Spinal muscular atrophy

Spinal muscular atrophy is not a single nosologic unit, but a whole group of clinically and genetically heterogeneous hereditary pathologies provoked by the increasing processes of degeneration of motoneurons of the anterior spinal horns. The term encompasses different variants of genetically determined peripheral paresis and muscular atrophy resulting from degeneration of spinal motor neurons and/or brainstem. The most common cause of the problem is an autosomal recessive mutation on the long q-shoulder of the fifth chromosome. Treatment is nonspecific, aimed at improving the trophicity of the nervous tissue and providing palliative support to improve quality of life. [1]

Epidemiology

Spinal muscular atrophy occurs in one case per 6,000 to 10,000 newborns (according to the American Journal of Medical Genetics 2002).

The prevalence of SMN gene exon 7 deletion carriers is 1:50 people.

Bulbo-spinal muscular atrophy (Kennedy syndrome) occurs in one child in 50,000 and is the most common adult type of spinal amyotrophy.

It is noted that half of the children with this disease do not overcome the two-year survival period.

The pathology is inherited according to the autosomal recessive principle. Most often, each parent of a sick child is a carrier of one copy of the mutated gene. Since the mutation is compensated for by the presence of a second "normal" gene copy, the parents have no manifestations of spinal muscular atrophy. Type 2 pathology usually does not inherit an additional copy from the parent. The problem occurs due to an accidental failure during the formation of germ cells, or directly at the time of fertilization. With spinal muscular atrophy of the first type, spontaneous development of the disease occurs in only 2% of cases (in this situation, the carrier is only one of the parents). [2]

Causes of the spinal muscular atrophy

The main cause of spinal muscle atrophy is a mutation of the gene responsible for the production of SMN protein localized on chromosome 5q. This disorder further causes the gradual death of motor nerve cells in the anterior horns of the spinal cord and brain stem. As a result of these processes, the tone of the musculature drops, atrophy of respiratory, pharyngeal, facial and skeletal muscles develops. The predominant type of inheritance of pediatric forms of spinal muscular atrophy is autosomal recessive, which implies the simultaneous carrying of defective genes by both parents. As for type IV pathology (adult form), there is a link to the X chromosome, so only males are affected.

The development of spinal muscle atrophy is based on the increasing processes of degeneration and death of motor neurons of the spinal anterior horns, damage to the brain stem nuclei. Pathologic changes are most intense in the zones of cervical and lumbar thickening. The cellular number is reduced to a minimum, replacement by connective tissue occurs, which is due to the failure of the cell death program - the so-called apoptosis. The change affects the structures of the motor nuclei of cranial nerves, anterior roots, motor nerves. There is a clinic of neurogenic fascicular atrophy. With a prolonged course of the disease at a late stage of connective tissue overgrowth occurs.

The appearance of the corresponding clinical picture is associated with a deficiency of the SMN protein, which influences the successful function of motor nerve cells in the anterior spinal horns. Protein deficiency as one of the links in the development of spinal muscular atrophy was discovered at the end of the XX century. Against the background of motoneuron damage, innervation of skeletal muscles (mainly proximal sections) is impaired. [3]

Risk factors

The diversity of clinical forms of spinal muscular atrophy 5q is explained by the presence of certain modifying factors that can be divided into two categories: those affecting and those not affecting the SMN protein score.

• Currently, the SMN2 gene is considered to be the basic factor in the development of spinal muscular atrophy: the more copies of the SMN2 gene, the lower the intensity of the disease symptoms. The second factor, which is directly related to the centromeric copy of the SMN gene, is a 1-nucleotide substitution c.859G>C in exon 7 of the SMN2 gene, leading to the formation of a new enhancer-binding splice site: the result is the inclusion of exon 7 in the transcript from the SMN2 gene. This variation is associated with an increase in the blood level of full-length SMN protein in patients with spinal amyotrophy of the second or third type.

Other factors affecting the number of SMNs:

• Splicing-regulatory factors (Tra2β - induces exon skipping of exon 7, SF2/ASF - increases exon 7 inclusion, hnRNPA1 - suppresses exon 7 inclusion of the SMN2 gene).
• Transcription regulatory factors (CREB1 - increases SMN transcription, STAT3 - favors axon growth, IRF1 - increases SMN number, PRL - increases lifespan in severe stages).
• MRNA stabilizing factors (U1A -reduces SMN, HuR/p38).
• Factors affecting post-translational modification (RCA - suppresses SMN degradation, GSK3 - increases survival).
• Exogenous factors (starvation, hypoxia, oxidative stress).

The effects of the above factors were determined predominantly in vitro.

• Factors that are not associated with the SMN gene - in particular, proteins that optimize endocytosis at synapses (laminin 3, coronin, neurocalcin delta, calcium-neurin-like protein).

