Charcot-Marie-Tooth disease

Peroneal muscle atrophy, syndrome or Charcot-Marie-Tooth disease is a whole group of chronic hereditary diseases with damage to peripheral nerves.

According to ICD-10 in the section of diseases of the nervous system, the code of this disease is G60.0 (hereditary motor and sensory neuropathy). It is also included in the list of orphan diseases.

Epidemiology

According to clinical statistics, the prevalence of all types of Charcot-Marie-Tooth disease per 100 thousand population is 19 cases (according to other sources, one case per 2.5-10 thousand population).

CMT type 1 accounts for about two-thirds of cases (one case per 5-7 thousand population), and almost 70% of them are associated with duplication of the PMP22 gene. In the world, this type of disease affects more than 1.2 million people.

The incidence of type 4 CMT is estimated at 1-5 cases per 10 thousand children. [1]

Causes charcot-Marie-Tooth disease

According to the  classification of polyneuropathic syndromes , peroneal (peroneal) muscle atrophy, Charcot-Marie-Tooth neural amyotrophy or Charcot-Marie-Tooth disease (abbreviated as CMT) refers to genetically determined motor-sensory polyneuropathies. [2]

That is, the reasons for its occurrence are genetic mutations. And depending on the nature of genetic abnormalities, the main types or types of this syndrome differ: demyelinating and axonal. The first group includes type 1 Charcot-Marie-Tooth disease (CMT1), which occurs as a result of duplication of the PMP22 gene on chromosome 17, which encodes a transmembrane peripheral myelin protein 22. As a result, segmental demyelination of the axonal sheath (processes of nerve cells) and a decrease in the speed of nerve conduction occurs. Signals. In addition, there may be mutations in some other genes.

The axonal form is Charcot-Marie-Tooth disease type 2 (CMT2), which affects the axons themselves and is associated with pathological changes in the MFN2 gene at the 1p36.22 locus, which encodes the membrane protein mitofusin-2, which is necessary for mitochondrial fusion and the formation of functional mitochondrial networks within cells peripheral nerves. There are more than a dozen subtypes of CMT2 (with mutations in specific genes).

It should be noted that more than a hundred genes have now been identified, the damage of which, inherited, causes various subtypes of Charcot-Marie-Tooth disease. For example, mutations in the RAB7 gene develop type 2B CMT; an alteration of the SH3TC2 gene (which encodes one of the proteins of the Schwann cell membranes) causes type 4C CMT, which manifests itself in childhood and is characterized by demyelination of motor and sensory neurons (one and a half dozen forms of type 4 of this disease are distinguished).

A rare type 3 SMT (called Dejerine-Sott syndrome), caused by mutations in the PMP22, MPZ, EGR2, and others genes, also begins to develop in early childhood.

When CMT type 5 occurs at the age of 5-12 years, not only motor neuropathy (in the form of spastic paraparesis of the lower extremities) is noted, but also damage to the optic and auditory nerves.

Muscle weakness and optic nerve atrophy (with loss of vision), as well as problems with balance, are characteristic of CMT type 6. And with type 7 Charcot-Marie-Tooth disease, not only motor-sensory neuropathy is observed, but also retinal disease in the form of retinitis pigmentosa.

The more common X-linked SMT or Charcot-Marie-Tooth disease with tetraparesis of the extremities (weakening of the movement of both arms and legs) among men is a demyelinating type and is considered the result of a mutation in the GJB1 gene on the long arm of the X chromosome, which codes for connexin 32, a transmembrane protein Schwann cells and oligodendrocytes, which regulates the transmission of nerve signals. [3]

Risk factors

The main risk factor for CMT is the presence of this disease in a family history, that is, in close relatives.

According to geneticists, if both parents are carriers of the autosomal recessive gene of Charcot-Marie-Tooth disease, the risk of having a child who will develop this disease is 25%. And the risk that a child will carry this gene (but he himself will not have any symptoms) is estimated at 50%.

In the case of X-linked inheritance (when the mutated gene is on the woman's X chromosome), there is a 50% risk that the mother will pass this gene on to her son, and he will develop CMT disease. When a female child is born, the disease may not occur, but the daughter's sons (grandchildren) can inherit the defective gene - with the development of the disease.

Pathogenesis

In any type of Charcot-Marie-Tooth disease, its pathogenesis is due to a hereditary anomaly of peripheral nerves: motor (motor) and sensory (sensory).

If the CMT type is demyelinating, then the destruction or defect of the myelin sheath, which protects the axons of the peripheral nerves, leads to a slowdown in the transmission of nerve impulses of the peripheral nervous system - between the brain, muscles and sensory organs.

In the axonal type of the disease, the axons are directly affected, which negatively affects the strength of nerve signals, which is insufficient for full stimulation of muscles and sensory organs.

Also read:

• Hereditary neuropathies
• Causes and pathogenesis of polyneuropathy

How is Charcot-Marie-Tooth syndrome spread? Defective genes can be inherited in an autosomal dominant or autosomal recessive manner.

The most common - autosomal dominant inheritance - occurs when there is one copy of the mutated gene (carried by one of the parents). And the probability of transmission of CMT to each of the children born is estimated at 50%. [4]

In autosomal recessive inheritance, the disease requires two copies of the defective gene (one from each parent who has no signs of the disease).

