Practice Essentials
Spinal muscle atrophy (SMA; also known as spinal muscular atrophy) is a rare debilitating autosomal recessive hereditary disease characterized by progressive hypotonia and muscular weakness. The characteristic muscle weakness occurs because of a progressive degeneration of the alpha motor neuron from anterior horn cells in the spinal cord. The weakness is more severe in the proximal musculature than in the distal segments.
In certain patients, the motor neurons of cranial nerves (especially cranial nerves V-XII) can also be involved. Sensation, which originates from the posterior horn cells of the spinal cord, is spared, as is intelligence. Several muscles are spared, including the diaphragm, the involuntary muscles of the gastrointestinal system, the heart, and the sphincters. [1, 2, 3, 4]
In 1890, Werdnig described for the first time the classic infantile form of SMA. [5] Many years later, in 1956, Kugelberg and Welander described the less severe form of SMA. [6] Werdnig, in 1890, [5] and Hoffman, in 1891, [7] reported cases of muscular dystrophy occurring in infants that were otherwise similar to cases of muscular dystrophy found in older children and adults (eg, Duchenne muscular dystrophy).
SMA is the most common diagnosis in girls with progressive weakness. It is one of the most common genetic causes of death in children.
No two children with SMA will be exactly the same. Accordingly, treatment and care plans for each family should be tailored to meet specific individual needs. Ideally, a team-based comprehensive supportive approach to care optimizes outcomes in these children. The team should consist of a neurologist, a pulmonologist/intensivist, an orthopedic surgeon, a nutritionist, genetic counselors, social workers, an orthoptist, and occupational and physical therapists.
Pathophysiology
SMA is caused by a mutation in the survival motor neuron (SMN) gene. This gene is normally inactive during the fetal period and allows normal apoptosis in the developing fetus. The gene becomes active in the healthy mature fetus to stabilize the neuronal population.
In a healthy person, this gene produces a protein that is critical to the function of the nerves that control our muscles; without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness. In the absence of the gene, programmed cell death persists. [8] The mechanism and timing of abnormal motor neuron death remain unknown. [9, 10]
Classification
SMA is commonly divided into four types on the basis of the patient's age at onset and the highest physical milestone achieved, as follows:
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Type I (Werdnig-Hoffmann disease) - Onset between birth and age 6 months
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Type II - Onset between the ages of 6 and 12 months
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Type III (Kugelberg-Welander disease) - Onset between the ages of 2 and 15 years
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Type IV - Adult onset
Etiology
Patients with SMA have a homozygous deletion of the telomeric SMN gene SMN1, which is found in arm 5q13 (bands q11.2-13.3). [9] This deletion has been demonstrated in as many as 98% of patients with SMA.
SMN1 encodes the SMN protein, which is part of a multiprotein complex required for the biogenesis of small nuclear ribonucleoproteins. [11, 12] The SMN protein is critical to the health and survival of the nerve cells in the spinal cord that are responsible for muscle contraction (motor neurons). SMN1 has been linked to pre-mRNA splicing, spliceosome biogenesis, and the nucleolar protein fibrillarin. The absence or dysfunction of SMN is reflected by an enhanced neuronal death. A heterozygous deletion leads to an asymptomatic carrier state. [13]
A second gene also plays a role in producing the SMN protein—namely, SMN2, often called the SMA "backup gene." SMN2 is present in most individuals, including those with SMA. It is almost identical to SMN1, differing only by five nucleotides. Several versions of the SMN protein are produced by SMN2, but only one version (isoform d) is complete and functional. The other proteins produced by SMN2 are more labile and are unable to compensate fully for the absence of SMN1. [14] Thus, only 10-15% of all functional SMN protein is produced from SMN2.
Most people have two copies of SMN1 and one or two copies of SMN2. The number of copies of SMN2 is variable, and some people have as many as eight copies. The severity of SMA is inversely related to the number of copies of SMN2. Most severely affected individuals will have fewer copies of this gene. [15] The SMN2 gene copy number is related to, but not predictive of, disease severity, and care decisions should not be made on the basis of copy number alone. Other genetic modifiers, such as the protein plastin-3 (PLS3), may influence disease severity. [16]
A significant increase in nuclear DNA vulnerability was detected in fetuses with SMA at 12-15 weeks' gestational age. This reflected a decrease in the number of anterior horn neurons. This vulnerability is no longer seen in the rest of the antenatal or postnatal period. Abnormal cell morphology was seen only in the postnatal period. [17]
Epidemiology
United States statistics
The incidence of SMA is about 1 case in 10,000 live births. The prevalence of persons with the carrier state is 1 in 50. SMA can affect any race or gender.
In North Dakota, the incidence is about 1 case in 6720 (15 per 100,000) live births, the prevalence is 1.5 cases in 10,000, and the prevalence of persons with the Werdnig-Hoffman disease carrier state is 1 in 41. [18] SMA appears to be three to 10 times more common in North Dakota than in other areas.
SMA is the most common degenerative disease of the nervous system in children. After cystic fibrosis, it is the second most common disease inherited in an autosomal recessive pattern that affects children. It is the leading heritable cause of infant mortality. [19]
International statistics
The incidence of SMA is generally higher in Central and Eastern Europe than in Western Europe.