Additional attention is paid to DNA methylation, the most stable modification that affects the nature of gene expression. The methylation of a group of genes that are possibly involved in pathogenetic processes was found to be correlated with the severity of spinal muscular atrophy. [4]

Pathogenesis

Spinal muscular atrophy is a genetic pathology for which any of the types of inheritance - both autosomal dominant and autosomal recessive or X-linked - are inherent. Most often we are talking about early childhood autosomal recessive pathology. Responsibility for the formation of such spinal amyotrophy is the SMN gene, localized in the locus 5q13. The deletion of exon 7 in the SMN gene results in pathology with possible involvement of the nearby genes p44 and NAIP.

The SNM genome encodes a protein that includes 294 amino acids and has a MM of ~38 kDa. The protein has the following functions:

• is part of the RNA-protein complex;
• participates in the formation of the spliceosome site that catalyzes pre-RNA splicing;
• Involved in processes controlling protein production and protein isoforms;
• provides axonal transport of mRNA;
• Favors nerve cell growth and provides neuromuscular communication.

A couple types of SMN genes are known:

• telomeric SMNt (SMN1);
• centromeric SMNc (SMN2).

The vast majority of cases of spinal muscular atrophy are due to alterations in the SMN1 gene.

Kennedy spinal muscular atrophy has a linkage to the Xq12 locus containing the NR3C3 gene, which encodes an androgen receptor protein. It has an X-linked inheritance variant. When the number of CAG repeats in one gene exon increases, the pathology develops.

Suppression of SNM protein production is accompanied by the following changes:

• due to impaired axon coordination, excessive branching of axons occurs;
• the growth of axons slows down and their size decreases;
• there is improper clustering of calcium channels in the growth cone;
• Irregular presympathetic terminals of motor nerve cell axons are formed.

The spinal cord begins to actively lose motor neurons in the anterior horns, which accounts for the development of atrophy of the proximal limb muscles. [5]

Symptoms of the spinal muscular atrophy

Symptomatology of spinal muscular atrophy Werdnig-Hoffman most often debuts in the period of newborn and up to six months, manifested by the syndrome of a "sluggish" baby. The bell-shaped chest, intense hypotonia, lack of reflexes, muscle twitching of the tongue and respiratory distress are noticed. Sick infants more often die before reaching the age of two years: lethal outcome is due to increasing respiratory failure against the background of the adherence of infectious processes.

The intermediate form of spinal muscular atrophy of the second type is detected from the age of six months. In addition to the syndrome of a "sluggish" child, there is low blood pressure, lack of reflexes, respiratory disorders and tongue twitching. Even if children are able to sit up, multiple contractures of the large joints develop.

Kugelberg-Wielander spinal muscular atrophy also starts in early childhood, with children able to move independently. There is weakening of the iliac, quadriceps and adductor muscles, low blood pressure, decreased reflexes and tongue twitching. Many patients lose the ability to move (walk) independently over the years.

Spinal muscular atrophy type 4 starts at an older age. It is characterized by slow progression and relatively benign prognosis. [6]

Kennedy atrophy manifests itself most often in middle age (generally may debut in patients 15-60 years of age). Symptomatology includes muscle soreness and weakness, gynecomastia, distal weakness, lethargy, tongue twitching and atrophy. Signs of bulbar dysfunction are present:

• difficulty swallowing;
• aspiration;
• weakening of the masticatory muscles;
• dysarthria;
• postural and motor tremors in the hands.

First signs of androgen deficiency:

• gynecomastia (in about 60% of patients), often asymmetric;
• deterioration of sexual function (oligospermia, testicular atrophy, erectile dysfunction).

First signs

Spinal amyotrophy is manifested by weakness of muscles and general impotence. All sensory and intellectual abilities are not affected.

Major indices of neuromuscular pathology:

• musculature "lazy", weakened, laxity and laxity of muscles are noted;
• muscle tone is low, tendon reflexes are minimized or absent;
• normal or absent plantar reflexes;
• Short twitches of individual muscle groups are noted (can be seen under the skin, on the tongue);
• there are signs of muscle atrophy.

Werdnig-Hoffman syndrome is manifested by pronounced hypotonia of the muscles, general lethargy, inability of the child to hold the head, turn over and sit up. When trying to support the baby in the abdominal area in a suspended state, the body seems to "sag". Coughing, swallowing and sucking reflex is unsatisfactory, food often gets into the respiratory tract, breathing is problematic. There may be joint distortion associated with intrauterine hypotonia. Anamnestic information collected during pregnancy often indicates low fetal activity.

Basic signs of spinal muscular atrophy type I:

• severe retardation in motor development;
• Rapid onset of joint contractures and thoracic curvature;
• increasing respiratory and bulbar disorders, problems with swallowing (both food and saliva) and expectoration of sputum;
• increased risk of aspiration inflammation;
• infection, progressive respiratory failure.

