3. Definition
◦ Spinal muscular atrophy (SMA; ) is a heterogeneous group of
hereditary diseases that occur with damage / loss of motor
neurons of the anterior horns of the spinal cord. A genetic disease
in which all types of inheritance are possible: autosomal
dominant, autosomal recessive, X-linked, associated with
mutations in the SMN1 and SMN2 genes encoding a protein
involved in the synthesis of the spliceosome (а spliceosome is a
nuclear structure consisting of RNA and protein molecules and
performing the removal of non-coding sequences (introns) from
mRNA precursors).
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5. Genetic cause
◦ To date, about 20 genetic variants of SMA characterized by different age
of manifestation and severity of clinical manifestations. It is proved that
the largest number of genetic variants is inherited by an autosomal
recessive type. A genetic defect was detected on the long arm of
chromosome 5. The most important role in the development of SMA
from the genes of chromosome 5 is probably played by SMN Survival
Motor Neuron - "motor neuron survival gene". And it is completely or
partially absent on both chromosomes 5 in patients.
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7. 1 General information
◦ SMA is one of the most common causes of infant mortality caused by hereditary diseases.
◦ Spinal muscular atrophy of childhood is inherited by autosomal recessive type.
◦ The spinal muscular atrophy gene is mapped on the 5th chromosome, q11.2 - 13.3.
◦ The SMA gene was identified in 1995, its designation is SMN (survival motor neuron).
◦ On average, one out of 6,000 - 10,000 children is born with SMA, the frequency varies greatly in
different countries.
◦ 50% of children with SMA do not live up to two years (these are children mainly with the 1st
form of the disease).
◦ SMA can manifest at any age, "soft" forms manifest in middle and old age.
◦ On average, every 50th person has a recessive gene capable of causing SMA.
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8. 2 History and pathogenesis
◦ Spinal muscular atrophy in children was first described by G. Werdnig in 1891. G.
Werdnig presented a description of pathomorphological changes in various muscle
groups, peripheral nerves and spinal cord, noting the symmetrical atrophy of the cells
of the anterior horns of the spinal cord and the anterior roots. In 1892, I. Hoffman[de]
proved the nosological independence of the disease. Later, Werdnig and Hoffman
(1893) proved that the disease is accompanied by degeneration of the cells of the
anterior horns of the spinal cord. In 1956 , E. Kugelberg and L. Wellander identified a
new nosological form of spinal muscular atrophy, which is characterized by a later
onset and a relatively benign course compared to that described by Werdnig and
Hofmann. SMA is caused by a mutation in the SMN1 gene, which normally produces
the SMN protein. Due to a gene mutation, people with SMA produce less SMN
protein, which leads to the loss of motor neurons.
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10. Currently, according to ICD-10, the following
types of spinal muscular atrophy are
distinguished:
1. Type I SMA (Werdnig-Hoffman);
2. SMA type II (intermediate);
3. SMA type III (Kugelberg-Velander);
4. SMA type IV;
5. Spinal muscular atrophy with late onset - X-linked bulbar spinal amyotrophy
(Kennedy's disease);
6. Bulbospinal SMA of childhood Fazio-Londe;
7. Bulbospinal form Violetta-Valerie;
8. Distal form of spinal amyotrophy and others.
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11. Classification of SMA types
◦ 1. Infantile SMA I, Werdnig-Hoffman disease, 0-6 months;
◦ 2. Intermediate SMA II, 7-18 months;
◦ 3. Juvenile SMA III, Kugelberg-Velander disease, >18 months;
◦ 4. Adult SMA IV, or adult form, after 35 years.
12. Infantile Spinal muscular atrophy, type I
(Werdnig-Hoffman)
◦ autosomal recessive type of inheritance;
◦ acute spinal amyotrophy;
◦ it occurs with a frequency of 1:25,000 newborns;
◦ it is characterized by an early onset of the disease: from birth or in the
first 5-6 months of life;
◦ often during pregnancy, the mother notes a later, sluggish movement of
the fetus.
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13. The symptoms pathognomonic for this disease are:
1. The onset of the disease – the prenatal period and the first 6 months of life
2. the symptom complex of a "sluggish child" - generalized muscular hypotension,
weakness of the muscles of the trunk and mainly of the proximal extremities,
fasciculations;
3. delayed motor development;
4. the presence in skeletal muscle biopsies of groups of small round fibers,
hypertrophied fibers of type I and atrophied fibers of types I and II;
5. signs of denervation during EMG examination;
6. rapidly progressing course;
7. unfavorable prognosis. Children usually die at an early age from intercurrent diseases.
The main cause of death: respiratory and cardiovascular insufficiency.
