Parents and caregivers of children with spinal muscular atrophy (SMA) often need to learn a lot quickly. One challenging topic is genetics, which helps explain your child’s condition. SMA is an inherited disease caused by mutations (changes) in the two survival motor neuron (SMN) genes, SMN1 and SMN2. These genes make the SMN protein.

As its name suggests, SMN protein is crucial for the survival of motor neurons. SMN’s job is to help send signals from the brain to the spinal cord and muscles, telling them to move. When motor neurons don’t get enough SMN protein, they die, which leads to muscle weakness and degeneration (wasting away).

Read on to find out more about the SMN1 and SMN2 genes and their roles in the type, severity, and treatment of SMA.

SMN1 and SMN2 Genes

In people with SMA, mutations in the SMN1 gene and the number of copies of the SMN2 gene affect:

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

The SMN1 and SMN2 genes make SMN protein to help motor neurons work. In someone without SMA, the SMN1 gene produces 85 percent to 90 percent of the SMN protein needed for muscles to function. The SMN2 gene makes only around 10 percent to 15 percent.

The SMN2 gene makes many types of SMN proteins. However, just one version, isoform D, is full length and functional. This is the same protein made by the SMN1 gene.

Most people without SMA have two copies of the SMN1 gene and one or two copies of the SMN2 gene. However, some people have as many as eight SMN2 copies.

Mutations in the SMN1 and SMN2 Genes

Most people with SMA (95 percent to 98 percent) have deletion mutations in the SMN1 gene. This means that a piece of the gene is missing, so no functional protein can be made. The other 2 percent to 5 percent of people with SMA have smaller, more specific mutations that cause less SMN protein to be made.

As a result of improved treatments, people with SMA are living longer, healthier lives.

Genetic testing can show if a person carries an SMN1 mutation. These mutations are recessive, meaning 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 and 1 in 60 people are carriers of SMA. If both parents have a mutated SMN1 gene, there’s a 25 percent chance their child will have SMA.

Genes and Types of Spinal Muscular Atrophy

The descriptions of developmental milestones and age of onset for different types of SMA are based on averages observed before treatments became available. New research is showing that SMA treatments are improving life expectancy and reducing disease severity. As a result, people with SMA are living longer, healthier lives, with better motor skills like walking and coordination, as well as improved breathing.

Type 0

SMA type 0 can be noticed during pregnancy when a fetus doesn’t move much. After birth, the disease causes severe muscle weakness, trouble moving facial muscles, and sometimes congenital heart defects (problems present at birth). Infants with type 0 SMA usually have only one copy of the SMN2 gene, which can’t make enough protein to keep nerve cells working.

Type 1

Also called Werdnig-Hoffmann disease, SMA type 1 is diagnosed when SMA symptoms appear between birth and 6 months of age. Babies with type 1 usually have muscle weakness, don’t reach developmental milestones, and may have trouble breathing, swallowing, and eating. Most babies with type 1 have just two or three SMN2 copies.

Type 2

SMA type 2 — also called intermediate SMA or Dubowitz disease — develops between ages 6 and 18 months. People with type 2 usually can’t stand or walk on their own and may develop scoliosis (a curved spine) due to weakened back muscles. They usually have three copies of SMN2.

Type 3

SMA type 3, which is also known as Kugelberg-Welander disease, accounts for 30 percent of SMA cases. It typically starts in children (juvenile onset), but symptoms can appear anywhere from 18 months into adulthood. People with type 3 can move around independently but may still have muscle weakness that makes some activities difficult. They usually have three or four copies of the SMN2 gene.

Type 4

SMA type 4 develops later in life, usually at age 30 or older, and makes up just 5 percent of SMA cases, according to the Muscular Dystrophy Association. This is a milder form because people with type 4 have at least four copies of the SMN2 gene. These extra copies of SMN2 help make up for the missing SMN1 function, allowing people to maintain their mobility.

Genes and Gene Therapy for Spinal Muscular Atrophy

Although there’s no cure for SMA, the U.S. Food and Drug Administration (FDA) has approved three treatments:

• Nusinersen (Spinraza)
• Onasemnogene abeparvovec-xioi (Zolgensma)
• Risdiplam (Evrysdi)

All three treatments modify SMN gene expression. Nusinersen is given by injection into the spinal canal and is believed to raise functional SMN protein levels made by the SMN2 gene. It’s approved for people of all ages with SMA. Risdiplam also increases SMN protein from the SMN2 gene and is taken by mouth as a liquid or tablet. This drug is available for people of all ages, depending on the form.

Onasemnogene abeparvovec-xioi is a one-time injection for infants under age 2. It’s thought to work by replacing the SMN1 gene with a working copy that helps make more functional SMN protein.

Ongoing clinical trials are studying new treatments to improve the quality of life for those living with SMA.

Read more about how gene therapy works.

Talk With Others Who Understand

MySMAteam is the social network for people with spinal muscular atrophy and their loved ones. On mySMAteam, 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? Do you have a child with SMA who is receiving gene therapy? Share your thoughts in the comments below, or start a conversation by posting on mySMAteam.