Duchenne dystrophy symptoms in children. Severe genetic duchenne myodystrophy. Mental Disorders

Duchenne muscular dystrophy is a rare disease. Its other name is Duchenne muscular dystrophy or progressive Duchenne muscular dystrophy. The name is due to the fact that the disease progresses rapidly. The disease occurs in about 3 out of 100,000 people. The pathology is caused by a congenital genetic anomaly, is severe and affects a large group of muscles. Over time, dystrophy of the muscular system leads to the complete inability to move independently.

Duchenne myodystrophy leads to the pathology of other organs, which significantly reduces a person's life expectancy.

The vast majority of patients with Duchenne muscular dystrophy are boys. Girls suffer from this disease extremely rarely. It is a congenital disease that is caused changes in the X chromosome. There is a gene on the X chromosome that controls the production of the dystrophin protein. This protein affects the integrity of the membranes of muscle fibers (sarcolemmas) and the resistance of muscles to stretching. It also controls calcium levels in muscle tissue and muscle growth. If a deficiency of dystrophin protein is formed in the human body, then this leads to the gradual destruction of muscle cells (myocytes). Degenerative changes occur in the muscles, muscle fibers atrophy, break down and are replaced by adipose and connective tissue.

With progressive Duchenne muscular dystrophy, the content of normal dystrophin drops sharply due to a gene mutation. This protein is either completely absent, or the body contains defective dystrophin. In sick people, the level of normal dystrophin in the body is not more than 3%.

Girls and women very rarely suffer from this type of muscular dystrophy. But they are often carriers of the altered gene. This is due to the way the disease is transmitted through the X chromosome. As you know, the chromosome set of a man is XY, and women - XX. If the boy's mother has a defective X chromosome in her genetic set, then the boy can be born sick, even if the father is not sick.

A girl is born with Duchenne muscular dystrophy only if the mother is a carrier of the defective gene, and the father suffers from this disease. Such cases are very rare. Most often, a girl born from a mother who is a carrier of a defective gene also becomes a carrier of the disease and passes it on to her sons.

However, progressive Duchenne dystrophy is not necessarily transmitted to the child from the parents. There are cases when a genetic failure occurs as a result of a random mutation. It also happens that a sick child is born to absolutely healthy parents who are not carriers of defective genes.

Symptoms of Duchenne muscular dystrophy

Usually the disease manifests itself at the age of 1-5 years. It affects not only the muscles of the skeleton, but also other organs.

1. Skeletal muscle damage is an early sign of a disease that occurs in a young child.
2. Progressive muscle weakness.
3. Due to muscle damage, the bones of the skeleton are deformed.
4. The disease affects not only the muscles of the skeleton, but also leads to changes in the heart. Some children with Duchenne muscular dystrophy lag behind in mental development.
5. The disease leads to disruption of the endocrine glands.

Skeletal muscle injury

Muscle damage is the main and early sign of the disease. Muscle symptoms become noticeable at the age of 1-5 years.

In infancy, the child looks healthy. One can only notice that such children under the age of one year are inactive and reluctant to make any movements. Most often, parents do not attach any importance to this and associate the child's low physical activity with individual developmental characteristics.

The disease progresses, many children lose the ability to walk by the age of 12. They have to use a wheelchair.

In adolescence, the respiratory muscles are involved in the painful process. It becomes difficult for the child to breathe, he is disturbed by asthma attacks, especially at night. Because of this, children are afraid to sleep. This can lead to respiratory failure.

Bone lesions

Changes in the muscles lead to damage to the bones of the skeleton. There are curvature of the spine (scoliosis, lordosis), stoop (kyphosis). And also the chest and feet are bent. Bones become thinner and brittle (diffuse osteoporosis). Bone damage further limits the ability of patients to move independently.

Heart disorders

Duchenne muscular dystrophy causes cardiomyopathy. The heart muscle is also involved in the pathological process. The heart increases in size, while its functions are violated. Patients complain of arrhythmia and jumps in blood pressure. Over time, heart failure may develop.

Hormonal disorders

Duchenne muscular dystrophy often leads to the development of Cushing's syndrome. Obesity occurs with fatty deposits in the upper body. Obesity is combined with insufficiency of gonadal function. Sometimes the genitals are underdeveloped. Patients with Duchenne muscular dystrophy are often short and overweight.

