Spinal Muscular Atrophy (SMN1)
Spinal muscular atrophy (SMA) is a pan-ethnic, autosomal recessive disease caused by loss of function of the SMN1 gene. In over 95% of cases, patients are missing both copies of the SMN1 gene. The disease is characterized by the degeneration of alpha motor neurons of the spinal cord anterior horn cells, leading to progressive symmetric weakness, atrophy of the proximal voluntary muscles and early death. Age of onset can be anywhere on a continuum from the prenatal period to adulthood. SMA 0 represents the most severe form. Infants are born with severe hypotonia and joint contractures; no motor milestones are achieved and patients die before 6 months of age. SMA I has an age of onset in the first six months of life. These cases are associated with death usually by age 2 and the lack of development of motor skills. SMA II has an age of onset between 3 and 15 months; patients may be able to sit independently. Intelligence is not affected. Life expectancy may vary from early childhood to early adulthood. SMA III has an age of onset after 18 months of age and as late as adolescence; patients may learn to stand and to walk short distances. These patients may have a normal lifespan. SMA IV is an adult-onset disorder of muscle weakness; life span is not shortened. Most patients, regardless of the severity of disease, have a deletion of both SMN1 copies. Patients with later-onset disease usually have three or more copies of SMN2, which encodes a small amount of residual protein and lessens the severity of the symptoms. However, other factors besides SMN2 copy number may affect the phenotype, and therefore the severity of the disease may not be able to be accurately predicted in all patients based on genotype.
For information about carrier frequency and residual risk, please see the residual risk table.