Spinal muscular atrophy type II is manifested by a clear inhibition of motor development. Although many patients can sit unaided, and sometimes even crawl and stand, these abilities are often lost over time. Finger tremors, muscle and joint (bone) distortions, and respiratory problems are noted. Possible calf pseudohypertrophy.

The main features of type II pathology:

• developmental delays, including stopping and reversing the development of already acquired skills and abilities;
• increasing weakness of the intercostal muscles;
• superficiality of diaphragmatic breathing, weakened cough reflex, gradual worsening of respiratory failure;
• curvature of the thorax and spinal column, contractures.

In Kugelberg-Wielander syndrome, the manifestations are milder, slowly progressing. The patient is able to move around, but there are problems with jogging or climbing stairs. Delayed symptoms often include difficulty swallowing and chewing.

Spinal muscular atrophy type IV reveals itself already in older (adult) age and is characterized by the most "mild" and favorable course. The main signs: gradual loss of the ability to move. [7]

Forms

Spinal muscular atrophy is part of a group of hereditary pathologies characterized by degenerative changes, death of motor nerve cells of the anterior spinal horns and, often, the motor nuclei of the brainstem. The process can make itself known in different life periods, the clinical picture is not always the same. The types of inheritance and course may also differ.

Pediatric spinal muscular atrophy was first described as early as the late 19th century. Around the middle of the 20th century, the main forms of the disease were identified:

• Congenital (manifests itself almost immediately after the birth of the infant);
• Early infantile form (occurs against the background of previous normal development of the baby);
• late infantile form (reveals itself starting at age 2 and older).

Some specialists combine the second and third forms into one pediatric type of spinal amyotrophy.

It is generally accepted to divide pathology into pediatric and adult. Spinal muscular atrophy in children is classified into early (with a debut in the first few months after the child's birth), late and adolescent (adolescent, or juvenile). The syndromes most commonly involved are:

• Werdnig-Hoffman atrophy;
• the Kugelberg-Wielander form;
• chronic infantile spinal muscular atrophy;
• Vialetto-van Lare syndrome (bulbospinal type with absence of hearing);
• Fazio-Londe syndrome.

Adult spinal muscular atrophy debuts over the age of 16 years and until approximately 60 years of age, distinguished by a relatively benign clinic and prognosis. Adult pathologies include:

• Kennedy's bulbospinal atrophy;
• scapuloperoneal atrophy;
• facial-lap-shoulder and oculo-pharyngeal forms;
• distal spinal atrophy;
• monomelic spinal atrophy.

Separately separate isolated and combined spinal atrophy. Isolated pathology is characterized by the predominance of damage to spinal motor neurons (which is often the only sign of the problem). Combined pathology is rare and represents a complex of neurological and somatic disorders. There are descriptions of cases of combined syndrome with congenital coronary malformations, lack of auditory function, oligophrenia, cerebellar hypoplasia.

Spinal muscular atrophy in the elderly is most commonly represented by Kennedy bulbospinal amyotrophy. This pathology is inherited recessively X-linked. The course of the disease is slow, relatively benign. It begins with atrophy of the proximal musculature of the lower extremities. Possible tremor of the hands, head. At the same time, endocrine problems are also detected: testicular atrophy, gynecomastia, diabetes mellitus. Despite this, in adults, the pathology proceeds in a milder form than in children.

A variant of spinal muscular atrophy.	The debut of the pathology	Detectable problem	Age of death	Characteristic symptomatology
Spinal muscular atrophy type 1 (other name Verding-Hoffman spinal muscular atrophy)	From birth to six months	The baby can't sit up	Up to two years	Severe muscle weakness, hypotonia, trouble holding up the head, impaired crying and coughing, swallowing and salivation problems, development of respiratory failure and aspiration pneumonia
Spinal muscular atrophy type 2	Six months to one and a half years	The baby can't stand	More than two years	Motor retardation, weight deficiency, cough weakness, hand tremors, spinal curvature, contractures
Spinal muscular atrophy type 3 (other name Kugelberg-Welander spinal muscular atrophy)	After a year and a half.	Can initially stand and walk, but at a certain age this ability may be lost	In adulthood.	Weakened muscles, contractures, joint hypermobility
Spinal muscular atrophy type 4.	Adolescence or adulthood	Can initially stand and walk, but at a certain age this ability may be lost	In adulthood.	Increasing proximal muscle weakness, decreased tendon reflexes, muscle twitching (fasciculations)

About distal spinal atrophy is said in the case of lesions of motor nerve cells of the spinal cord, which innervate the lower part of the body. Characteristic signs of such pathology are:

• atrophy of the thigh muscles;
• weakness in the knees, foot extensors, and hip adductor muscles.

No change in tendon reflexes.

Distal spinal muscular atrophy is represented by two allelic variations with an overlapping phenotype:

• scapulo-perineal spinal muscular atrophy;
• Hereditary motor-sensory neuropathy of Charcot-Marie-Tooth type 2C.

