What Is Spinal Muscular Atrophy (SMA)?

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in SMN1 (encoding survival motor neuron protein (SMN)). It is an autosomal recessive genetic disease. Mutations in SMN1 lead to the progressive loss of motor neurons in the anterior horn of the spinal cord, resulting in muscle weakness and atrophy. The incidence of Spinal Muscular Atrophy (SMA) is approximately 1 in 10,000 to 1 in 20,000 live births, with a carrier frequency of 1 in 40 to 1 in 70 in the general population. Because of its severity in infants, SMA is often referred to as “the leading genetic killer of infants.”

SMA was once considered an incurable disease. However, since the beginning of the 21st century, advancements in SMA diagnosis and treatment have changed its outlook. The discovery of SMN1 and SMN2 genes, along with the development of FDA-approved SMA therapies, now offers patients real hope.

SMA Symptoms and Classification

The clinical presentation of SMA varies according to the age of onset and disease severity. SMA is classified into five main types (Type 0–IV):

• Type 0 – The most severe form, with onset before birth and rapid progression to severe respiratory failure after delivery.
• Type I (Werdnig–Hoffmann disease) – Severe type, with onset before 6 months of age; affected infants are unable to sit independently.
• Type II (Dubowitz disease) – Intermediate type, with onset before 18 months of age; patients can sit without support but cannot stand or walk independently.
• Type III (Kugelberg–Welander disease) – Mild type, with onset after 18 months of age; patients can stand and walk independently.
• Type IV – The mildest form, with onset after 30 years of age.

Genetics of SMA: SMN1 and SMN2 Genes

In 1990, Gilliam et al. in the United States and Melki et al. in France independently mapped the genetic locus of SMA to the same region on chromosome 5q13. In 1995, two SMA-related genes, SMN1 and SMN2, were identified in 5q13 region. These two genes were paralogs. The SMN1 gene, located in the telomeric side, is the gene responsible for SMA; its loss or defect causes SMA with different phenotypes. The SMN2 gene, located in the centromeric side, is a modifier gene for SMA; its copy number is associated with the severity of the disease. SMN1 and SMN2 were originally reported to exist in an inverted duplication; however, recently, a tandem duplication model has been presented.