Hereditary sensorimotor neuropathies. Hereditary motor-sensory neuropathy (NMSN, cmt, Charcot-Marie-Tooth disease) type I, II

This is the name of a large heterogeneous group of genetically determined diseases that manifest themselves multiple lesions motor and sensory fibers peripheral nerves. Hereditary motor-sensory neuropathies differ in the type of inheritance, variability of the clinical symptom complex and course characteristics, as well as the nature of electroneuromyography (ENMG) and morphological changes.

Symptoms of the development of hereditary motor-sensory neuropathies

This group hereditary diseases, characterized by genetically determined damage to the axial cylinder or myelin sheath of the nerves. Depending on the type of nerve fiber affected, two subgroups of the disease are distinguished:

hereditary motor-sensory neuropathies;

hereditary sensory or sensory-vegetative forms of the disease.

The disease was first described by French neurologists J.M. Charcot and P. Marie (Charcot Jean Martin (1825–1893), Marie Pierre (1853–1940)) in 1886. At the same time, the demyelinating type of hereditary motor-sensory neuropathy was described by Howard Tus, who first suggested a hereditary nature of this disease. From that moment on, long-term debates began about the classification of the found forms of hereditary polyneuropathies and methods of their treatment. Only with the development of electroneuromyographic and morphological research techniques nervous system managed to create an acceptable classification. P. J. Dyck and E. G. Lambert (Dyck, Lambert), analyzing the speed of impulse conduction and morphological changes in the structure of the nerve fiber, identified two types of this hereditary polyneuropathy: the first (NMSN I), called demyelinating or hypertrophic, was characterized by a decrease in SPI and the presence of onion-like changes in the biopsy specimen; the second (NMSMN II), called axonal, was characterized by normal or slightly reduced SPI and signs of degeneration of the axial cylinder (axon). Later in 1975, Dyck proposed to distinguish 5 more types of the disease:

• Dejerine-Sotta disease;
• Refsum's disease;
• the third type was characterized by a combination of signs of NMSN with spastic paraplegia;
• the fourth type was characterized by a combination of signs of NMSN with atrophy optic nerves;
• the fifth type was characterized by a combination of symptoms of hereditary motor-sensory neuropathy with retinitis pigmentosa.

Starting from the 1980s, a new period of studying polyneuropathies began - molecular genetics. On this moment 12 loci were mapped and 8 genes responsible for NMSI type I were identified, 11 loci were mapped and 3 genes responsible for NMSI type II were identified, 6 loci were mapped and 4 genes were identified responsible for NMSI with an autosomal recessive type of inheritance.

Symptoms of type I hereditary neuropathy

There are several types of disease caused by axonal degeneration or demyelination.

Type I of the disease is demyelinating. This includes Charcot-Marie-Tooth-Hofmann disease (Charcot-Marie-Tooth-Hofmann disease) – peroneal muscular atrophy. This type is a segmental demyelinating and remyelinating neuropathy manifested by peripheral nerve hypertrophy, neural muscle atrophy, degenerative changes in the anterior and posterior spinal roots, cells of the anterior horns spinal cord, posterior funiculi, spinocerebellar tracts.

Type of inheritance: autosomal dominant, less often autosomal recessive with varying expressivity of the mutant gene. Accounts for 51% of all inherited peripheral neuropathies in children. Mostly men are affected. Currently, in the group of hereditary motor-sensory neuropathy type 1, 12 loci have been mapped and 8 genes have been identified: PMP22, MPZ, EGR2, Cx32, MTMR2, PRX and NDRG1 and GDAPI.

1.PMP22 (peripheral myelin protein gene). 17p11.2–2 Mutation of this gene leads to the development of type 1 neuropathy. The main type of mutation is duplication (up to 3–4 copies) as a result of unequal crossing over.

MPZ (myelin basic protein gene). 1q22.1–23. Mutation of this gene leads to the development of hereditary motor-sensory neuropathy type J - a violation of the synthesis of myelin basic protein. The main type of mutation is point mutation.

EGR2 (early grow response). 10q21-22. It is a transcription factor for late myelin genes. Mutation of this gene leads to cessation of expression of the structural genes of mature myelin (MPZ and MBP).

