Spinal muscular atrophy (SMA) is an inherited disease caused by a mutation in the genetic instructions for making survival motor neuron (SMN) proteins. SMN proteins are necessary for motor neurons to work. Their job is to send signals from the brain to the spinal cord and muscles, telling them to move. When motor neurons do not have enough SMN protein, they die, causing muscle weakness and degeneration (wasting away).

The two SMN genes in humans are called SMN1 and SMN2. In people with SMA, differences in how many copies of each SMN gene they have and what type of mutation has occurred determine:

• The type of SMA
• The severity of SMA symptoms
• The age at which symptoms begin

Learn more details about the role of SMN1 and SMN2 genes in SMA below.

SMN1 and SMN2 Genes

Both SMN1 and SMN2 genes are responsible for making SMN proteins to help motor neurons work. In a person without SMA, the SMN1 gene makes 85 percent to 90 percent of the protein needed for muscles to work. The SMN2 gene only makes around 10 percent to 15 percent of the protein.

The SMN2 gene makes many different types of SMN proteins. However, only one version of the protein (isoform D) is the full-length, functional protein. The other versions are smaller and broken down by the nerve cells quickly. Isoform D is very similar to the protein made by the SMN1 gene.

Generally, people without SMA have two copies of the SMN1 gene and one to two copies of the SMN2 gene. However, some people may have no copies of the SMN2 gene, and others can have up to eight copies.

Mutations in the SMN1 and SMN2 Genes

SMA develops when there is a mutation in both copies of the SMN1 gene. Most people with SMA (95 percent to 98 percent) have deletions in the SMN1 gene. This means that a piece of the gene is missing entirely. When a deletion occurs, the SMN1 gene cannot make any SMN protein. The remaining 2 percent to 5 percent of people with SMA have smaller, more specific mutations that result in less SMN protein being made.

The SMA type and disease severity depend mainly on the number of copies of SMN2 a person has. The more copies a person has, the more SMN protein they can make. The age of onset (when a person begins showing symptoms) is also influenced by the SMN2 copy number.

Genetic testing can be done to find out if a person carries an SMN1 mutation. These mutations are recessive, meaning that a person must inherit two mutated copies (one from each parent) to develop SMA. According to the American College of Obstetricians and Gynecologists, between 1 in 40 to 1 in 60 people are carriers of SMA. If both parents have one mutated copy of the SMN1 gene, there is a 25 percent chance they will have a child with SMA.

Genes and SMA Types

The descriptions of physical abilities and age of onset are based on historical averages of people with those types of SMA. These predictions were developed before SMA treatments became available. Long-term studies to predict differences in abilities in children who receive early treatment are not yet available.

Type 0 SMA

Type 0 SMA is noticeable in fetuses that do not move much during pregnancy. After birth, the disease is associated with severe muscle weakness, occasionally congenital heart defects, and the inability to move the muscles in the face. Typically, infants with type 0 SMA have only one copy of the SMN2 gene, which cannot make enough protein for the nerve cells to function properly.

Type 1 SMA

Type 1 SMA — also known as Werdnig-Hoffmann disease — is diagnosed when SMA symptoms are noticeable between birth and 6 months of age. Generally, babies have muscle weakness, difficulty breathing, and weak cries. They also cannot swallow or suck well and have difficulties eating. Babies with type 1 SMA only have one to two copies of the SMN2 gene.

Type 2 SMA

Type 2 SMA — also known as intermediate SMA, or Dubowitz disease — develops in babies between the ages of 3 to 15 months. Typically, they are not able to stand or walk on their own because the muscles in their legs and arms are weak. Babies with type 2 SMA usually have three copies of the SMN2 gene.

Type 3 SMA

Type 3 SMA — also known as Kugelberg-Welander disease — accounts for 30 percent of SMA cases. It typically develops in children (juvenile onset). However, the symptoms can be noticed anywhere from 18 months into adulthood. People with type 3 SMA can become independent and move well on their own, but they may still have some muscle weakness that makes some activities difficult. These individuals usually have three to four copies of the SMN2 gene.

Type 4 SMA

Type 4 SMA develops later in life — typically at age 30 and older — and makes up only 5 percent of SMA cases. This is a mild form of SMA because individuals have anywhere from four to eight copies of the SMN2 gene. The extra copies of the SMN2 gene can compensate for the mutations in SMN1, typically allowing people with type 4 SMA to maintain their mobility.

Genes and Gene Therapy for SMA

Although there is currently no cure for SMA, there are gene therapies approved for treating the disease. Nusinersen (Spinraza) and onasemnogene abeparvovec-xioi (Zolgensma) are two treatments approved by the U.S. Food and Drug Administration for treating SMA.

Both Spinraza and Zolgensma are gene therapies given to modify the function of the SMN genes. Spinraza is given by injection into the spinal canal, and it is thought to increase the amount of SMN protein made by the SMN2 gene. It is given to infants with SMA and children between the ages of 2 and 12. Zolgensma is a one-time injection for infants under the age of 2. It is thought that it works on the SMN1 gene, helping it make more SMN protein.

There are also ongoing clinical trials looking at new treatments for SMA in hopes of improving the quality of life for those living with the disease.

Talk With Others Who Understand

On mySMAteam, the social network for people with spinal muscular atrophy and their loved ones, more than 1,400 members come together to ask questions, give advice, and share their stories with others who understand life with SMA.

Do you have questions about SMN1 and SMN2 genes? Share your thoughts in the comments below, or start a conversation by posting on mySMAteam.