Spinal muscular atrophy is a genetic disease manifested by muscular atrophy and caused by degenerative changes in spinal motor neurons and motor nuclei of the brain stem. A common symptom complex is symmetrical flaccid paralysis with muscle atrophy and fasciculations against the background of an intact sensitive sphere. Disease is diagnosed according to family history, neurological status, EPI of the neuromuscular apparatus, MRI of the spine, DNA analysis and morphological examination of a muscle biopsy. Treatment is ineffective. The prognosis depends on the form and the age of its debut.
General information
Spinal muscular atrophy (spinal atrophy, SMA) is a hereditary disease based on degeneration of the motor neurons of the spinal cord and brain stem. Described at the end of the XIX century. Their frequency is 1 case per 6-10 thousand newborns. About 85% of spinal muscular atrophy consists of proximal forms with more pronounced weakness and atrophy of the proximal muscle groups of the extremities. Distal forms account for only 10% of SMA. To date, disease is of practical interest for a number of disciplines: pediatric and adult neurology, pediatrics, genetics.
Causes
Thanks to modern genetics, it has been established that the emerging degenerative processes of motor neurons are caused by mutations in the SMN, NAIP, H4F5, VTF2p44 genes located on the 5th chromosome at the 5q13 locus. Despite the fact that spinal atrophy is determined by aberrations of one chromosomal locus, they represent a group of heterogeneous nosologies, some of which manifest in infancy, and others manifest in adults. In most cases, amyotrophy is inherited autosomal recessive.
Pathogenesis
Genetic mutations lead to the development of degenerative changes in the anterior horns of the spinal cord. The innervation and neurotrophy of the striated musculature are disturbed. As a result, muscle tissue atrophy gradually occurs. The predominant lesion of individual muscle groups (proximal or distal parts of the upper or lower extremities) in various forms of spinal atrophy differs. The absence of sensitivity disorders is characteristic.
Classification
It is generally accepted to divide spinal muscular atrophy into children and adults. Children’s SMA are classified into early (debuting in the first months of life), later and juvenile. Children’s spinal atrophy is represented by:
- Werdnig-Hoffmann amyotrophy;
- the juvenile form of Kugelberg-Velander;
- chronic infantile SMA;
- Vialetto-van Laere syndrome (bulbospinal form with deafness);
- Fazio-Londe syndrome.
Adult forms of SMA manifest at the age of 16 to 60 years and differ in a more benign clinical course. Adult SMA includes:
- bulbospinal amyotrophy of Kennedy;
- scapuloperoneal;
- facial shoulder and oculopharyngeal forms;
- distal SMA;
- monomelic SMA.
Isolated and combined spinal atrophy are also distinguished. Isolated SMA is characterized by a predominance of spinal motor neurone damage, which in many cases is the only manifestation of the disease. Combined spinal atrophy are rare clinical forms in which the symptom complex of amyotrophy is combined with another neurological or somatic pathology. Combinations of SMA with congenital heart defects, deafness, oligophrenia, pontocerebellar hypoplasia, and congenital fractures are described.
Spinal muscular atrophy symptoms
Common to spinal muscular atrophy is a symptom complex of symmetrical flaccid peripheral paralysis: weakness, atrophy and hypotension of the muscle groups of the limbs of the same name (more often at the beginning of both legs, and then the arms) and the trunk. Pyramidal disorders are not typical, but can develop in late stages. There are no sensitivity disorders, the function of the pelvic organs is preserved. Attention is drawn to a more pronounced lesion of proximal (with proximal SMA) or distal (with distal SMA) muscle groups. The presence of fascicular twitching and fibrillation is typical.
Werdnig-Hoffman disease
It occurs in 3 clinical variants. The congenital variant debuts in the first 6 months of life and is the most malignant. Its symptoms may manifest even in the intrauterine period with weak fetal movement. Children from birth have muscular hypotension, are unable to turn over and hold their heads, at a later debut — they cannot sit. The frog’s pose is pathognomonic — the child lies with his limbs spread apart and bent at the knees and elbows.
Amyotrophy has an ascending character — first it occurs in the legs, then the arms are involved, later — the respiratory muscles, the muscles of the pharynx and larynx. Accompanied by a delay in mental development. By the age of 1.5, a fatal outcome occurs.
Early spinal atrophy manifests up to 1.5 years, often after an infectious disease. The child loses motor abilities, cannot stand or even sit. Peripheral paresis is combined with contractures. After the involvement of the respiratory muscles, respiratory failure and congestive pneumonia develop. Death usually occurs before the age of 5 years. The late version debuts after 1.5 years, is distinguished by the preservation of motor ability until the age of 10. The fatal outcome occurs by the age of 15-18.