Proximal spinal muscular atrophy 5q is characterized by increasing symptomatology of flaccid paralysis and muscular atrophy, which is due to degenerative changes in the alpha motor neurons of the anterior spinal horns. Congenital disease with postpartum asphyxia is the most severe form: from the moment the baby is born, motor activity is practically absent, there are contractures, swallowing and respiratory problems. In most cases, such a child dies. [8]

Complications and consequences

Further progression of spinal amyotrophy leads to weakness and reduction of muscle mass of the limbs (especially legs). The baby initially does not have or gradually loses acquired skills - that is, loses the ability to walk, sit without support. Motor activity of the upper limbs decreases, joints become stiff, over time contractures are attached, and the spinal column becomes curved.

In order to preserve motor abilities for as long as possible and prevent the development of complications, it is recommended:

• practice correct body posture (anti-gravity position), both in bed and when sitting, walking, etc..;
• regular physical therapy, stretching exercises, massage, physiotherapy, regardless of the type of spinal muscular atrophy;
• use special beds, chairs (wheelchairs), mattresses and pillows;
• Select and use supportive orthotics, corsets;
• practice hydrotherapy and kinesiotherapy, which has a favorable effect on the respiratory, musculoskeletal and digestive apparatus, nervous and cardiovascular system;
• Perform regular diagnostic check-ups, including clinical tests, spinal and pelvic radiographs;
• systematically consult with a physiotherapist and orthopedist with experience in working with similar patients;
• Adjust corsets, orthoses, orthopedic devices, wheelchairs, etc. Depending on the dynamics.

Caregivers of a patient with spinal muscular atrophy should be familiarized:

• with the basics of safe behavior, physiotherapy, massage, physical therapy;
• with the rules of maintaining independent activity of the patient, use of orthopedic devices;
• with the rules of care, hygiene.

Spinal amyotrophy is often complicated by impaired chewing, swallowing and conduction of food, which threatens aspiration and the development of aspiration inflammation of the lungs or obstruction of the respiratory tract, which is most characteristic of the pathology of the first type. Swallowing problems are evidenced by symptoms such as significant and persistent prolongation of the period of eating, reluctance to eat, food falling out of the mouth, regular gagging, and worsening weight loss.

Disorders of digestive motility reveal themselves constipation, weak peristalsis, prolonged stay of food in the stomach (gastric stasis), the development of gastroesophageal reflux. In order to prevent such complications it is necessary:

• monitor the correct position of the patient while eating;
• If necessary, use a gastric tube or gastrostomy to ensure adequate fluid and nutrient intake and reduce the risk of aspiration;
• adhere to the rules of food and drink preparation, watch their consistency, and the frequency of meals;
• depending on the doctor's prescription, use medication, massage, physiotherapy, etc.

One of the most serious complications of spinal amyotrophy is respiratory system dysfunction associated with weakness of respiratory muscles. Respiratory disorders can be fatal, both in infants with type 1 pathology and in adolescent and adult patients with type 2 or 3 disease. The key problems are as follows:

• cough reflex is disturbed, there are problems with expectoration of sputum from the respiratory tract;
• Increasing deficit in the volume of air entering the lungs, impaired excretion of carbon dioxide from the lungs;
• distorts the chest, compresses and deforms the lungs;
• infectious processes in the form of bronchopneumonia.

To prevent such complications, patients are often recommended to perform breathing exercises using an Ambu bag. [9]

Diagnostics of the spinal muscular atrophy

In patients with suspected spinal amyotrophy, investigations such as these are of diagnostic value:

• blood chemistry;
• genetic DNA analysis;
• electroneuromyography.

Among additional methods, it is possible to appoint a biopsy of muscle fibers, ultrasound and resonance imaging of the musculature and brain.

Blood tests may indicate that creatine phosphokinase is physiologically normal, but in some cases it may be elevated to about 2.5 times.

The electroneuromyogram reveals changes due to the loss of motor spinal neurons. This is detected by a decrease in the amplitude of the interference curve, the occurrence of spontaneous active potentials, which are fibrillations and fascioculations that form a specific "frequency rhythm". The speed of impulse signal passing through peripheral motor fibers is normal or decreased due to secondary denervation disorders. [10]

Instrumental diagnosis is often also represented by ultrasound or MRI of the musculature, which allows detection of muscle replacement by fatty tissue. MRI reveals a typical pathologic process pattern unique to spinal muscular atrophy. However, this is only possible in the late stages of the lesion.

In the course of morphological analysis of muscle biopsy in patients, a nonspecific picture in the form of bundle atrophy and grouping of muscle fibers is determined. The overwhelming number of affected muscle fibers belong to type 1, immunohistological and chemical characteristics are within normal limits. The ultrastructural picture is nonspecific.

