"Amondis 45": a new medicine for Duchenne muscular dystrophy

Symptoms of muscular dystrophy

• Decreased tone of the affected muscles.
• Disorders of gait and posture.
• Muscle atrophy with preserved skin sensitivity.
• Fast fatiguability.
• An increase in the volume of the limbs due to the growth of connective tissue in place of the muscles.
• Cardiomyopathy.
• Breathing problems.
• Mental retardation.
• Impaired joint mobility.
• When facial muscles are damaged, facial expressions become poorer and speech becomes less intelligible.

Muscular dystrophy in children is manifested by the loss of physical skills acquired before the disease: the child stops walking, holding his head up, and sitting.

Causes

The disease is hereditary, linked to the X chromosome, so boys are almost always affected. Girls are carriers of a pathological gene (boys rarely survive to adulthood, and, moreover, are usually sterile). A change in the structure of the gene responsible for the synthesis of the dystrophin protein occurs on the chromosome.

Although the content of dystrophin in skeletal muscles is extremely small (thousandths of a percent), without it necrosis of muscle tissue quickly develops and progressive muscle dystrophy develops. If the gene is damaged in a site that completely destroys the synthesis of the dystrophin protein, Duchenne dystrophy develops. When insignificant parts of the protein are involved in the process, the disease takes the form of Becker's dystrophy.

Common types of disease

• Duchenne muscular dystrophy.

The disease develops in children aged 3–5 years. It begins with damage to the lower extremities and gradually rises higher. This is a rapidly progressive form that leads to muscle atrophy after 5 years. It is characterized by heart damage and the development of mental disorders.

• Becker muscular dystrophy.

The process also begins from the lower extremities. Weakness in the legs and fatigue first appear at the age of 15–20 years. The transition of the disease to the upper limbs due to muscular dystrophy is observed in adults after 50 years.

Read also:  Granulomatous amebic encephalitis

A heterogeneous group of diseases. All of them are hereditary progressive muscle degenerative processes, but differ in their clinical and pathological features and mode of inheritance. The genetic mechanism of many of them has now been clarified (Table 180-1).

Clinical manifestations of individual diseases (see Table 180-1)

Duchenne dystrophy.

X-linked muscular dystrophy, which exclusively affects boys. Onset of the disease before the age of 5 years; symmetrical and steadily progressive weakness in the muscles of the hips and shoulder girdle, making it difficult to move when lifting, running, and jumping. By the age of 8-10, most children require orthopedic devices; By age 12, most children cannot walk. Patients rarely live more than 25 years.

Associated disorders.

Tendon and muscle contractures (including Achilles tendons), progressive kyphoscoliosis, impaired pulmonary function, cardiomyopathy, reduced intelligence. Muscle weakness is combined with a palpable increase and density of some muscles (for example, gastrocnemius), which is initially the result of hypertrophy and then replacement of muscles with fat and connective tissue.

Laboratory research.

Significant increase (20-100 times) of muscle enzymes (CPK, aldolase), myopathic EMG curve; in biopsy samples - the presence of necrotic muscle fibers with regeneration, phagocytosis and fatty degeneration of muscle tissue. The diagnosis can be made accurately when dystrophy is detected in muscle tissue using Western blotting and (or) immunochemical labeling. Mutations in the dystrophin gene can be proven in about two thirds of patients using cDNA testing. ECG changes (enlarged RS complex in lead V, deep Q in the chest leads) indicate the presence of cardiomyopathy.

Determination of carrier status.

Serum CPK is elevated in 50% of female carriers. Although the gene and its derivative (dystrophies) have not yet been identified, cDNA tests can be used in practice to determine carrier status and prenatal diagnosis.

Complications.

Includes respiratory failure and infectious diseases, aspiration and acute gastrectasis. CHF and cardiac arrhythmias also complicate the course of cardiomyopathy. Passive muscle stretching, tenotomy, pinning, physical therapy, mechanical assistive devices, and avoidance of prolonged immobilization are all symptomatic measures that may be helpful.

Table 180-1 Progressive muscular dystrophies

Type

Table 180-1
Continued

Source: Mendell JR, Griggs RC, NRS-13, p. 2384.

Treatment.

Not developed yet. Prednisone, 0.75 mg/kg/day can slow the progression of the disease for up to 3 years.

Becker's dystrophy (benign pseudohypertrophic).