4.NDRG1 (N-myc downstream-regulated gene 1). 8q24-qter. The function of the gene is not precisely determined. It is believed to be a signaling protein between the cytoplasm and the nucleus.

Cx32. Xq13.1. The main type of mutation of this type is point mutations. Mutation of this gene leads to disruption of the synthesis of a protein involved in the formation of glial intracellular channels.

MTMR2, 11q23. The main type of mutation is point mutation. Encodes the MTMR2 protein. It is believed that a decrease in the amount of this protein, mediated through an unknown substrate, increases the proliferation of Schwann cells and leads to the formation of disease-specific myelin folding.

GDAP1 (glycoprotein induced differential association gene). 8q21.1. The gene is believed to be involved in the process of signal transduction during neuron development.

The disease usually begins before puberty. Rarely develops in infancy (it requires differential diagnosis with NMSN-Sh).

Symptoms of hereditary motor-sensory neuropathy type I with different types inheritance

Signs of hereditary motor-sensory neuropathy type I for autosomal dominant and autosomal recessive types of inheritance:

atrophy of the muscles of the distal limbs with attached later atrophy muscles upper limb; atrophy usually does not extend above the elbows and knee joints; intentional tremors, trophic disorders in the limbs;

ENMG: reduction in the speed of impulses along motor and sensory fibers;

tendon reflexes as a symptom of hereditary motor-sensory neuropathy type I: a decrease or disappearance is detected in the affected area tendon reflexes in 60% of patients;

sensitivity: decreased vibration and muscle-articular sensitivity, much less often pain and temperature in the form of hypoesthesia in 70% of patients;

V in some cases polycythemia, paralysis eye muscles, bulging eyes, optic nerve atrophy.

Symptoms of the disease for an autosomal dominant type of inheritance:

onset of the disease in the first two decades of life;

thickening and compaction of peripheral nerve trunks, axonal atrophy with segmental demyelination;

slowly progressive course.

Symptoms of the disease characteristic of an autosomal recessive type of inheritance:

debut of hereditary motor-sensory neuropathy in the first 10 years of life;

delayed motor development;

ataxia and orthopedic deformities: symmetrical atrophy of small muscles of the foot and lower leg with the formation of a hollow foot, hammertoes, skeletal deformities, scoliosis, kyphoscoliosis, increased lordosis;

progressive course.

Symptoms of neuropathy in Rusi-Lewy syndrome

At the moment, this syndrome has lost its nosological independence and is considered as a variant of hereditary motor-sensory neuropathy and is caused by duplication of the PMP22 gene.

Clinical manifestation:

ataxia during the first attempts to walk, foot abnormalities; scoliosis of the spine;

progressive distal atrophy of the muscles of the legs (stork legs);

moderate atrophy of the eminences thumb and little finger;

lack of tendon reflexes in the arms and legs.

Babinski's sign (I) is sometimes positive in this type of hereditary motor-sensory neuropathy; disorders of deep sensitivity; impaired hand coordination (slight weakness and awkwardness); sometimes – pupillotonia; Congenital strabismus, cataracts, and mental retardation are often observed.

Manifestations of hereditary motor-sensory neuropathy type II

Type II of hereditary motor-sensory neuropathy – axonal (peroneal muscular atrophy, axonal type).

There are two subtypes of type II neuropathy:

• type A – Lambert type is autosomal dominant, inherited;
• type B – Ouvrier type is autosomal recessive, inherited.

The disease is based on axonal degeneration with preservation of the myelin sheath. With electroneuromyography, the impulse conduction velocity is usually normal, but the amplitude of muscle responses is significantly reduced. Both diseases (Lambert type and Ouvrier type) are very similar in their symptoms to hereditary motor-sensory neuropathies type I.

Eleven loci have been mapped for this disease, but only three genes have been identified.

LMNA/C. 1q21.2-q21.3. The proteins encoded by the gene, lamin A and C, form a fibrous layer on the inner nuclear membrane, which is the framework of the nuclear envelope.

NEFL. 8p21 Type of mutation - point. Encodes the light chain of neurofilament, a decrease in which leads to a decrease in axon diameter, leading to suppression of axonal transport and axon degeneration.