In 40-50% of cases, an autosomal dominant hereditary demyelination occurs, that is, CMT type 1; in 12-26% of cases - axonal CMT, that is, type 2. And in 10-15% of cases, X-linked inheritance is observed. [5]

Symptoms charcot-Marie-Tooth disease

Usually, the first signs of this disease begin to appear in childhood and adolescents and gradually develop throughout life, although the syndrome can make itself felt later. The combination of symptoms is variable, and the rate of progression of the disease, as well as its severity, cannot be predicted.

There are such typical symptoms of the initial stage as increased general fatigue; decreased tone (weakness) of the muscles of the feet, ankles and lower legs; lack of reflexes. This makes it difficult to move the foot and leads to dysbasia (gait disturbance) in the form of a higher elevation of the legs, often with frequent stumbling and falling. Signs of Charcot-Marie-Tooth disease in a small child may be pronounced clumsiness and difficulty walking, unusual for age, associated with a  bilateral dangling foot . Deformities of the foot are also characteristic: high arch (hollow foot) or strong flat feet, curved (hammer-like) fingers.

In the case of walking on toes against the background of muscular hypotension, the neurologist may suspect that the child has CMT type 4, in which children by adolescence may not be able to walk.

As it progresses, muscle atrophy and weakness spread to the upper extremities, making it difficult for fine motor skills and normal hand activities. A decrease in tactile sensations and the ability to feel warm and cold, as well as numbness in the feet and hands, indicates damage to the axons of the sensory nerves.

With manifested in childhood Charcot-Marie-Tooth disease of types 3 and 6, there is a sensitive ataxia (impaired coordination of movements and balance), muscle twitching and tremor, damage to the facial nerve, optic atrophy with nystagmus, hearing loss.

In later stages, there may be uncontrollable tremors (tremors) and frequent muscle cramps; problems with movement can lead to the development of pain: muscle, joint, neuropathic.

Complications and consequences

Charcot-Marie-Tooth disease can have complications and consequences such as:

• more frequent sprains and fractures;
• contractures associated with shortening of the periarticular muscles and tendons;
• scoliosis (curvature of the spine);
• breathing problems - with damage to the nerve fibers that innervate the muscles of the diaphragm:
• loss of the ability to move independently.

Diagnostics charcot-Marie-Tooth disease

Diagnostics includes clinical examination, history (including family history), neurological and systemic examination.

Tests are performed to check range of motion, sensitivity and tendon reflexes. Nerve conduction can be assessed by instrumental diagnostics - electromyography or  electroneuromyography . An ultrasound or MRI may also be required. [6]

Genetic or DNA diagnostics to identify the most common genetic mutations that cause CMT on a blood sample are limited, as DNA tests are not currently available for all types of CMT. For details see -  Genetic research

In some cases, biopsy of the peripheral nerve (usually the gastrocnemius) is done.

Differential diagnosis

Differential diagnosis is carried out with other peripheral neuropathies, Duchenne muscular dystrophy, myelopathic and myasthenic syndromes, diabetic neuropathy, with myeloaptias in case of multiple and amyotrophic lateral sclerosis, Guillain-Barré syndrome, trauma of the peroneal nerve and its disc atrophy (including spine), damage to the cerebellum or thalamus, as well as side effects of chemotherapy (when treated with cytostatics such as Vincristine or Paclitaxel). [7]

Treatment charcot-Marie-Tooth disease

Today, the treatment of this hereditary disease consists in physiotherapy exercises (aimed at strengthening and stretching the muscles); occupational therapy (which helps patients with muscle weakness in the hands); using orthopedic devices to facilitate walking. If necessary, take painkillers or anticonvulsants. [8]

In cases of pronounced flat feet, osteotomy can be performed, and in case of deformation of the heels, their surgical correction is indicated - arthrodesis. [9]

Research is underway on both the genetic component of the disease and methods of its treatment. The use of stem cells, some hormones, lecithin or ascorbic acid has not yet yielded positive results.

But thanks to the latest research, in the near future, a new one may really appear in the treatment of Charcot-Marie-Tooth disease. So, since 2014, the French company Pharnext has been developing, and since mid-2019, clinical trials of the drug PXT3003 are underway for the treatment of CMT type 1 in adults, which suppresses the increased expression of the PMP22 gene, which improves myelination of peripheral nerves and weakens neuromuscular symptoms. 

Specialists of the medical company Sarepta Therapeutics (USA) are working on a gene therapy for type 1 Charcot-Marie-Tooth disease. This therapy will use a harmless adeno-associated virus (AAV) of the genus Dependovirus with a linear single-stranded DNA genome, which will carry the NTF3 gene into the body, which encodes the neurotrophin-3 (NT-3) protein necessary for the functioning of Schwann nerve cells.

By the end of 2020, Helixmith will begin clinical trials of the Engensis gene therapy (VM202) developed in South Korea to treat muscle symptoms in type 1 CMT. [10]

Prevention

Prevention of CMT can be genetic counseling of future parents, especially if someone from a married couple has this disease in the family. However, cases of de novo gene point mutations have been identified, that is, in the absence of the disease in the family history.

During pregnancy, a chorionic villus sampling (from 10 to 13 weeks of gestation), as well as analysis of amniotic fluid (at 15-18 weeks), allows you to check the likelihood of Charcot-Marie-Tooth disease in an unborn child.

Forecast

In general, the prognosis for different types of Charcot-Marie-Tooth disease depends on the clinical severity, but in any case, the disease progresses slowly. Many patients have disabilities, although this does not reduce life expectancy.