The most important diagnostic procedure for suspected spinal muscular atrophy is testing that can detect the SMN gene mutation. By direct DNA analysis, it is possible to detect the presence or absence of the seventh and eighth exons of the SMNc and SMNt genes. The most informative method is quantitative analysis, which can determine the gene copy number and elucidate the form of spinal muscular atrophy. The quantitative method is also important in assessing the status of the patient. It is a necessary measure carried out for the purpose of further medical and genetic family counseling.

Additional diagnostic tests are performed only after a negative result of SMN gene deletion is obtained. If the detection of point mutations is required, direct automated sequencing of the SMNt gene may be used. [11]

Differential diagnosis

The differential diagnosis is performed with pathologic processes that reveal the symptom complex of "sluggish patient", with congenital muscular dystrophies, structural or mitochondrial myopathy. In particular, the presence of such pathologies should be excluded:

• motor neuron disease;
• primary lateral myosclerosis;
• muscular dystrophy;
• congenital myopathies;
• diseases associated with glycogen accumulation;
• polio;
• autoimmune myasthenia gravis.

The diagnostic algorithm is developed depending on the peculiarities of symptomatology in a particular child. Thus, a special classification of patients is used, depending on the functional status (Europrotocol TREAT-NMD):

1. Unable to sit up without support (bedridden).
2. Able to sit but unable to walk (sedentary).
3. Able to move independently (walking patients).

The following diagnostic algorithm is recommended for patients in the first group:

• Physical examination (detection of chest curvature, assessment of respiratory and cough function, and skin condition);
• cardiac and respiratory monitoring, polysomnography, and identification of symptoms of pulmonary ventilation deficit;
• pulse oximetry to determine the degree of oxygenation;
• Assessment of the frequency of infectious-inflammatory pathologies and antibiotic courses during the extreme six-month period;
• Chest x-rays with repeat dynamics studies;
• assessment of swallowing function.

For patients in the second group, the following algorithm applies:

• physical exam;
• cardiac and respiratory monitoring, polysomnography to detect pulmonary ventilation deficit;
• pulse oximetry;
• Assessment of the frequency of infectious-inflammatory processes and antibiotic courses during the extreme six-month period;
• Examination of the spinal column, X-rays of the spine, assessment of the degree of curvature.

Patients in the third group are indicated for such studies:

• physical exam;
• Respiratory function testing (includes spirometry, calculation of lung volume, assessment of respiratory muscle function);
• To find out the frequency of infectious-inflammatory pathologies and antibiotic courses during the extreme annual period.

The practice of differential diagnosis may be complicated by the similarity of SMN1 and SMN2 genes. To avoid errors, it is recommended to use the MLPA method, which allows to detect the copy number of exon 7 in the SMN1 gene.

In most cases of spinal muscular atrophy, there is a homozygous deletion of exon 7 and/or 8 in the SMN1 gene. However, other genes (ATP7A, DCTN1, UBA1, BSCL2, EXOSC3, GARS, etc.) can also be "culprits", which should be paid attention to if the SMN1 test is negative.

The biomaterial for the study can be peripheral blood or fetal blood, dry blood spot maps. Diagnosis is mandatory:

• in the presence of an aggravated history of spinal muscular atrophy;
• when suspicious symptoms are detected, regardless of hereditary history.

In addition, research is also recommended for all couples who are responsible in planning a pregnancy.

Treatment of the spinal muscular atrophy

Patients with spinal muscular atrophy need comprehensive treatment that includes:

• care, help, support;
• diet food;
• drug therapy;
• non-medication rehabilitation measures, including kinesiotherapy and physiotherapy.

A therapeutic regimen that involves a polymodal effect on all body systems, not just the musculoskeletal system, is standard.

Unfortunately, it is impossible to radically cure spinal muscle atrophy. But it is often possible to improve the patient's quality of life through the competent use of amino acids and multivitamin complexes, neurotrophic agents, calcium channel blockers, vasodilators, cardiotrophic and cytostatic drugs, protease inhibitors, steroidal drugs, antioxidants, immunoglobulins and immunosuppressants, and so on. It has been experimentally proven that treatment with stem cells, neuroprotective compounds and muscle-strengthening molecules can lead to unpredictable systemic disorders. At the same time, positive dynamics after the application of such treatment has not been proven so far.

Since the problem is caused by a deficiency of normal SMN protein, patients can be improved by increasing SMN protein levels by 25% or more. For this reason, drugs that can activate the production of this protein are being actively researched, including Gabapentin, Riluzole, Hydroxyurea, Albuterol, valproic acid and sodium phenylbutyrate.

Modern medicine also offers surgical treatment for spinal muscular atrophy. It consists of surgical alignment of the spinal column - correction of neuromuscular curvature. Surgeons perform multilevel fixation of the spine, using special constructions. The sacrum, pelvis, and vertebrae of the upper thoracic or other vertebrae are used as points of support. The surgery helps to align the spinal column, evenly distribute the load on it, eliminate discomfort when changing the position of the body, avoid adverse effects on internal organs (including the lungs). [12]

Medications

Currently, there is no etiologic treatment for spinal muscular atrophy: scientific medicine continues to work on this task. Previously, scientists have already succeeded in isolating drugs that can enhance the production of mRNA from the SMN2 gene. But large-scale international clinical trials involving people with spinal muscular atrophy have not yet been conducted.