KIF1B. 1р35-р36. The type of mutation is missense. The kinesin protein encoded by this gene is involved in mitochondrial transport. This disrupts the functioning of axonal microtubules and vesicle transport. There are similar forms of hereditary motor-sensory neuropathy in which the kinesin gene mutation is not detected.

Symptoms of this type of neuropathy with different types of inheritance

Signs characteristic of an autosomal dominant type of inheritance (Lambert type):

autosomal dominant type of inheritance;

the onset of hereditary motor-sensory neuropathy occurs predominantly in adults;

lack of expression of atrophy of the distal limbs and sensitivity disorders;

ENMG: unmarked decrease in the speed of impulse transmission along the motor and sensory nerves;

axonal degeneration;

The course is benign, stabilization of the process is possible.

Symptoms of type II disease, characteristic of an autosomal recessive type of inheritance (Ouvrier type):

autosomal recessive type of inheritance;

debut of hereditary neuropathy in early age;

severe atrophy of the muscles of the distal limbs;

deformation of the hands and feet;

ENMG: decreased speed of impulse conduction along peripheral nerves (less than 38 m/s);

axonal degeneration;

rapidly progressing course.

Symptoms of types III and IV of hereditary motor-sensory neuropathy

Type III neuropathy - Dejerine-Sottas disease (morbus Dejerine-Sottas, degeneration Gombault, hypertrophic interstitial neuropathy of early childhood, interstitial hypertrophic progressive polyneuritis) is a demyelinating and remyelinating neuropathy, which is based on hypertrophy of the Schwann sheath of nerve fibers with compression and degeneration of axons, combined with significant bone deformations of the limbs and chest.

Inheritance: autosomal recessive type of inheritance with a large number sporadic cases. It occurs as a result of mutations in 4 genes: PMP22, MPZ, EGR2, NDRG.

The disease usually appears in the first year of life. The first sign is a decrease in motor development. About half of patients become wheelchair-bound as the disease progresses.

Clinical symptoms of hereditary motor-sensory neuropathies type III

autosomal recessive type of inheritance;

onset of the disease in the first years of life;

delayed motor development in the first year of life;

symmetrical progressive muscle atrophy, pes varus, pes equinivarus, as it progresses, involvement occurs proximal sections, in the area of ​​atrophy – disorders of trophism and sensitivity; weakness of the facial muscles with the expression of “pouting lips”;

sensory ataxia, instability in the Romberg position;

impairment of all types of sensitivity, loss of deep tendon reflexes;

eye symptoms hereditary motor-sensory neuropathy: nystagmus, paralysis of the eye muscles, delayed pupil reaction to light, anisocoria, miosis;

orthopedic deformities: deformities of the hands and feet, severe scoliosis;

ENMG: reduction in the speed of impulse conduction along peripheral nerves to 12 m/s or less;

pronounced segmental demyelination, onion-like formations in biopsy samples of peripheral nerves;

rapidly progressive course of hereditary motor-sensory neuropathy with profound disability by the 2nd–3rd decade of life.

Signs of hereditary motor-sensory neuropathy type IV

Type IV neuropathy – Refsum disease. Rare neurological disease. Chronic progressive polyneuropathy, which is based on the accumulation of phytanic acid in the body, formed from phytol; the latter is part of the chlorophyll that enters the body with food plant origin. The reason for the accumulation of phytanic acid is a metabolic defect - blockade of the oxidation of a-phytanic acid into a-hydroxyphytanic acid.

Features of the treatment of hereditary motor-sensory neuropathies

At the moment, treatment for type I disease has not been developed, so it is supportive in nature. Treatment options for hereditary motor-sensory neuropathy include:

physiotherapy, wearing special orthopedic shoes;

massotherapy;

surgical treatment– arthrodesis of the ankle joint with “drop foot”.

Treatment of other types of neuropathies is also supportive:

physiotherapy;

orthopedic measures according to indications.

