hand muscles) usually score lower than proximal muscles. This pattern helps distinguish CMT from other diseases.NCBI

6. Romberg test for balance
   The person stands with feet together, first with eyes open and then closed. If they sway or fall more with eyes closed, it suggests loss of position sense in the legs, which is common in sensory neuropathies like CMT4.NCBI+1

7. Heel-toe and tandem walking tests
   The doctor asks the person to walk on heels, on toes, and in a straight line, placing one foot directly in front of the other. Difficulty with these tasks shows weakness and balance problems typical of peripheral neuropathy.Cleveland Clinic+1

8. Hand function and grip strength tests
   Simple tasks such as buttoning a shirt, picking up small objects, or squeezing the examiner’s fingers give quick information about hand weakness and fine motor problems, which often appear later in CMT4.Mayo Clinic+1

Lab and pathological tests

9. Basic blood tests to rule out other neuropathy causes
   Blood tests (such as fasting glucose, vitamin B12, thyroid? function, kidney? and liver? tests) are done to rule out acquired causes of neuropathy like diabetes or vitamin deficiency. These tests do not diagnose CMT4 directly but help confirm that the neuropathy is likely inherited.NCBI+1

10. Genetic testing for CMT4-related genes
    A blood sample is taken and DNA is analyzed for known CMT genes. Panels now include genes such as GDAP1, MTMR2, SBF2, SBF1, SH3TC2, NDRG1, EGR2, PRX, HK1, FGD4, and FIG4. Finding disease-causing variants in both copies of one of these genes confirms autosomal recessive CMT4.PubMed+2nhs.uk+2

11. Targeted or whole-exome sequencing when panel is negative
    If a standard CMT panel does not find a mutation, broader genetic tests such as whole-exome sequencing may be used. This can discover rare or new variants and helps classify unusual or unclear cases of autosomal recessive neuropathy.ARUP Consult+1

12. Nerve biopsy (usually sural nerve)
    In a few cases, a small piece of a sensory nerve (often the sural nerve near the ankle) is removed and studied under the microscope. In CMT4, pathologists often see loss of myelinated fibers, onion-bulb formations, and sometimes myelin outfoldings, which support a demyelinating inherited neuropathy.Muscular Dystrophy Association+2NCBI+2

Electrodiagnostic tests

13. Nerve conduction studies (NCS? / NCV)
    Small electrodes stimulate a nerve and record how fast and how strongly the signal travels. In CMT4, motor nerve conduction velocities are usually very slow, showing demyelination. NCS helps confirm neuropathy, classify it as demyelinating, and separate CMT4 from axonal or acquired neuropathies.NCBI+2NCBI+2

14. Electromyography (EMG)
    A thin needle electrode is inserted into muscles to record their electrical activity. EMG shows signs of chronic denervation and reinnervation, meaning that nerves have been slowly failing and muscles are trying to adapt. EMG is very useful to confirm that weakness comes from neuropathy, not from muscle disease.NCBI+1

15. F-wave and late response studies
    Special nerve conduction tests called F-waves and H-reflexes check the whole length of motor pathways from limb to spinal cord and back. In CMT4, these responses are often delayed or absent, supporting widespread demyelinating neuropathy.NCBI+1

16. Somatosensory evoked potentials (SSEPs) in selected cases
    In some centers, SSEPs are used to measure how sensory signals travel from the limb to the brain. Delayed responses can show that sensory pathways are affected along their length, which is expected in severe inherited neuropathies like some CMT4 subtypes.NCBI+1

Imaging tests

17. X-rays of feet and spine
    Plain X-rays can document high arches, hammer toes, ankle deformities, and scoliosis. This helps orthopedic planning and also provides objective proof of long-standing muscle imbalance caused by the neuropathy.malacards.org+1

18. MRI of the spine or brain (to exclude other causes)
    MRI imaging is sometimes used to make sure that weakness is not caused by problems in the spinal cord or brain, such as tumors or inflammation. In CMT4, MRI of the nervous system is often normal or shows only mild changes, supporting a peripheral nerve problem.NCBI+1

19. Ultrasound of peripheral nerves
    High-resolution ultrasound can show thickened or abnormally shaped peripheral nerves in some inherited neuropathies. It is a painless test and can support the diagnosis when combined with nerve conduction and genetic results.NCBI+1

20. MRI of muscles (muscle imaging)
    MRI of the legs and feet can show patterns of muscle wasting and fatty replacement that match a chronic neuropathy. Different neuropathies can show different patterns, so muscle MRI can sometimes help distinguish CMT4 from other nerve or muscle diseases.NCBI+1

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Last Updated: December 31, 2025.