A near-identical backup gene decides how severe spinal muscular atrophy becomes
People with spinal muscular atrophy lack a working SMN1 gene, which motor neurons need to survive. Almost everyone, though, carries a nearly identical understudy, SMN2, that makes a small amount of the same protein. The more copies of that backup a person has, the milder the disease tends to be.
Spinal muscular atrophy, or SMA, is a rare disorder in which the motor neurons linking spinal cord to muscles die off, leading to progressive weakness, usually first in the legs, arms and breathing muscles. It is typically noticed in infancy or early childhood and, untreated, is the most common genetic cause of infant death, although some forms start later in life and run a much milder course. Outcomes range from death within weeks of birth to a normal lifespan.
Both genes sit side by side on chromosome 5. SMN2 differs from SMN1 by a single DNA letter, but that tiny change makes cells cut its message differently, so only 10 to 20 percent of its output becomes full, working protein; the rest is a shortened version quickly broken down. Most people with SMA have two to four copies of SMN2, enough to keep some neurons alive for a time. Most babies with the severest type carry one or two copies, while late-onset patients usually have four or more, though the link is not absolute.
The disease is inherited recessively: a child must receive a faulty SMN1 from each parent, who are usually healthy carriers. Roughly one person in 50 is a carrier, and SMA affects all ethnic groups at similar rates, unlike sickle cell disease or cystic fibrosis. In around 2 percent of cases the mutation arises fresh. Genetic testing picks up a missing SMN1 in over 95 percent of patients and can count SMN2 copies at the same time.
Before its genetics were understood, doctors thought the infant and adult forms were separate illnesses, named Werdnig–Hoffmann and Kugelberg–Welander disease; in 1990 they were recognised as one spectrum. Medicines now target the genetic cause, including a gene therapy, and because they work best before symptoms appear, newborn screening has spread, joining the US recommended list in 2018.
Source: Spinal muscular atrophy