Juvenile spinal atrophy of Kugelberg-Velander
It is characterized by a debut in the period from 2 to 15 years. It begins with a lesion of the proximal muscles of the legs and pelvic girdle, then captures the shoulder girdle. About a quarter of patients have pseudohypertrophy, which makes the clinic similar to the manifestations of Becker muscular dystrophy. In terms of differential diagnosis, the presence of muscle fasciculations and EMG data is of great importance. The course of Kugelberg-Velander amyotrophy is benign without bone deformities, for a number of years patients remain capable of self-care.
Bulbospinal amyotrophy of Kennedy
Inherited recessively linked to the X chromosome, manifests only in men after the age of 30. Typically slow, relatively benign course. Debuts with amyotrophy of the proximal leg muscles. Bulbar disorders appear after 10-20 years and, due to their slow progression, do not cause violations of vital functions. There may be a tremor of the head and hands. The pathognomonic symptom is fascicular twitching in the perioral muscles. Endocrine pathology is often noted: testicular atrophy, decreased libido, gynecomastia, diabetes mellitus.
Distal Duchenne-Aran SMA
It can have both recessive and dominant inheritance types. The debut occurs more often at the age of 20, but can occur in any period up to 50 years. Amyotrophy begins in the hands and leads to the formation of a “clawed hand”, then covers the forearm and shoulder, in connection with which the hand takes the form of a “skeleton hand”. Paresis of the muscles of the shins, thighs and trunk are joined much later. Cases of manifestation of the disease by monoparesis (defeat of one hand) are described. The prognosis is favorable, except in cases of a combination of this type of SMA with torsion dystonia and Parkinsonism.
Scalulo-peroneal SMA Vulpian
Manifests in the period from 20 to 40 years with amyotrophy of the shoulder girdle. Typical “wing-shaped shoulder blades”. Then the lesion of the peroneal muscle group (extensors of the foot and lower leg) joins. In some cases, the peroneal muscles are first affected, and then the shoulder girdle. Spinal atrophy of the Vulpian is characterized by a slow course with the preservation of the ability to move 30-40 years after its debut.
Complications
The most frequent adverse consequences include constant falls and associated pathological fractures, which is associated with gradually increasing muscular atrophy of the muscles of the lower extremities. With bulbospinal Kennedy amyotrophy, complications from the endocrine and reproductive systems are often observed – erectile dysfunction, primary infertility, diabetes mellitus.
More severe conditions are less common, mainly in Werdnig-Hoffman disease or in the late stages of other amyotrophy. Due to severe atrophy of the muscles of the pharynx and respiratory muscles, food enters the respiratory tract (aspiration), respiratory failure develops. Severe bone and joint deformities, loss of the ability to walk and self-care are possible. In isolated cases, breast cancer is detected.
Diagnostics
Patients with spinal atrophy are supervised by neurologists, and in case of manifestation in childhood – pediatricians or neonatologists. If necessary, it may be necessary to involve other specialists – endocrinologists and geneticists for consultation. For the diagnosis of some varieties of amyotrophy, anamnestic data are of great importance, namely the age of the appearance of symptoms (for example, Werdnig-Hoffman disease always debuts in children under 6 months, and Kugelberg-Velander amyotrophy – after 2 years).
During the examination of the patient, attention is drawn to a decrease in overall muscle tone, weakening or loss of tendon reflexes, musculoskeletal deformities. Some patients have pseudohypertrophy of the calf muscles. To confirm or exclude the diagnosis, the following additional examination is prescribed:
- Laboratory tests. In laboratory tests, almost all indicators are within normal values. The exception is the concentration of creatine phosphokinase, which may be high in a small part of patients.
- EMG. During needle electromyography, signs of degeneration of motor spinal neurons are detected – a decrease in the speed and amplitude of evoked action potentials, registration of spontaneous bioelectric activity at rest (fasciculations, fibrillations), “palisade rhythm”.
- Muscle biopsy. Histological examination of muscle tissue shows changes typical of amyotrophy: necrosis of myofibrils, proliferation of adipose and connective tissue, alternation of atrophy and hypertrophy in combination with intact areas of muscle tissue.
- Spirometry. When the respiratory muscles are affected during the performance of the function of external respiration, restrictive disorders are detected in the form of a decrease in the vital capacity of the lungs.
- Genetic analysis. The main diagnostic method that allows to reliably establish the diagnosis of spinal atrophy. With the help of a polymerase chain reaction, genetic mutations are detected.