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14. From birth, generalized muscular hypotension is expressed with a
characteristic pose:
◦ the legs are unbent, rotated outward,
◦ the arms are located along the trunk,
◦ the shoulders are raised (the "frog" pose),
◦ the spontaneous motor activity, in severe cases, only movements in the
fingers of the hands are observed,
◦ the feet hang down.
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15. ◦ Tendon reflexes are not triggered.
◦ Early(the first months of life), atrophy and fascicular twitching occur in
the muscles of the back, trunk, proximal parts of the upper and lower
extremities.
◦ The face is hypomimic, in some cases there are early signs of bulbar
disorders: weak screaming, sluggish sucking, dysphagia, fibrillation of
the muscles of the tongue.
◦ The chest is flattened due to the weakness of the intercostal muscles.
During the first months of life , most patients have frequent aspiration,
respiratory infections, often pneumonia.
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16. Intermediate SMA II
The main criteria for the diagnosis of type II SMA are:
1. autosomal recessive type of inheritance;
2. the onset of the disease – the first 18 months of life;
3. generalized muscle weakness and hypotension;
4.18- diffuse muscular atrophy with a predominant lesion of the proximal extremities;
5. fascicular tremor of the fingers, muscles of the proximal parts of the upper and lower
extremities;
6. the presence in skeletal muscle biopsies of groups of small round fibers, hypertrophied
fibers of type I and atrophied fibers of types I and II;
7. ENMG indicates a lesion of the anterior horns of the spinal cord;
8. progressive course;
9. unfavorable prognosis.
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17. ◦ Clinical manifestations are more often detected at 8-14 months, but in
1/3 of cases, mothers already notice weak fetal movement during
pregnancy.
◦ The earlier the pathological process develops, the more severe the
disease is.
◦ As a rule, for no apparent reason or after an infection, preventive
vaccinations, injuries patients develop weakness in the legs, mainly in
proximal parts.
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18. ◦ The support on the legs is lost, lying on their back’s they stop holding them
up;
◦ in the sitting position they support them selves by leaning on their hands.
◦ With the development of the disease at a later age, children quickly get tired
when walking, often fall.
◦ Attention is given to symmetrical hypotension, muscle hypotrophy, mainly in
the proximal parts of the legs. In the early stages, atrophied muscles can be
"veiled" by well-defined fatty tissue.
◦ As the process progresses adipose tissue practically disappears. Muscle
weakness, hypotension, hypotrophy become generalized.
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19. ◦ The proximal parts of the upper extremities are included in the process.
◦ Due to the weakness of the shoulder girdle muscles, there is a symptom
of "free shoulders".
◦ Deep reflexes decrease.
◦ First of all, the knee muscles disappear, then the reflexes from the
biceps and triceps, later the Achilles and carporadial ones. The disease
is progressing. Can pseudohypertrophy of the calf muscles, less often of
the gluteal muscles, is observed.
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20. ◦ Fascicular, fibrillar twitches appear in the muscles of the tongue, in the
proximal parts of the extremities.
◦ Osteoarticular deformities are formed (flexion contractures in the
extremities, kyphoscoliosis, flattening of the chest, funnel-shaped chest,
pathological installation of the feet).
◦ As a result of the development of contractures, children become
"sedentary".
◦ With type II SMA, symptoms increase more slowly than with the disease
Werdnig-Hoffman, however, the course of the disease is unfavorable.
Children die at an early age from intercurrent diseases. The immediate
cause of death is usually pneumonia.
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21. Juvenile SMA III, Kugelberg-Velander
disease
◦ Syn. - benign spinal amyotrophy; spinal progressive juvenile
amyotrophy; pseudomyopathic or juvenileamyotrophy.
◦ It was first described in 1956 by Swedish neurologists.
◦ It occurs with a frequency of 1.2 per 100,000 population.
◦ Inherited by autosomal recessive type, less often by autosomal
dominant.
◦ The first symptoms occur after 18 months, more often from 2 to 5 years.
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22. ◦ The cases of the beginning are described diseases before the age of 17
and later.
◦ At birth, the child is healthy. The motor activity of the fetus and
newborn is not impaired. The process develops in children who have
already learned to walk.
◦ A typical manifestation is weakness of the muscles of the pelvic girdle
and the proximal parts of the lower extremities, which leads to difficulty
walking, getting up, climbing stairs. Children get tired quickly, can't run,
often fall.
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23. ◦ Symmetrical hypotrophy of the affected muscles is noted, moderate
"pseudohypertrophy" of the calf muscles may be observed.
◦ The gait gradually changes, acquires the character of a "duck".
◦ First of all, the supra- and subacute muscles suffer, the volume of active
movements in the hands decreases, the symptom of "wing-shaped
shoulder blades" appears,
◦ muscle hypotension is observed.