Less severe and less common than Duchenne dystrophy, with a slower course and later onset (5-15 years), but with similar clinical and laboratory features. This disease also results from a defect in the dystrophin gene.

Myotonic dystrophy.

An autosomal dominant disorder in which muscle weakness appears between the ages of 20 and 30, with initial involvement of the muscles of the face, neck and distal muscles of the extremities. This leads to a typical appearance, characterized by ptosis, hypotrophy of the temporal regions, drooping lower lip and drooping lower jaw. Myotonia is manifested in the patient's characteristic inability to quickly relax muscles after strong tension (for example, after tightly clenching the hand into a fist) and prolonged muscle contraction after tapping (for example, on the tongue or the eminence of the thumb).

Associated disorders:

frontal alopecia, posterior subcapsular cataract, gonadal atrophy, respiratory and cardiac disorders, endocrine pathology, intellectual disorders and hypersomnia.

Laboratory research.

CPK levels are normal or slightly elevated, characteristic signs of myotonia and myopathy on EMG, typical signs of fiber damage in muscle biopsies. Cardiac complications, including complete heart block, pose a serious threat to the patient's life. Respiratory function should be carefully monitored, as chronic hypoxia can lead to the development of cor pulmonale.

Early diagnosis.

Patients have an unstable DNA region with an increased number of CTG triplet repeats in the chromosomal locus 19ql3.3. Molecular genetic studies contribute to early detection and prenatal diagnosis.

Treatment.

Phenytoin, procainamide, quinine are used in the treatment of myotonia, but caution is required in patients with heart disease (risk of worsening cardiac conduction). Pacemaker implantation is necessary for patients with syncope or heart block. The use of orthopedic devices can strengthen “drop” feet, stabilize ankle joints, and reduce the frequency of falls.

Humerofacial dystrophy.

Usually a slowly progressive, moderately severe disease, the onset of which occurs at the age of 30-40 years. Muscular weakness of the face, shoulder girdle and proximal muscles of the arms develops, which is accompanied by atrophy of the biceps and triceps muscles, the appearance of “winged shoulder blades” and sloping shoulders. Weakness of the facial muscles is expressed in the inability to whistle and loss of facial expression. Dropping of the feet and weakness of the legs can cause the patient to fall and cause progressive difficulty in movement.

Laboratory research.

CK levels are normal or slightly elevated, mixed signs of myopathy-neuropathy on EMG and muscle biopsy. Patients are diagnosed with mutations in chromosome 4q35. Genetic research specific to this locus is carried out to identify carriage and in prenatal diagnosis. Orthotics and other stabilization measures may be helpful in selected patients.

Less common dystrophies

Scapuloperoneal dystrophy.

The clinical picture is the same as with glenohumeral-facial dystrophy, but there is no facial muscle weakness, and cardiomyopathy is possible. In most cases, the disease begins in middle age and is inherited in an autosomal dominant manner, but a form of the disease with an early onset, a different mechanism of genetic transmission (X-linked, recessive), with clinical manifestations of joint contractures and cardiomyopathy (Emery type) may also occur. —Dreyfus).

Oculopharyngeal dystrophy

(progressive external ophthalmoplegia). The onset of the disease is at the age of 50-60 years with symptoms of ptosis, limitation of extraocular movements, facial and cricopharyngeal muscle weakness. Cricopharyngeal muscle weakness leads to achalasia, dysphagia, and aspiration. Since eye movement disorders are chronic, they rarely lead to diplopia. Most patients are of Spanish or French-Canadian origin.

Dystrophy of the muscles of the limb girdles.

Possibly a group of diseases in which the key symptom is weakness of the proximal muscles of the upper and lower extremities. Depending on the specific subtype, differences are observed in the age of patients at the onset of the disease, the rate of progression, the severity of clinical manifestations and in associated complications (cardiac, respiratory). Laboratory findings include elevated CPK levels and signs of myopathy on EMG and muscle biopsies.

Table 180-2 Toxic myopathies

Focal myopathies: pentazocine, meperidine, heroin. Generalized myopathy: A. Inflammatory: Qimetidine, D-Penicilllamine, Prokainamide B. Muscle weakness and myalgia: Zidovudin, Chlorochin, Clophibrat, Colchicin, Glucocorticoids, Emetin, Aminocaproneic acid, Labetalol, Pergexile, Prophanolol, Vincristine, Niazin, Tsilosorin V. Rabdor. myolis and myoglobinuria: alcohol, heroin, amphetamine, clofibrate, lovastatin, gemfibrozil, aminocaproic acid, phencyclidine, barbiturates, cocaine D. Malignant hyperthermia: halothane, ethylene, diethyl ether, methoxyflurane, ethyl chloride, trichlorethylene, gallamine, suxinylcholine, lidocaine, mepiva Cain Source: Mendell JR, Griggs RC, HPIM-13, p. 2392.