Differential diagnosis
Differential diagnosis of spinal atrophy should be carried out with other hereditary neurodegenerative diseases affecting muscle tissue. Such pathologies include:
- pseudohypertrophic Duchenne muscular dystrophy;
- juvenile amyotrophic lateral sclerosis;
- cerebral palsy.
Spinal muscular atrophy treatment
Non-drug therapy
All patients, without exception, should be hospitalized in a hospital. In severe situations (for example, with respiratory failure due to weakness of the respiratory muscles), patients are transferred to the intensive care unit and connected to a ventilator. All measures are aimed at alleviating the patient’s condition. Despite this, an integrated approach and strict adherence to the recommendations of doctors can improve the quality of life of the patient. Types of conservative therapy used for the treatment of spinal atrophy:
- Provision of food. With a significant violation of the act of swallowing, special attention is paid to the issue of feeding. The consistency of the food should be semi-solid, the patient’s position vertical. It may be necessary to install a nasogastric probe.
- Physical therapy. In order to increase muscle tone and slow down their atrophy, regular physical activity is recommended. The most effective combination of active (performed by a specialist) and passive exercises (performed by the patient himself).
- Physiotherapy. To activate metabolism in muscle tissues, sessions of electrostimulation with modulated current, mud applications, electrophoresis are prescribed.
- Massage. To improve blood circulation and lymph outflow in the muscles, various types of massage are performed – manual (stimulating, relaxing) and hardware (vibration massage).
- Orthopedic treatment. To prevent and correct bone deformities and joint contractures, the use of orthopedic devices is recommended: corsets, orthoses, orthopedic shoes.
- Respiratory support. Often there is a need to eliminate oxygen deficiency. Depending on the severity of the patient’s condition, oxygen inhalation through a facial mask / nasal cannula or non-invasive ventilation of the lungs through portable ventilators are prescribed.
To achieve maximum effect, treatment should be carried out continuously and selected individually for a particular patient.
Drug therapy
Etiotropic therapy with proven effectiveness is currently absent. Medications used for the treatment of spinal atrophy are as follows:
- Metabolic agents. To improve metabolic processes in motor neurons and muscle tissues, drugs that stimulate the function of mitochondria (coenzyme Q10, succinic acid), nootropics (piracetam, gamma-aminobutyric acid), L-carnitine are used.
- Valproates and Clenbuterol. Studies have shown that antiepileptic drugs from the group of valproic acid derivatives and beta-adrenergic receptor agonist Clenbuterol are able to increase the formation of motor neurone survival protein (SMN) and, accordingly, improve the clinical course of the disease.
- PPIs and prokinetics. Patients with gastroesophageal reflux, which often develops with swallowing disorders, are prescribed proton pump inhibitors (esomeprazole) and drugs that stimulate the motility of the gastrointestinal tract (itoprid).
- Mucolytics and expectorants. In patients with respiratory muscle weakness, drugs that dilute sputum (acetylcysetine) and stimulate its expectoration (terpinghydrate) are used to eliminate problems such as weak expectoration and accumulation of thick sputum in the respiratory tract.
- Hormonal drugs. People with endocrinological complications are shown insulin, hypoglycemic drugs (metformin), testosterone and antiandrogens (dutasteride).
Surgical treatment
With the development of gross deformities of the chest and spine or extremely pronounced contractures of the joints, orthopedic operations are indicated. Bedridden patients suffering from recurrent pneumonia are undergoing tracheostomy. With gastroesophageal reflux resistant to drug treatment, laparoscopic Nissen fundoplication is resorted to.
Experimental treatment
Numerous research works are constantly being carried out to develop drugs that can stop or at least slow down the process of neurodegeneration. Significant progress has been made in the field of gene therapy. Drugs that correct defects in the matrix RNA of the SMN – Spinrase gene and Risdiplam are already used in clinical practice. At the end of 2019, the drug Zolgensma, which contains a functionally complete SMN1 gene, was registered and approved for clinical use.
Forecast
The prognosis depends entirely on the clinical variant of SMA and the age of its manifestation. The most unfavorable prognosis has children’s spinal atrophy, when they begin in infancy, they often lead to death during the first 2 years of a child’s life. Spinal atrophy of adult age is characterized by the ability of patients to independently serve themselves for many years, and with slow progression they have a favorable prognosis not only for life, but also for the ability to work of patients (when creating optimal working conditions for them).
Prevention
There are no specific methods of primary prevention. The only way to prevent the occurrence of the disease is prenatal diagnosis (detection of mutations in chorionic villi or amniotic fluid) with termination of pregnancy. Timely initiation of complex therapy allows you to prevent the development of complications and maximize efficiency.