Intellectual impairment

Mental retardation is not observed in all cases. Approximately 30% of patients with Duchenne myodystrophy have mental retardation and a low IQ. This is due to a lack of apodystrophin in the brain. A general lack of dystrophin protein in the body leads to a deficiency of its special form - apodystrophin. This substance is necessary for the normal functioning of the brain, its deficiency leads to mental disorders. The degree of mental retardation in this disease is in no way related to the severity of muscle disorders. With severe muscle weakness, there may be normal intelligence.

Due to the inability to move normally, such children are often isolated from the society of their peers, they cannot attend preschool and school institutions. This can exacerbate mental impairment.

Diagnosis of Duchenne myodystrophy

For the diagnosis of myodystrophy, several types of research are used:

Treatment of Duchenne muscular dystrophy

To date, there is no radical treatment for this disease. The disease is considered incurable and progressive. It inevitably leads to disability of the patient.

Symptomatic therapy is possible to alleviate the manifestations of the disease.

Medications in the treatment of Duchenne myodystrophy

Physiotherapy

Physiotherapeutic methods of treatment help to preserve the patient's motor function for a while. Patients are contraindicated in complete immobility and bed rest, this only leads to a very rapid development of the disease. Patients need moderate activity.

• Useful sessions of massage and exercise therapy.
• In order to normalize the function of breathing, breathing exercises are shown.

Orthopedic care

When motor functions are lost as a result of the disease, orthopedic devices have to be used. For muscle contractures, orthoses and special splints are used. If a serious curvature of the spine has formed, then the use of corsets helps. With the complete impossibility of moving and standing independently, verticalizers and electric wheelchairs are used.

Development of new treatments

Even with the use of all modern methods of treatment, it is not possible to completely defeat Duchenne muscular dystrophy. The life expectancy of patients is very short. Therefore, research into new treatment methods is underway.

• The possibility of replacing a defective gene with a healthy gene is being studied.
• Stem cell therapy is under investigation.
• Research is underway to transplant cells capable of producing the protein dystrophin.
• Experiments are being conducted on animals to replace the protein dystrophin with utrophin.
• The possibility of slowing down the disease by correcting the gene (exon skipping) is being studied.

Forecast and prevention of the disease

To date, the prognosis of Duchenne muscular dystrophy is unfavorable. The disease progresses and leads to death. Most patients do not survive to the age of 20-30 years. Death occurs due to heart and respiratory failure and associated infections.

Prenatal diagnosis plays an important role in disease prevention. If the family already has a child with Duchenne muscular dystrophy, then in most cases this means that the mother is a carrier of a defective X chromosome. And this means that there is a risk of having a sick child in subsequent pregnancies. Therefore, it is necessary to consult a geneticist and conduct prenatal studies (amniocentesis, chorionic biopsy). These methods can accurately determine if a fetus has a genetic disorder.

Etiology and incidence of Duchenne muscular dystrophy. Duchenne muscular dystrophy (MIM #310200) is a pan-ethnic X-linked progressive myopathy caused by mutations in the DMD gene. The incidence is approximately 1 in 3500 newborn boys.

The pathogenesis of Duchenne muscular dystrophy. The DMD gene codes for dystrophies, an intracellular protein expressed predominantly in smooth, skeletal, and cardiac muscle, as well as in some brain neurons. In skeletal muscle, dystrophies form part of a large complex of sarcolemma-associated proteins that provide stability to the sarcolemma.

Mutations in gene DMD Causes of Duchenne muscular dystrophy include large deletions (60-65%), large duplications (5-10%), and small deletions, insertions, or nucleotide substitutions (25-30%). The largest deletions occur in one of the two hotspots. Nucleotide substitutions occur throughout the gene, predominantly in CpG dinucleotides.

De novo mutations occur with comparable frequency during oogenesis and spermatogenesis; the largest de novo deletions occur during oogenesis, while most de novo nucleotide substitutions occur during spermatogenesis.

Mutations that cause a phenotypic absence of dystrophin result in more severe muscle damage than DMD mutant alleles that express partially functional dystrophies. No correlation was found between genotype and phenotype for intellectual decline.

Phenotype and development of Duchenne muscular dystrophy

Men with Duchenne muscular dystrophy. Myodystrophy is a progressive myopathy leading to muscle degeneration and weakness. Beginning with the muscles of the hip girdle and neck flexors, muscle weakness progressively captures the shoulder girdle and distal muscles of the limbs and trunk. Although occasionally diagnosed incidentally during the neonatal period due to hypotonia or developmental delay, usually sick boys are diagnosed between 3 and 5 years of age when gait abnormalities appear.