Most of the drugs included in the standard treatment regimen have a general principle of action with relatively low evidence of efficacy.

L-Carnitine

A naturally occurring amino acid, a "relative" of the B-group vitamins. It is produced in the body, is present in the liver and transverse striated muscles, belongs to a number of vitamin-like substances. Takes part in metabolic processes, supports CoA activity, is used to normalize metabolism. It has anabolic, antithyroid, antihypoxic ability, stimulates lipid metabolism and tissue repair, optimizes appetite. L-Carnitine is prescribed in an amount of about 1 thousand mg per day. The course of treatment can last up to 2 months.

Coenzyme Q10 (Ubiquinone)

A coenzyme benzoquinone group that contains a number of isoprenyl groups. These are fat-soluble coenzymes, mainly present in mitochondria of eukaryotic cellular structures. Ubiquinone is included in the electron transport chain, participates in oxidative phosphorylation. The greatest presence of the substance is found in energy-rich organs - in particular, in the liver and heart. Among other things, coenzyme Q10 has antioxidant properties, can restore the antioxidant capacity of alpha-tocopherol. Usually prescribed from 30 to 90 mg of the drug per day, a two-month course.

Cerebrolysin

A nootropic drug with neurotrophic properties. It is often used in therapeutic regimens for the treatment of neurological pathologies, including vascular dementia, stroke. The active fraction includes peptides with a limiting molecular weight of 10 thousand daltons. The drug is administered as an intravenous injection of 1-2 ml. The course of treatment consists of 10-15 injections.

Actovegin

The composition of the drug is represented by low molecular weight peptides and amino acid derivatives. Actovegin is a hemoderivative: it is isolated by dialysis with ultrafiltration. Thanks to the use of the drug, the absorption and utilization of oxygen is increased, energy metabolism is accelerated. The drug is used in the form of intravenous injections of 1-2 ml, the course requires 10-15 injections.

Solcoseryl

It is a deproteinized hemodialysate capable of optimizing pre-cellular oxygen and glucose transport, enhancing intracellular ATP production, stimulating regenerative tissue reactions, activating fibroblast proliferation and collagen production in vascular walls. The course of treatment consists of 10-15 intra-muscular injections of the drug (1-2 ml daily).

Neuromultivit (vitamin B complex)

Multivitamin, actively used in the deficiency of vitamins B-group. It is often able to become a quality substitute for a course of injections of vitamin preparations. Activates metabolic processes in the brain, promotes the restoration of tissues of the nervous system, has an analgesic effect. Neuromultivit take 1-2 tablets daily, a course of 4 or 8 weeks.

Vitamin E

A well-known antioxidant, fat-soluble vitamin. It is prescribed in courses of 1-2 months in the amount of 10-20 IU daily.

Valproate

They have sedative and relaxing activity, demonstrate anticonvulsant ability, increase the level of GABA in the CNS. Used only for the treatment of children over one year of age, 10 to 20 mg per kg per day.

Salbutamol

A bronchodilator, which belongs to the group of selective beta2-adrenoreceptor agonists. Regular use of the drug causes increased production of mRNA and SMN protein, which positively affects the clinical picture of spinal muscular atrophy. Salbutamol is used cautiously, 2-4 mg four times a day (the maximum amount is 32 mg per day).

One of the newest drugs used in spinal muscular atrophy is the Zolgensma® genotherapeutic drug Zolgensma®, which ensures the activity and correct function of transduced motor nerve cells. The drug is administered in combination with immunomodulatory drugs according to a special protocol and administered once intravenously, based on a nominal dosage of 1.1 ͯ¹⁰¹⁴ vg/kg (the total volume of administration is determined depending on the weight of the patient).

Before starting Zolgensma treatment, it is mandatory to determine the level of antibodies to AAV9 using a validated diagnostic method, assess hepatic function (ALT, AST, total bilirubin), perform general clinical blood examination and troponin I test, determine creatinine level. If acute and chronic active infectious conditions are detected, administration of the drug is postponed until cure or completion of the relapse phase of the infectious process.

The most frequent side effect of the drug is considered to be liver failure, which can be fatal.

Other approved medications your doctor may prescribe for spinal muscle atrophy:

• Spinraza is a preparation of nusinersen sodium, an antisense oligonucleotide specifically designed for the treatment of spinal amyotrophy. It is intended for intrathecal administration by lumbar puncture. The recommended dosage is 12 mg. The treatment regimen is determined by the attending physician.
• Risdiplam is a drug that modifies splicing of the mRNA precursor of the motor nerve cell survival gene 2. Risdiplam is taken orally, once a day. The dosage is determined by the doctor individually, taking into account the age and weight of the patient. The use of the drug in children younger than 2 months is contraindicated. Embryofetal toxicity of this drug is noted, so reproductive-potential patients should take careful contraceptive measures both during and some period after treatment.