First description NMSN, known in world literature, was made by French neurologists Charcot and Marie in 1886, in the article “Regarding specific shape progressive muscle atrophy, often familial, beginning with the feet and legs, and later affecting the arms.” At the same time, the disease was described by Howard Tut in his dissertation “Peroneal type of progressive muscular atrophy,” who was the first to make the correct assumption about the connection of the disease with defects in the peripheral nerves. In Russia, a neurologist, Sergei Nikolaevich Davidenkov, for the first time in 1934 described a variant of neural amyotrophy with increased muscle weakness when cooling.

Charcot-Marie-Tooth disease ( CMT), or Charcot-Marie neural amyotrophy, also known as hereditary motor-sensory neuropathy (HMSN), is a large group of genetically heterogeneous diseases of the peripheral nerves, characterized by symptoms of progressive polyneuropathy with predominant defeat muscles of the distal limbs. NMSI are not only the most common hereditary diseases of the peripheral nervous system, but also one of the most common hereditary human diseases. The frequency of all forms of NMSI varies from 10 to 40:100,000 in different populations.

The clinical and genetic heterogeneity of Charcot-Marie neural amyotrophy was the basis for the search for loci associated with these diseases. To date, more than 40 loci responsible for hereditary motor-sensory neuropathies have been mapped, and more than twenty genes have been identified, mutations in which lead to the development of the clinical phenotype of NMSN. All types of inheritance of NMCH have been described: autosomal dominant, autosomal recessive and X-linked. Autosomal dominant inheritance is the most common.

Primary nerve damage leads to secondary weakness and muscle atrophy. Fat “fast” people suffer the most nerve fibers, covered with a myelin sheath (“meat” fibers) - such fibers innervate skeletal muscles. Long fibers are more damaged, so the innervation of the most distal (remote) muscles, which experience greater stress, is first disrupted. physical activity These are the muscles of the feet and legs, and to a lesser extent the muscles of the hands and forearms. Damage to sensory nerves leads to impaired pain, tactile and temperature sensitivity in the feet, legs and hands. On average, the disease begins at the age of 10-20 years. The first symptoms are weakness in the legs, changes in gait (stamping, “cock” gait, or “steppage”), tucking of the shins, and sometimes mild transient pain occurs in the lower legs. Subsequently, muscle weakness progresses, atrophy of the leg muscles occurs, the legs take on the appearance of “inverted bottles”, deformation of the feet often occurs (the feet acquire a high arch, then the so-called “hollow” foot is formed), the muscles of the hands and forearms are involved in the process. When examined by a neuropathologist, a decrease or loss of tendon reflexes (Achilles, carporadial, less often knee) and sensory disturbances are revealed.

All motor-sensory neuropathies are currently assessed by electroneuromyographic (ENMG) and morphological characteristics are usually divided into three main types: 1) demyelinating (NMCNI), characterized by a decrease in impulse conduction velocity (ISV) along the median nerve, 2) axonal variant (NMSNII), characterized by normal or slightly reduced ISV along the median nerve, 3) intermediate variant (intermedia ) with SPI along the median nerve from 25 to 45 m/s. SPI value equal to 38 m/s, determined by the motor component median nerve, is considered a conditional boundary between NMSNI (SPI<38м/с) и НМСНII (СПИ>38m/s). Thus, ENMG research takes on special meaning for DNA diagnostics, since it allows one to select the most optimal algorithm genetic testing for every family.

The age of onset of the disease, its severity and progression depend on the type of neuropathy, but can vary greatly even within the same family. The most common form of the disease is NMSIA - from 50% to 70% of all cases of NMSI type 1 in various populations. In 10% of cases, X-linked forms of NMCH are detected, among which the form with a dominant type of inheritance, NMCHIX, predominates, accounting for 90% of all X-linked polyneuropathies. Among NMSII type II, the most common dominant form is NMSIIIA - in 33% of all cases (Table 1).

Hereditary motor-sensory neuropathies with an autosomal recessive type of inheritance are relatively rare, but are clinically indistinguishable from NMSN with an autosomal dominant type of inheritance. NMCH 4D(Lom), 4C, 4H and 4J are some of these diseases. It is noteworthy that frequent mutations characteristic of Roma are localized in the NDRG1 and SH3TC2 genes.