By the age of 5, most affected children use Gowers techniques and have pseudohypertrophy of the muscles of the legs, i.e. an increase in the legs due to the replacement of muscles with adipose and connective tissue. By the age of 12 years, the majority of patients are immobilized in a wheelchair and have contractures and scoliosis. Most patients die from impaired lung function and pneumonia; the median age at death is 18 years.

Nearly 95% of patients Duchenne muscular dystrophy have some form of cardiac abnormality (dilated cardiomyopathy or electrocardiographic abnormalities), and 84% have visible cardiac muscle lesions at autopsy. Chronic heart disorders occur in almost 50% of patients; occasionally, heart failure causes complaints in them. Although dystrophies are also present in smooth muscle, smooth muscle complications are rare and include gastric dilatation, volvulus, and hypotonia of the bladder.

Sick Duchenne muscular dystrophy have an IQ about 1 standard deviation below normal, and almost a third have some degree of mental retardation. The reasons for this have not been established.

Women with Duchenne muscular dystrophy

Age of onset and severity Duchenne myodystrophy in women, they depend on the degree of X-chromosome inactivation bias. If the X chromosome carrying the mutant DMD allele is active in most cells, the woman develops signs of Duchenne muscular dystrophy; if the X chromosome carrying the normal DMD allele is predominantly active, women have few or no symptoms of the disease.

Whether or not they have clinical symptoms skeletal muscle weakness, carrier women have abnormal heart muscle function, such as dilated cardiomyopathy, left ventricular dilatation, and electrocardiographic changes.

Features of the phenotypic manifestations of Duchenne dystrophy:
Age of onset: childhood
Muscle weakness
Hypertrophy of the legs
Slight intellectual disability
High serum creatine kinase

Treatment of Duchenne muscular dystrophy

Diagnosis of Duchenne muscular dystrophy based on family history and DNA analysis or muscle biopsy with immunohistochemical determination of dystrophin.

Currently treatment of Duchenne muscular dystrophy impossible, although improved symptomatic management has increased the average life span from late childhood to early adulthood. The goals of therapy are to slow the progression of the disease, provide mobility, prevent or correct contractures and scoliosis, control body weight, and improve lung and heart function.

Glucocorticoid therapy can slow down the development of the disease for several years. Several types of experimental treatments are being explored, including gene transfer. Most patients also need extensive counseling as they deal with the psychological effects of a chronic fatal illness.

Risk of inheriting Duchenne muscular dystrophy

The third part of mothers who gave birth to a single patient son, are themselves carriers of mutations in the DMD gene. However, determination of carriage remains a difficult task because currently available molecular methods do not detect small mutations such as single nucleotide substitutions. Determining the risk of carriage in families without a deletion or duplication found is based on linkage analysis, a series of serum creatine kincase levels, and mosaic dystrophin expression in muscle biopsy specimens (due to accidental inactivation of the X chromosome). The high frequency of mosaicism in germ cells (approximately 14%) should be taken into account when counseling in connection with the assessment of the risk of recurrence.

If the mother is a carrier, each son has a 50% risk of developing Duchenne muscular dystrophy, and each daughter has a 50% risk of inheriting a DMD mutation. Reflecting the random nature of X-chromosome inactivation, daughters who inherit a mutation in the DMD gene have a low risk of Duchenne muscular dystrophy; however, for reasons not fully understood, the risk of cardiac abnormalities can be as high as 50-60%. If a mother is not a carrier based on DNA testing, she has an approximately 7% risk of having a boy with Duchenne muscular dystrophy due to sex mosaicism. For these mothers, genetic counseling and possibly prenatal diagnosis are indicated.

An example of Duchenne muscular dystrophy. AI, a 7-year-old boy, is being examined for mild developmental delay. He has difficulty climbing stairs, running, reduced strength and endurance with intense physical exertion. His parents, two brothers and sister are completely healthy; other family members do not have similar complaints. Examination revealed difficulty in jumping, Gowers maneuvers (a sequence of movements that facilitate getting up from the floor), weakness of the proximal muscles, a waddling (“duck”) gait, thickening of the Achilles tendons, and markedly hypertrophied calf muscles. Serum creatine kinase level was 50 times higher than normal.

Because the anamnesis and physical examination findings, including an elevated creatine kinase level, suggested myopathy, the child was referred to a neurogenetics clinic for further examination. Muscle biopsy results showed marked change in muscle fiber size, fiber necrosis, proliferation of adipose and connective tissue, and no staining for dystrophy. Based on these results, the child is provisionally diagnosed with Duchenne muscular dystrophy and tested for a deletion in the dystrophin gene; it turned out that he had a deletion from exon 45 to 48.