Physiotherapeutic treatment for spinal muscular atrophy

Physiotherapy is used as one of the links of complex therapy and rehabilitation of patients with spinal muscular atrophy. The main points of such treatment are:

• use of unloading by means of suspension systems, active-passive training, use of percutaneous electrical stimulation of the spinal cord;
• breathing exercises and physical therapy;
• half-hour verticalization sessions;
• translingual electrostimulation treatments (20-minute sessions, combined with exercises to improve fine motor skills);
• manual techniques;
• paraffin applications on different groups of articulations;
• darsonval to improve muscle performance.

The method of darsonvalization is based on the effect on tissues using an alternating high-frequency pulse current of high voltage and low strength. After a course of procedures there is an increase in muscle performance, strengthening of microcirculation, expansion of arterioles and capillaries, elimination of ischemia, improvement of nutrition and oxygen supply to muscles, which has a positive effect on the course of regenerative and atrophic processes.

One of the most significant problems in patients with spinal amyotrophy is respiratory muscle weakness, often leading to respiratory dysfunction and death of the patient.

In spinal amyotrophy, the entire skeletal musculature, including that responsible for breathing, is underperforming. Weakness and gradual muscle atrophy adversely affects the quality of the respiratory act, leads to the development of complications and increasing respiratory failure. Therefore, it is necessary to take measures to strengthen the muscles, the prevention of respiratory complications and respiratory tract infections. A special role in this plays gymnastics with the Ambu bag, which is carried out in conjunction with physical therapy, stretching exercises, massage. The use of Ambu bag allows you to "expand" the volume of the chest and lungs. For children's activities is suitable bag with a volume of at least one and a half liters, equipped with a valve to release excessive pressure (to prevent barotrauma).

Exercises should not be performed on a full stomach. Body position - sitting, semi-sitting, lying on the side or back (if there are no problems with phlegm): it is optimal to perform the procedures in different positions each time. It is important that the patient's back is straightened. If necessary, a corset is used. Before starting the procedure, make sure that the airway is free of sputum.

Massage for spinal muscular atrophy

Massage for the treatment of spinal amyotrophy should be light and gentle. In areas of muscular resistance apply general effects, including tapping, and in areas of preserved innervation use deep stroking (longitudinal, transverse), kneading.

In general, practicing different types of massage, depending on the individual characteristics of the course of the disease, the age of the patient. These can be:

• kneading to stimulate deep-seated muscles;
• rubs to optimize blood and lymph circulation;
• spot treatment of trigger points;
• of the fiber-strengthening pounding.

It is important that the effect is spread over the entire problem area.

Contraindications to massage for spinal muscular atrophy:

• acute inflammation, elevated body temperature;
• blood disorders, bleeding tendencies;
• purulent processes;
• infectious, fungal dermatologic diseases;
• Vascular aneurysms, thrombangiitis, endarteritis, lymphadenitis;
• benign and malignant neoplasms.

The course of any massage for a patient with spinal muscle atrophy is prescribed strictly individually. Improper conduct of the procedure, excessively rough and incorrect impact can harm the patient's condition.

Prevention

Direct and indirect DNA diagnosis and prenatal DNA diagnosis are now being actively pursued. This significantly reduces the likelihood of a sick baby being born, which is especially important for couples who have already experienced the birth of children with spinal muscular atrophy.

Preventive measures represent an important medical trend and are categorized into primary, secondary and tertiary measures.

Primary measures are aimed at directly preventing the influence of an unfavorable factor and preventing the development of the disease. Such prevention consists in correcting diet and daily regimen, leading a healthy lifestyle.

Secondary prevention consists in the elimination of obvious risk factors and includes early diagnosis of pathologies, establishment of surveillance in dynamics, directed treatment.

Tertiary prevention is carried out in relation to a sick person who is deprived of certain motor capabilities. In this situation, we are talking about medication, psychological, social and labor rehabilitation.

According to information from the World Health Organization, more than 2% of babies in the world are born with some kind of developmental disorder. At the same time, 0.5-1% of such disorders are of genetic origin. Prevention of such problems is reduced to medical genetic counseling and quality prenatal diagnosis, which allows minimizing the risks of giving birth to a baby with genetic pathology.

A person's risk of getting spinal muscular atrophy or another genetic disease depends on the genes inherited from his mother and father. Early identification of hereditary factors, calculation of individual risks of genetically determined pathology can be called a way of targeted prevention.

Prenatal diagnostic measures include direct and indirect research methods. Initially, women who require indirect prenatal diagnosis are identified. These may include:

• pregnant women 35 years of age and older;
• who have had 2 or more previous spontaneous abortions;
• who have children with genetic developmental defects;
• with an unfavorable hereditary history;
• who have had viral infections or radiation exposure (including during the planning stage of pregnancy).