Distal dystrophy.

A group of rare diseases, among which there are several variants with onset at different ages and different types of inheritance. Usually manifested by muscle weakness of the hands and feet with a slow spread to the proximal muscle groups. Increased CPK levels; signs of myopathy on EMG and muscle biopsies.

Metabolic myopathies

They arise as a result of impaired muscle utilization of glucose and fatty acids as energy sources. Patients are diagnosed with either an acute syndrome of myalgia, myolysis and myoglobinuria, or chronically progressive muscle weakness. For an accurate diagnosis, it is necessary to conduct a biochemical and enzymatic study of muscle biopsies. However, muscle enzymes, EMG and muscle biopsies usually reveal pathological changes, and on their basis, a specific disease can be suspected.

In childhood and infant forms of glycogen storage disease, concomitant disorders are often identified with dysfunction of the heart, liver and endocrine system, the symptoms of which can complicate the diagnosis of muscle disorders. Forms found in children and adults can mimic muscular dystrophy or polymyositis. In some types of the disease, its manifestation may be one of the attacks of muscle cramps or muscle fatigue provoked by exercise. The lactate test for forearm ischemia has diagnostic value, since there is no increase in the level of lactic acid in the serum after exercise (characteristic of the norm). Disorders of fatty acid metabolism manifest themselves with clinical signs similar to those described above. In some patients, muscle cramps provoked by exercise, myolysis and myoglobinuria are detected; in others, the clinical picture resembles polymyositis or muscular dystrophy. Sometimes a special diet (including medium-chain fatty acids enriched in triglycerides), oral carnitine supplementation, or glucocorticoids are effective.

Other myopathies

Myopathies may be associated with endocrine disorders, especially with hypo- or hyperfunction of the thyroid gland, parathyroid glands and adrenal glands. Drugs (especially glucocorticoids) and certain toxins (including alcohol) are common causes of myopathy (Table 180-2); in most cases, muscle weakness is symmetrical and affects the proximal muscles of the limb girdles. Frequent symptoms: muscle weakness, myalgia, cramps. Diagnosis often depends on the interpretation of the signs of myopathy in the treatment of the underlying disease or elimination of the etiological agent, since laboratory studies of muscle enzymes, EMG, and even muscle biopsies do not provide specific data for diagnosis.

Diagnostics

A neurologist treats and examines patients with muscular dystrophy. The patient's symptoms and complaints allow one to suspect the disease. To clarify the diagnosis, use:

• determination of the level of the enzyme CPK (creatine phosphokinase) in the blood. In case of illness, this indicator increases several times;
• electromyography. The disease is indicated by a decrease in the electrical activity of the muscles;
• biopsy. The method involves taking material and subsequent analysis under a microscope. The study helps exclude other diseases;
• genetic analysis.

Examination for myopathy

Clinical signs characteristic of muscular dystrophy are symptoms of flaccid paralysis in different muscle groups of a sick person without signs of damage to motor neurons and peripheral nerves. Neurologists around the world cannot explain this.

Doctor Nikonov

My opinion: protein swelling between muscle fibers makes muscle movement impossible.

Not knowing this phenomenon bewilders doctors all over the world: “How is this possible? The muscle fiber is intact and undamaged. “Are motor neurons and peripheral nerves intact, in their proper places, and perfectly transmitting impulses from the brain to the muscles and from the muscles to the brain, but movements are difficult?”

Neurologists prescribe electromyography. And again it’s a mystery to them: there are no changes in the structure of the muscle fiber. A decrease in the amplitude of the M-response, increased interference and polyphasic potential indicates difficulty in muscle movement without any pathology!

Treatment

To date, scientists have not invented any means to get rid of this disease.

All existing methods and drugs can only reduce the severity of symptoms and alleviate the condition:

• corticosteroids (prednisolone). Increase muscle strength and delay the development of certain forms of the disease;
• physical exercise. Allows you to maintain joint mobility and normal posture longer;
• mobile devices. Used to support weakened muscles and facilitate movement.