In England, the incidence is 1 case in 24,100 (4 per 100,000) live births. Prevalence is 1.2 cases per 100,000 population. In Italy, the incidence is 7.8 cases in 100,000 live births (all types). In Germany, the incidence of Werdnig-Hoffmann disease is 1 case in 10,202 (9 per 100,000) live births. [20] The incidence of SMA in Slovakia is 1 case in 5631 (18 per 100,000) live births (all types). In Poland, the incidence of Werdnig-Hoffmann disease is 1 case in 19,474 (5 per 100,000) live births.
Age-related demographics
The three different types of SMA that occur in the pediatric population are genetically similar but differ with respect to patient age at presentation and clinical course, as follows:
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Type I (Werdnig-Hoffmann disease) - This acute infantile SMA is usually identified in patients from birth to age 6 months; it is the most severe and common form of the disease, accounting for 60% of all cases of SMA, and it is often fatal early in life
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Type II - This chronic infantile SMA is diagnosed in infants aged 6-24 months
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Type III (Kugelberg-Welander disease) - This type of SMA is diagnosed in children aged 2-15 years
Sex-related demographics
Males are more commonly affected with SMA than females are. The male-to-female ratio is 2:1. The clinical course in males is more severe. Life expectancy has not been demonstrated to be influenced by sex. [21] As the age at onset increases, incidence of SMA in females decreases. With age at onset older then 8 years, females are affected much less frequently. In cases where the patient is older than 13 years at onset, incidence in females is the exception.
Race-related demographics
The incidence of SMA in black Africans is very low.
Prognosis
The age of onset and the achievement of functional abilities are better predictors of prognosis than the number of copies of SMN2. Genetic modifiers (eg, PLS3) may also influence disease severity and prognosis. [16]
As a general rule, the younger the patient at disease onset, the worse the prognosis. The overall median age at death exceeds 10 years. Intelligence is unaffected by SMA. Patients with type I SMA usually die by age 2 years. Patients with type II SMA have a greater expected lifespan than patients with type I SMA. Some patients with type II SMA live into the fifth decade of life. Patients with type III SMA have nearly normal life expectancy.
Death occurs as a result of respiratory compromise. The lifespan of affected individuals has significantly increased with the use of intermittent positive-pressure ventilation (PPV), with or without a tracheostomy.
Patient Education
Antenatal diagnosis in the first trimester and proper genetic counseling are possible with DNA analysis. This enables more accurate carrier detection. [22] Not all parents of children with SMA are obligate carriers. [23] The American College of Medical Genetics and Genomics (ACMG) has recommended that because SMA is found in all populations, carrier screening should be offered to couples of all races and ethnicities. The ACMG suggests that the testing be performed either before conception or early in pregnancy to allow carriers to make informed reproductive decisions. Approximately 3% of cases are sporadic.
A potential medicolegal pitfall is poor counseling of parents and patients regarding possible complications before surgical treatment. These patients lose function after spinal stabilization, and their ability to ambulate may be hindered. The possibility of recurrence or worsening of the hip dislocation must be emphasized; the risk of recurrent deformity is present even with foot and ankle procedures.
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Spinal muscle atrophy, Werdnig-Hoffman disease. Small muscle fibers within separate muscle fascicles.
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Spinal muscle atrophy, Werdnig-Hoffman disease. Marked variation in muscle fiber size, as well as relative increase in associated connective tissue.
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Spinal muscle atrophy, Kugelberg-Welander disease. Marked variation in muscle fiber size, along with increased perimysial connective tissue.
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Spinal muscle atrophy, Kugelberg-Welander disease. Muscle-fiber variation with some demonstrating internal nuclei.
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Spinal muscle atrophy. At age 4 years, this boy's chest radiograph already reveals presence of significant 32° left thoracic scoliosis. Diagnosis is type I spinal muscle atrophy (Werdnig-Hoffmann disease). This radiograph captures the lumbar curvature incompletely.
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Spinal muscle atrophy. By age 6 years, child's curve is starting to decompensate. Note development of right-side truncal shift. He now has 40° thoracic curve and 60° lumbar curve.
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Spinal muscle atrophy. Spine anteroposterior view. Spinal curvature is progressing. Lumbar curve now is 70°, and thoracic curve is 35°. It is now clearly apparent that right hip is dislocated. Also note marked pelvic obliquity in this patient.
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Spinal muscle atrophy. By age 9 years, this patient with type I spinal muscle atrophy now has thoracic curve of 60° and lumbar curve of 110°. Note that patient has tracheostomy tube and nasogastric tube as well.
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Spinal muscle atrophy. Immediate postoperative anteroposterior radiograph of patient at age 9 years. Thoracic curve is now at 18°, and lumbar curve is 35°, which represents more than 67% curvature correction.
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Spinal muscle atrophy. Immediate postoperative lateral view with good sagittal balance.
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Spinal muscle atrophy. Follow-up radiographs in patient at age 13 years reveal some spinal decompensation. Note so-called coathanger appearance of ribs in dysplastic right hemithorax.
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Spinal muscle atrophy. Anteroposterior radiograph of pelvis demonstrating right hip dislocation.
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Spinal muscle atrophy. Lauenstein lateral view of hips on patient with spinal muscle atrophy type I. Note near-universal pelvic dysmorphology (eg, widened obturator foramina) in addition to dislocated right hip.
