Background

Spinal muscle atrophy (SMA; also known as spinal muscular atrophy) is an 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.

SMA is commonly divided into four types on the basis of patient age at onset, as follows:

• Type I (Werdnig-Hoffmann disease) - Onset between birth and age 6 months
• Type II - Onset between the ages of 6 and 12 months
• Type III (Kugelberg-Welander disease) - Onset between the ages of 2 and 15 years
• Type IV - Adult onset

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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. The gene becomes active in the healthy mature fetus to stabilize the neuronal population. In its absence, programmed cell death persists.^[8] The mechanism and timing of abnormal motor neuron death remain unknown.^{[9, 10]}

Epidemiology

Frequency

United States

The incidence of SMA 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 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.^[11] 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. 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.^[12]

International

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.^[13] 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.

Mortality/Morbidity

In SMA, death occurs because of 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

The incidence of SMA in black Africans is very low.

Sex

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.^[14] 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 in which the patient is older than 13 years at onset, incidence in females is the exception.

Age

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:

• 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 Presentation