Spinal muscular atrophy

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting.^[3][4][5] It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death.^[6] It may also appear later in life and then have a milder course of the disease. The common feature is the progressive weakness of voluntary muscles, with the arm, leg, and respiratory muscles being affected first.^[7][8] Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.^[2][8]

The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into several types.^[4]

Spinal muscular atrophy is due to an abnormality (mutation) in the SMN1 gene^[1][2] which encodes SMN, a protein necessary for the survival of motor neurons.^[8] Loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles.^[8] Another gene, SMN2, is considered a disease modifying gene, since usually the more the SMN2 copies, the milder is the disease course. The diagnosis of SMA is based on symptoms and confirmed by genetic testing.^[9][1]

Usually, the mutation in the SMN1 gene is inherited from both parents in an autosomal recessive manner, although in around 2% of cases it occurs during early development (de novo).^[1][10] The incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births,^[11] with 1 in 7,000 and 1 in 10,000 commonly quoted for Europe and the US respectively.^[2]

Outcomes in the natural course of the disease vary from death within a few weeks after birth in the most acute cases to normal life expectancy in the protracted SMA forms.^[8] The introduction of causative treatments in 2016 has significantly improved the outcomes. Medications that target the genetic cause of the disease include nusinersen, risdiplam,^[12] and the gene therapy medication onasemnogene abeparvovec. Supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support.^[1]