◦ Tendon reflexes decrease: first of all, knee reflexes, then with biceps
and triceps muscles of the shoulder. There are fascicular and fibrillar
twitches in various muscle groups.
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24. ◦ Bone deformities and contractures in the joints may develop.
◦ The disease progresses slowly. For many years, the disease does not
cause deep disability, the possibility of self-care and even working
capacity remains.
◦ Electromyography indicates distinct signs of anterior horn lesion.
◦ Muscle biopsy reveals a "bundle" atrophy characterized by groups of
atrophic muscle fibers alternating with indistinct or preserved elements
of muscle tissue. The transverse striation of even atrophied muscle
fibers persists for a long time.
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25. Procedure for examination of patients with
suspected SMA1
1. Collection of complaints and anamnesis (onset of clinical manifestations, the
nature of the course of the disease, determination of the probable type of
inheritance);
2. Identification of the "sluggish child" symptom complex;
3. Search for neurological symptoms characteristic of SMA (muscle fibrillation
and fasciculation, mainly symmetrical muscle atrophy of the proximal
extremities, lack of deep reflexes);
4. ENMG research;
5. Differential diagnosis;
6. DNA diagnostics.
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26. The main diagnostic signs of SMA:
◦ 1. As a rule, autosomal recessive type of inheritance
◦ 2. The appearance of the first signs of the disease in the first 6 months of life (type I),
at the age of 1.5 years (type II) or after 1.5 years (type III)
◦ 3. Weakness and symmetrical atrophy of the muscles of the trunk and limbs(mainly
lower)
◦ 4. Fibrillation and fasciculation of limb muscles
◦ 5. Characteristic ENMG changes
◦ 6. Typical changes in muscle tissue (atrophy of muscle fibers)
◦ 7. Absence of disorders of sensitivity and pelvic functions22
◦ 8. Progressive course with unfavorable prognosis at I and II types and relatively
favorable for type III disease
◦ 9. Positive results in molecular genetic research (DNA diagnostics).
27. Treatment
◦ Treatment of patients with SMA should be comprehensive, continuous and individual.
1. Physical therapy. The goal is to correct metabolic disorders, improve neuromuscular
conduction, increase muscle tone, and prevent the development of contractures
2. Physical therapy. The goal is prevention of development and correction contractures
of the extremities, maintenance of motor activity, improvement of muscle tone, delay in
the development of atrophy, prevention of complications caused by inactivity.
28. Treatment
◦ 3. Orthopedic correction. The goal is to prevent and eliminate contractures and bone
deformities, compensate for limb shortening, and ensure maximum long-term
mobility for patients with type III SMA.
◦ 4. Drug therapy. The goal is to compensate for the energy deficit of muscle tissue, improve
tissue metabolism and peripheral blood circulation.
Modern methods:
1. Increasing the level of SMN protein. Valproic acid preparations are used - 15-20 mg / kg
per day.
2. Gene therapy (Zolgensma, Spinraza (nusinersen)).
3. Stem cell therapy under development.
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29. ◦ In December 2016, the first specialized drug for the treatment of SMA of any type was
approved in the USA — Spinraza (Spinraza, nusinersen). Nusinersen, developed by
Biogen and Ionis Pharmaceuticals, is an antisense oligonucleotide for alternative
splicing of the pre-mRNA of the SMN2 gene, which is almost identical to SMN1, and
therefore the synthesis of the full-size SMN protein is enhanced. Spinraza is
administered intrathecally.
◦ In May 2019, the US FDA approved Zolgensma (onasemnogen abeparvovek) — gene
therapy of spinal muscular atrophy with a biallel mutation of the motor neuron
survival gene 1 (SMN1) in children under the age of two years. The drug is suitable for
both symptomatic patients and pre-symptomatic patients detected by genetic testing.
Regulatory approval was granted to AveXis, which Novartis bought for $8.7 billion.
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30. ◦ Onasemnogene abeparvovec (AVXS-101) is a gene therapy treatment based on the
AAV9 vector, after a single dose, providing replacement of the missing or defective
SMN1 gene with its functional copy without changing the child's DNA. The result is
the normal production of SMN protein - and the corresponding cessation of the
progression of spinal muscular atrophy. In any case, a single administration of the
drug Zolgensma demonstrates[11] that patients begin not only to get rid of
dependence in the ventilator, but also to demonstrate a significant improvement in
motor skills (the ability to sit, stand up, walk), in some cases fully corresponding to
normal age development [12]. The drug is considered the most expensive drug with a
course cost (1 injection) of more than $2 million.
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31. Prevention
◦ Only passive prevention is possible — counseling parents at risk of SMA
about possible consequences and prenatal DNA diagnostics during
pregnancy through a chorionic villi biopsy to make a decision about
birth or termination of pregnancy.
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