Spinal muscular atrophy (SMA) is caused by mutations in a gene called SMN1, which provides instructions for making a protein essential to the survival of motor neurons. Most people with SMA are missing a piece of this gene entirely, leaving their bodies unable to produce enough of this protein. Without it, the motor neurons in the spinal cord gradually break down, leading to progressive muscle weakness.
SMA follows an autosomal recessive inheritance pattern, meaning a child must inherit a faulty copy of SMN1 from both parents to develop the condition. About 1 in 40 to 1 in 60 people carry one defective copy without ever showing symptoms.
The SMN1 Gene Deletion
The root cause of SMA is straightforward compared to many genetic diseases. The SMN1 gene sits on chromosome 5 and is responsible for producing survival motor neuron (SMN) protein. In most cases of SMA, a section of this gene is deleted or mutated on both copies, one inherited from each parent. Roughly 95% of cases can be identified through a standard blood test that checks for this deletion. The remaining 5% involve a rarer type of point mutation on one copy of the gene, which requires additional sequencing to detect.
SMN protein is needed by cells throughout the body, but motor neurons are uniquely vulnerable when levels drop. These are the nerve cells in the spinal cord that send signals to muscles, controlling voluntary movement. When they degenerate, the muscles they control weaken and eventually waste away.
How Low SMN Protein Damages Motor Neurons
Researchers have identified specific ways that low SMN protein disrupts motor neuron function at the cellular level. One key finding is that SMN depletion impairs the internal recycling system that motor neurons rely on to communicate with muscles. At the junction where a motor neuron meets a muscle fiber, tiny packages called synaptic vesicles carry chemical signals across the gap. These vesicles need to be constantly recycled and refilled for the connection to keep working.
When SMN protein levels are low, this recycling process breaks down. Studies in motor neurons have shown a 36% reduction in the total number of synaptic vesicles available at nerve terminals, along with significantly fewer vesicles docked and ready to release their signals. The machinery responsible for retrieving and repackaging used vesicles also malfunctions, with abnormal structures accumulating at the synapse, a sign of arrested recycling. Over time, these defects weaken the motor neuron’s ability to activate muscles, and the neuron itself degenerates.
Why SMN2 Copy Number Determines Severity
Humans carry a second, nearly identical gene called SMN2. It can produce SMN protein, but it does so inefficiently. A single letter change in the SMN2 gene’s code causes most of its protein product to come out shorter and nonfunctional. Only a small fraction of SMN2’s output is full-length, working protein.
This makes SMN2 a partial backup. The more copies of SMN2 a person has, the more functional protein they produce, and the milder their disease tends to be. A large study of 375 patients found a strong correlation between SMN2 copy number and SMA type:
- 1 to 2 copies: 80% of patients had the most severe form (Type I)
- 3 copies: 82% had intermediate severity (Type II)
- 3 to 4 copies: 96% had the milder form (Type III)
This relationship isn’t absolute. Some individuals with three copies still develop severe disease, and others with two copies have milder courses. But SMN2 copy number is the single strongest predictor of how SMA will progress, and it plays a central role in how modern treatments work.
The Five Types of SMA
SMA is classified into types based on when symptoms first appear and what motor milestones a child reaches. The types exist on a spectrum, and the boundaries between them can blur, but they give families and clinicians a useful framework.
Type 0 is the rarest and most severe form. Symptoms begin before birth, with reduced fetal movement. At birth, infants have profound weakness and serious difficulty breathing and feeding.
Type I appears before 6 months of age. Babies have severe muscle weakness and struggle to breathe, cough, and swallow. They never gain the ability to sit independently. This is the most common form diagnosed in infancy.
Type II becomes apparent between 6 and 18 months. Children with this type can sit without support but are unable to stand or walk on their own.
Type III shows symptoms after 18 months. Children can walk independently but may have difficulty running, climbing stairs, or getting up from a chair. Over time, some lose the ability to walk.
Type IV is the adult-onset form, developing after age 18. It causes mild to moderate leg weakness and progresses slowly.
Inheritance and Carrier Risk
SMA follows autosomal recessive inheritance. Both parents must carry a defective SMN1 gene for their child to be at risk. When both parents are carriers, each pregnancy has a 25% chance of producing a child with SMA, a 50% chance of producing a carrier, and a 25% chance of producing a child with two working copies. Carriers have one functional copy of SMN1 and do not develop symptoms.
Given that roughly 1 in 40 to 1 in 60 people carry the mutation, carrier screening is widely available. The American College of Obstetricians and Gynecologists includes SMA on its recommended carrier screening panel. A simple blood test can identify carrier status in most cases.
Newborn Screening and Early Detection
All 50 U.S. states plus Washington, D.C., now screen newborns for SMA at birth, achieving 100% coverage within six years of SMA being added to the federally recommended screening list. This matters enormously because treatment is far more effective when started before symptoms appear, while motor neurons are still intact.
A positive newborn screen is confirmed through genetic testing, which identifies the SMN1 deletion and counts SMN2 copies. The SMN2 count helps predict likely severity and guides treatment decisions.
How Treatments Target the Genetic Cause
Current treatments for SMA work by exploiting the SMN2 gene that every patient still carries. Since the problem with SMN2 is that it skips a critical section of its code during protein production (exon 7), therapies aim to force the gene to include that section, producing full-length, functional protein.
One approach uses a molecule injected into the spinal fluid that physically blocks a signal in the gene’s code that normally triggers exon 7 skipping. With that signal blocked, more of SMN2’s output becomes functional protein. Another approach uses an oral medication that binds directly to the SMN2 gene’s messenger RNA, changing its shape so that the cellular machinery reads exon 7 instead of skipping it. Both strategies increase the amount of working SMN protein available to motor neurons.
A third approach uses gene therapy to deliver a working copy of the SMN1 gene directly into cells via a one-time infusion. Rather than coaxing SMN2 to compensate, this replaces the missing gene entirely. All three treatment strategies are most effective when started early, before significant motor neuron loss has occurred, which is why newborn screening has become so critical to outcomes.