The Center for Molecular Genetics LLC has developed and is searching for the most frequent mutations of gypsy origin responsible for the development of NMCH 4D(Lom) (Arg148X) and 4C (Arg1109X). Also, the Center for Molecular Genetics LLC has developed a system for searching for repeated mutations in the genes GDAP1 (Leu239Phe), SH3TC2 (Arg954X and Arg659Cys), FIG4 (Ile41Thr) and FGD4 (Met298Arg and Met298Thr), responsible for autosomal recessive types of NMCH.

Table 1. Genes responsible for development various forms NMSN. (Genes are highlighted in blue, the analysis of which is carried out at the Center for Molecular Genetics LLC)

LLC Center for Molecular Genetics has developed and carries out diagnostics of NMSI I, II and intermediate types with autosomal dominant (AD), autosomal recessive (AR) and X-linked inheritance.

Developed by us. The kit is intended for use in molecular genetic diagnostic laboratories.

When conducting prenatal (antenatal) DNA diagnostics in relation to a specific disease, it makes sense to diagnose common aneuploidies (Down, Edwards, Shereshevsky-Turner syndrome, etc.) using existing fetal material, paragraph 54.1. Relevance this study due to the high total frequency of aneuploidy - about 1 in 300 newborns, and the absence of the need for repeated sampling of fetal material.

Most hereditary sensorimotor neuropathies are demyelinating (eg, Charcot-Marie-Tous disease type 1). The mode of inheritance can be autosomal dominant (most often), X-linked dominant, autosomal recessive and X-linked recessive; sporadic cases are common.

In childhood or adolescence, foot deformities (hollow feet with hammertoes, making it difficult to select shoes), foot drops, and progressive atrophy of the distal muscles of the legs and, later, the arms, appear. Due to atrophy of the muscles of the lower third of the thigh and lower leg, the legs take on the shape of inverted bottles. Tendon reflexes in the legs are lost early, in the arms much later. A moderate decrease in tactile, vibration and proprioceptive sensitivity also appears later.

Some patients have associated symptoms: optic nerve atrophy, retinal pigmentary degeneration, coordination disorders, extrapyramidal disorders, symptoms of damage to cortical motor neurons, scoliosis, dysraphism, autonomic disorders. Raynaud's syndrome is usually present, and thickened nerves are sometimes visible or palpable. Hollow foot is observed in a third of cases; this is a characteristic, but not pathognomonic symptom, not uncommon in healthy people.

Most cases are familial, although this is not always obvious (there are asymptomatic cases, some relatives consider their illness to be “arthritis”, etc.). In general, the disease progresses slowly, but can occur in different ways: while some patients lose their ability to work quite early, others work until retirement age.

The speed of propagation of excitation along the motor nerves is significantly reduced, the action potentials of the sensory nerves are reduced or absent. Nerve biopsies often show nerve hypertrophy with “onion-like” thickenings of Schwann cells resulting from alternating demyelination and remyelination.

Treatment is symptomatic; exercise therapy is important to prevent contractures and facilitate movements. Most patients need orthopedic shoes, some - retainers ankle joints, sometimes resort to surgical treatment contractures and paralysis.

Other hereditary sensorimotor polyneuropathies

Other forms of hereditary sensorimotor neuropathies include Charcot-Marie-Tous disease type 2, Dejerine-Sottes syndrome, and Refsum disease. Dejerine-Sotta syndrome is characterized by early start, severe course, severe thickening of nerves, ataxia, nystagmus, hyperkinesis, kyphoscoliosis, increased protein levels in the CSF.

Chronic demyelinating polyneuropathy with nerve hypertrophy is observed in some childhood leukodystrophies, combined in this case with optic atrophy, mental retardation or dementia, epileptic seizures and various movement disorders.

Sensorimotor neuropathy is included in clinical picture a number of hereditary metabolic disorders.

Among them, autosomal recessive ones predominate, but there are X-linked recessive ones (Fabry disease and adrenomyeloneuropathy). These diseases are rare but treatable, so it is important to diagnose them.

Prof. D. Nobel

Determination method Sequencing. An opinion from a geneticist is issued!

Material under study Whole blood (with EDTA)

Study of mutations in the LMNA gene.

Type of inheritance.

Autosomal recessive.

Genes responsible for the development of the disease.