Duchenne muscular dystrophy is a term used to refer to genetic disorders characterized by progressive muscle weakness and wasting of muscle tissue. The term dys means abnormal and troph represents growth.

The term "muscular dystrophy" refers to inadequate, defective muscle growth. There are several forms of muscular dystrophy that differ based on clinical symptoms, disease severity, and how the disease is transmitted from one generation to the next.

The three most important forms are:

• Duchenne muscular dystrophy (DMD)
• facioscapulohumeral dystrophy,
• Myotic dystrophy

Duchenne disease is the most common and most serious form of muscular dystrophy. The condition is named after the French neurologist Guillaume Benjamin Amand Duchenne, who first described the disease in 1868.

This form of muscular dystrophy occurs only in men. The condition affects about 1 in 3500-4000 men. The disease is widespread throughout the world.

It occurs due to a defect in the gene that is responsible for the production of dystrophin, a protein that helps maintain muscle strength and integrity. This disease is linked to the X chromosome, where defective genes are passed down from mothers who carry it.

Therefore, there is no transmission of the disease from father to son. Mothers who pass on the gene are not affected, but their father, brothers or uncles may be affected.

Clinical features

Symptoms of the disease appear up to 5 years. The earliest signs of Duchenne muscular dystrophy include speech and walking delays.

This is followed by a gradual

The victim has trouble climbing stairs from a chair.

For a certain time, there is a noticeable thickening of the muscles of the lower leg.

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With progressive involvement of the muscles of the chest, shoulder, back, a typical posture can be seen.

The child has difficulty balancing and constantly falls. Soon, he begins to walk on his toes due to the contraction of the tissues on the heels.

The shoulder blades, knees, hips, spine are affected as the disease progresses, leading to scoliosis (curvature of the spine).

The victim is restricted to a wheelchair until the age of 12.

Although most patients have a normal level of intelligence, signs of mental retardation can be observed in a small percentage of cases.

The muscles of the heart and lungs are also affected, leading to death from respiratory or heart failure.

Once the diaphragm/respirator muscles become involved, the patient becomes difficult to breathe and is dependent on a breathing support machine.

Diagnostics

Clinical examination

Clinical examination raises suspicion of DMD

Creatinine phosphokinase assay

When muscle cells die, the affected cells release the enzyme creatinine phosphokinase (CPK) into the blood. Thus, Duchenne patients have high levels of the enzyme in their blood (20 times the upper limit of normal). This test was the only available method for detecting the presence of the disease until 1982.

Electromyography

A study that tests the electrical activity of muscles. In duchenne dystrophy, the affected muscles show a decrease in electrical activity.

muscle biopsy

A test in which a small portion of the affected muscle is examined under a microscope for changes.

Dystrophin analysis

Because patients with Duchenne muscular dystrophy have a defective gene, there is a disturbance in the production of the protein dystrophin. As a rule, its complete deficiency is observed in 99% of the victims. The analysis is used to distinguish DMD from other forms of dystrophy.

This form of diagnostic tool produces accurate results, so it can be used to make a diagnosis.

Treatment of DMD

Despite the description of the disease as early as 1868, there is no reliable treatment for Duchenne muscular dystrophy.

However, it is possible to slow the progress of the disease and maintain muscle strength and joint function by allowing the patient to walk and sit.

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Since DMD affects almost every muscle in the body, those involved in the treatment process face a number of challenges. Effective management of a disabling disease requires a multidisciplinary approach.

Various forms of treatment are used, including light braces, physical therapy, pulmonary therapy (breathing support), surgery.

The choice of specific treatment largely depends on the clinical condition of the patient.

After identifying the gene, the researchers developed animal models that mimic the disease. Such clinical experiments have improved pre-existing knowledge about the disease.

There is active research being done to test whether injecting normal muscle cells (from healthy patients) or introducing an adjusted form of the dystrophin gene into muscle cells (gene therapy) can reverse the disease process.

Which doctor should be consulted

First of all, you should consult with a general practitioner, however, for long-term treatment, a team of doctors is required, including a physiotherapist, orthopedists.

Forecast

DMD is a progressive disorder and the patient usually dies before age 25.