For preventive purposes, such methods as ultrasound, hormonal tests (biochemical screening) are used. Sometimes invasive procedures such as chorionbiopsy, amniocentesis, placentocentesis, cordocentesis are also used. Reliable information about genetic risks allows you to adjust your lifestyle and pregnancy to prevent the birth of a sick child.

Spinal muscular atrophy vaccine

Of course, all parents of children with spinal amyotrophy would like to completely cure them of the disease. However, there is no vaccine that can eradicate the problem. Although research into optimizing treatment is ongoing.

In particular, in 2016, American scientists approved the unique drug Spinraza (nusinersen), which was subsequently approved for use in European countries.

Specialists are investigating the problem of treating spinal muscular atrophy in these ways:

• Fixing or replacing the "wrong" SMN1 gene;
• potentiation of the function of the normal SMN2 gene;
• Protection of motor nerve cells affected due to SMN protein deficiency;
• protection of muscles from atrophic changes to prevent or restore lost function against the background of pathology development.

Gene therapy involves targeting the damaged gene using viral vectors that pass through the blood-brain membrane and reach the appropriate area in the spinal cord. Then the virus "infects" the affected cell with a healthy DNA part, as if "suturing" the gene defect. Thus, the function of motor nerve cells is corrected.

Another direction is small molecule therapy, the essence of which is to enhance the function of the SMN2 gene. Infants with diagnosed spinal muscular atrophy have at least one copy of the SMN2 gene. This direction has been actively researched by American scientists, and at the moment several medicines aimed at enhancing the synthesis of a complete protein from the SMN2 gene are undergoing clinical trials.

Another avenue of possible therapeutic intervention is to explore neuroprotection to reduce motor neuron death, increase their adaptive capacity and improve functionality.

The third direction involves protecting the muscle from atrophic processes. Since SMN protein deficiency adversely affects motor nerve cells and muscle function, the goal of this treatment should be to protect the muscles from atrophy, increase muscle mass, and restore muscle function. This type of therapy will not affect the genetic apparatus, but it may slow down or even block the worsening of spinal muscular atrophy.

Screening for spinal muscular atrophy

Newborn screening is increasingly used in medical practice and often plays a decisive role. Detecting spinal muscular atrophy as early as possible can significantly improve the prognosis for the sick child. Screening diagnosis includes the following points outlined in the table:

A form of spinal muscular atrophy	Symptomatology
Spinal muscular atrophy type I (the child cannot sit up, average life expectancy - up to 2 years)	It manifests itself from birth until the age of six months. Insufficient muscle tone is detected, the cry is weak, muscle weakness (including chewing and swallowing muscles) increases. There are problems with head retention, the baby assumes a "frog" posture when lying down.
Spinal muscular atrophy type II (the child is able to sit up, life expectancy is usually more than 2 years, and more than half of patients live to be 20-25 years old)	It debuts starting at 7 months of age and up to one and a half years of age. Swallowing, respiratory and coughing problems are sometimes noticed. Permanent signs include muscle spasms, limited joint mobility, curvature of the spinal column, low blood pressure and muscle weakness.
Spinal muscular atrophy type III (the child can sit and move, but the above abilities are gradually lost, life expectancy is normal)	Debuts at the age of one and a half years. Curvature of the spinal column and thorax, muscular atrophy of the pelvis and proximal legs, and increased joint mobility are noted. Swallowing is difficult.
Spinal muscular atrophy type IV	Refers to the adult form. Symptomatology has much in common with that of spinal muscular atrophy type III. Weakness increases gradually, tremors and muscle fascioculations appear with the debut at 16-25 years of age.

Forecast

In Werdnig-Hoffman syndrome, the average life expectancy is 1.5-2 years. Fatal outcome in most cases is due to increasing respiratory failure and the development of inflammation in the lungs. With timely respiratory support in the form of artificial ventilation, it is possible to slightly increase the life expectancy of the baby. There is a special need for continuous palliative care, which is also required in spinal amyotrophy type II. Pathologies of the third and fourth types are characterized by a more favorable prognosis.

Any type of spinal muscular atrophy is a serious disease. All family members of the patient require constant psychological, informational and social support. It is important for the patient to ensure adequate diagnosis and professional support from specialists such as pediatrician, neurologist, neurologist, pulmonologist, cardiologist, orthopedist, physiotherapist, etc. Despite the lack of specific therapy for the disease, symptomatic treatment is carried out, special nutrition is prescribed (both parenteral and enteral), various rehabilitation measures that contribute to slowing the progression of the pathology and prevent the emergence of complications.

Many patients are granted a disability, and an individual rehabilitation scheme is drawn up.

Naturally occurring spinal muscular atrophy without the use of special equipment to support breathing and feeding in about half of cases ends in the death of the sick child before the age of two years (mostly type I disease).