The LMNA A/C (LAMIN A/C) gene encodes the lamin protein. Located on chromosome 1 in region 1q22. Consists of 12 exons.

Mutations in the lamin gene also lead to the development of dilated cardiomyopathy with rhythm and conduction disturbances (DCM), Emery-Dreyfus muscular dystrophy, Slovenian hand-heart syndrome, Hutchinson-Gilford progeria, familial partial lipodystrophy, Malouf syndrome, congenital muscular dystrophy, muscular dystrophy limb-girdle type 1B, mandibuloacral dysplasia, lethal restrictive dermopathy.

To date, more than 40 loci responsible for hereditary motor-sensory neuropathies have been mapped, and more than twenty genes have been identified, mutations in which lead to the development of the clinical phenotype of NMSN.

Definition of disease.

Charcot-Marie-Tooth disease (CMT), or Charcot-Marie neural amyotrophy, also known as hereditary motor-sensory neuropathy (HMSN) is a large group of genetically heterogeneous diseases of the peripheral nerves, characterized by symptoms of progressive polyneuropathy with predominant damage to the muscles of the distal extremities. NMSI are not only the most common hereditary diseases of the peripheral nervous system, but also one of the most common hereditary human diseases.

Pathogenesis and clinical picture.

The disease manifests itself at the age of 20-40 years and its clinical manifestations are largely similar to those of hereditary sensory neuropathies. The first signs of the disease are ulcers on the skin of the feet and legs, which often become infected. The occurrence of spontaneous amputations of the toes and severe sensitivity disorders is characteristic. Weakness and atrophy occur mainly in the muscles of the distal legs; involvement of the distal arms in the process was noted in only half of the patients. The appearance of pain and autonomic disorders not typical. There is significant intrafamilial variability in severity clinical manifestations.

Option B1 was described in 9 siblings from the same family with consanguineous parents. The disease manifests itself in the second decade of life and is characterized by typical clinical manifestations motor-sensory polyneuropathy with severe course. 80% of patients have equine foot deformity. Characterized by a decrease or disappearance of tendon reflexes in the legs. In 60% of patients in the described family, as the disease progressed, involvement in pathological process proximal muscle groups lower limbs. Kyphoscoliosis was detected in 30% of cases. The electromyogram reveals signs of axonal damage, a decrease in the amplitude of the M-response and sensory potential in the legs. The speed of impulse conduction along peripheral nerves, as a rule, is not changed.

Only at B2, a number of patients showed a decrease in the speed of impulse conduction along the motor and sensory fibers of the peripheral nerves (up to 30-40 m/sec). A morphological study of a peripheral nerve biopsy reveals a decrease in the number of myelin fibers, both small and large in diameter, processes of degeneration and regeneration of axons, as well as single bulbous thickenings of the nerves.

Frequency of occurrence:

For all forms, NMCH varies from 10 to 40:100,000 in different populations.

A list of mutations studied can be provided upon request.

Literature

1. Milovidova T.B., Shchagina O.A., Dadali E.L., Polyakov A.V. , Classification and diagnostic algorithms for various genetic variants of hereditary motor-sensory polyneuropathies // Medical genetics. 2011, vol. 10. N 4. p. 10-16.
2. Shchagina O.A., Dadali E.L., Tiburkova T.B., Ivanova E.A., Polyakov A.V., Features of clinical manifestations and algorithms for molecular genetic diagnosis of genetically heterogeneous variants of hereditary motor-sensory polyneuropathies. // Molecular biological technologies in medical practice, "Alfa Vista N", Novosibirsk, 2009 p.183-193.
3. Shchagina O.A., Mersiyanova I.V., Dadali E.L., Fedotov V.P., Polyakov A.V. Mapping and identification of genes for Charcot-Marie-Tooth disease type 2.// Medical Genetics, 2005, vol. 4, no. 8, pp. 378-382.
4. Bouhouche, A., Benomar, A., Birouk, N., Mularoni, A., Meggouh, F., Tassin, J., Grid, D., Vandenberghe, A., Yahyaoui, M., Chkili, T., Brice, A., LeGuern, E. A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am. J.Hum. Genet. 65: 722-727, 1999.
5. OMIM.