Duchenne disease (chronic progressive adult spinal amyotrophy, Duchenne-Aran disease) is a rare form of progressive neurogenic muscular atrophy. It is often referred to as chronic adult poliomyelitis, since the pathoanatomical basis of the disease is the slowly progressive degeneration of the cells of the anterior horns of the spinal cord, leading to their atrophy and death.

Many authors doubt the existence of adult progressive spinal amyotrophy as a separate disease, considering it only as a variant of amyotrophic lateral sclerosis. In the Anglo-American literature, adult chronic progressive spinal amyotrophy is combined with amyotrophic lateral sclerosis and treated as a single "motor neuron disease".

pathological anatomy

The morphological essence of Duchenne's disease is a slowly progressive atrophy of the cells of the anterior horns. Although clinically the disease proceeds as a selective anterohorn syndrome, the study often reveals damage to the pyramidal bundles; apparently, spastic symptoms are suppressed by advanced and predominant damage to the peripheral motor neuron.

Causes of Duchenne's disease

It is a disease of adults that almost never begins before the age of 20, usually after the age of 40 (between 40 and 60 years). Men get sick more often than women. The cause of the disease has not been established.

Symptoms of Duchenne's disease

The disease begins gradually and imperceptibly. Its main symptom is progressive muscle atrophy. First of all, atrophy of the small muscles of the hand develops more often on the right side, less often atrophy appears on both sides. There is weight loss of thenar and hypothenar muscles even before movement disorder. Later, the patient notices that it is difficult for him to hold anything between 1 and 2 fingers, especially small objects. The first interosseous gap sharply sinks, it becomes impossible to oppose the thumb. A "bony paw" appears. Over time, the entire hand appears to be devoid of muscles, immobile, hypotonic. The skin of the hand becomes smooth and thin. After the hand, atrophy captures the muscles of the forearm: first, the flexors lose weight, then the extensors and arch supports. Later, the muscles of the shoulder, shoulder girdle, neck, chest, and abdomen lose weight. The part of the trapezius muscle that attaches to the collarbone lasts the longest. The legs are not involved in the process for a long time. With the spread of weight loss, the flexors of the foot and hip first suffer, then all the muscles of the lower extremities gradually atrophy. The defeat of the respiratory muscles is observed later. In atrophied muscles there are fascicular twitches.

Electromyography reveals a pronounced decrease in the bioelectrical activity of muscles (up to a complete "bioelectrical silence" of paralyzed muscles), an increase in the duration and amplitude of the action potentials of motor units, and fluctuations in the type of fasciculations.

Muscle atrophy is accompanied by paresis and paralysis. Movement disorders follow weight loss. Their degree corresponds to the severity of the atrophic process. To the weakness of the fingers, which deprives the patient of the ability to make subtle movements (unfasten and fasten buttons, write, knit, flip), paresis joins, later paralysis of the lower and later upper segments of the hands, hands hang like whips. The head descends to the chest, and it is difficult for the patient to keep it straight. The general appearance of the patient changes: the neck becomes thinner, the chest sinks, and the stomach protrudes, the head is tilted forward. In advanced cases, there is weakness or paralysis of the legs. The pelvic organs function normally throughout the disease. Tendon and periosteal reflexes on the affected limbs become sluggish and later disappear. Abdominal reflexes behave differently depending on the degree of atrophy of the muscles of the abdominal wall. There are no pathological reflexes. Sometimes the process extends to the motor nuclei of the trunk with the development of bulbar palsy. Pain never happens. Some patients note moderately expressed paresthesias in hands. Sometimes cyanosis and cold extremities are observed. There are no mental disorders. Liquor is not changed. The blood is normal.

Duchenne disease lasts 5, 10 and even 15 years. Death occurs from intercurrent diseases, rarely due to respiratory disorders. Sometimes there are short pauses in the process. As a rule, atrophy progresses. In some cases, the disease is more severe and ends after 2-3 years.

Diagnostics

The disease is easily distinguished from acute poliomyelitis by the absence of symptoms of acute infection, the age of the patient, and especially by the course of the disease. It is more difficult to make a differential diagnosis with chronic infectious poliomyelitis associated with tick-borne encephalitis virus. It is necessary to take into account the nature of the onset and development of the disease, the state of the cerebrospinal fluid, the presence or absence of pyramidal signs, the data of serological reactions, the place of residence and occupation of the person before the disease. It is necessary to exclude syringomyelia, intramedullary tumor, cervical spondylosis, late myopathy.

Treatment of Duchenne's disease the same as in amyotrophic lateral sclerosis.