INTRODUCTION	Section 2 of 11
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Background: Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease characterized by progressive hypotonia and muscular weakness. The characteristic muscle weakness occurs due to 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 the CNV-CNXII) 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.

In 1890, G. Werdnig described for the first time the classic infantile form of SMA. Many years later, in 1956, Kugelberg and Welander described the less severe form of SMA. Werdnig, in 1890, and J. Hoffman, in 1891, 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.

Pathophysiology: SMA is caused by a mutation in the survival motor neuron gene. This gene is normally inactive during the fetal period and allows normal apoptosis in the developing fetus. This gene becomes active in the healthy mature fetus to stabilize the neuronal population. In its absence, programmed cell death persists. The mechanism and timing of abnormal motor neuron death remain unknown.

Frequency:

• In the US: Incidence is about 1 case in 15,000-20,000 (5-7 per 100,000) live births. The prevalence of persons with the carrier state is 1 in 80.

  In North Dakota, the incidence is about 1 case in 6,720 (15 per 100,000) live births, prevalence is 1.5 cases in 10,000, and prevalence of persons with the Werdnig-Hoffman disease carrier state is 1 in 41. SMA appears to be 3-10 times more common in North Dakota than in other areas.

  SMA is the most common degenerative disease of the nervous system in children. It is the second most common disease inherited in an autosomal recessive pattern, after cystic fibrosis, to affect children. It is the leading heritable cause of infant mortality.

• Internationally: The incidence in Slovakia is 1 cases in 5631 (18 per 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. In Italy, the incidence is 7.8 cases in 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. 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. The incidence is higher in Central and Eastern Europe than in Western Europe.

Mortality/Morbidity: Death occurs due to respiratory compromise. The younger the patient is at onset, the worse the prognosis is. The overall median age at death exceeds 10 years. Intelligence is unaffected by SMA.

Race: Incidence in black Africans is very low.

Sex:

• Males are more commonly affected than females. 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.

• As the age at onset increases, incidence in females decreases. With age at onset older then 8 years, females are affected much less frequently. In cases in which the patient is older than 13 years at onset, incidence in females is the exception.

Age: The 3 different types of SMA are genetically similar but differ in patient age at presentation and in their clinical courses.

• Type I (Werdnig-Hoffmann disease): This acute infantile SMA is usually identified in patients from birth to age 6 months.

• Type II: This chronic infantile SMA is diagnosed in infants aged 6-12 months.

• Type III (Kugelberg-Welander disease): This type of SMA is diagnosed in children aged 2-15 years.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• Type I: Most mothers report abnormal inactivity of the fetus in the latter stages of pregnancy. The patient with type I SMA is unable to roll over or sit. Progressive clinical deterioration occurs. Death usually occurs from respiratory failure and its complications in patients by age 2 years.

• Type II: Patients with type II SMA have normal development for the first 4-6 months of life. They may be able to sit independently, but they are never able to walk. They require a wheelchair for locomotion. They have a longer life span than patients with type I SMA. Some patients with type II SMA live into the fifth decade of life.

• Type III: In patients with type III SMA, the presenting complaint is difficulty climbing stairs or getting up from the floor (due to hip extensor weakness). The life span is nearly normal.

Physical:

• Physical findings specific for each type of SMA are as follows:

• Type I: Newborns with type I SMA are floppy and inactive. They move the extremities little, if at all. The hips are flexed, abducted, and externally rotated. The knees are flexed. Because the distal musculature is usually spared, the fingers and toes move. Infants cannot control or lift the head. Areflexia is universal.

• Type II: Patients with type II SMA have head control, and 75% of these patients can sit independently. Muscular weakness is greater in the lower extremities than the upper extremities. Patellar reflex is absent. The young may demonstrate bicipital and triceps tendon reflexes. Tongue fasciculations are present, as are upper extremity tremors. Scoliosis is universal, and most patients develop hip dislocation, either unilateral or bilateral, when younger than 10 years.

• Type III: These patients walk early in life and maintain their ambulatory capacity into adolescence. Weakness may cause foot drop, and patients have limited endurance. A third of the patients become wheelchair bound as adults (mean age 40 years).

• Other physical findings associated with SMA are as follows:

• A long C-shaped thoracolumbar scoliotic curve is present in patients with type II SMA and in half of patients with type III SMA. The curve progresses to a severe and incapacitating deformity if not treated. Thirty percent of patients have kyphotic deformities as well.

• Pseudohypertrophy of the calf is present, which may confound the diagnosis (ie, with Duchenne muscular dystrophy and Becker muscular dystrophy). Bouwsma reported that this finding was associated with elevated serum creatine kinase (CK). This combination was only observed in males; no females in his series had hypertrophy of the calves.

• Tongue fasciculations are pathognomonic of SMA (all types), as opposed to all other neuromuscular diseases of infancy. Presence of tongue fasciculations can aid in the diagnosis, as 56% of patients exhibit this symptom.

Causes: Patients with SMA have a homozygous deletion of the telomeric SMN1 (survival motor neuron) gene found in arm 5q (bands q11.2-13.3). This deletion has been demonstrated in up to 98% of patients with SMA. SMN is part of a multiprotein complex required for the biogenesis of small nuclear ribonucleoproteins. SMN1 has been linked to pre-mRNA splicing, spliceosome biogenesis, and, recently, to 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.