Spinal muscular atrophy (SMA) is caused by a missing or mutated gene called SMN1, which is responsible for producing a protein that keeps motor neurons alive. Without enough of this protein, the nerve cells that control voluntary muscle movement gradually break down and die, leading to progressive muscle weakness and atrophy. About 1 in every 15,000 babies in the United States is born with SMA, and roughly 1 in 50 Americans carries the gene silently.
The SMN1 Gene Deletion
More than 95% of SMA cases trace back to one genetic event: both copies of the SMN1 gene, located on chromosome 5, are deleted or non-functional. The most common specific change is a deletion of a critical section called exon 7. About 95% of people with SMA either have this deletion on both copies of the gene or have a deletion on one copy combined with a smaller mutation on the other.
That smaller mutation can take several forms. Some people carry a missense mutation, where a single building block in the gene’s code is swapped for the wrong one. Others have nonsense mutations, splice site errors, or small insertions and duplications. The most frequently reported point mutation in SMN1 occurs in exon 6, but hot spots for small mutations also appear in exon 3. Regardless of the specific error, the end result is the same: the gene can no longer produce a working version of the survival motor neuron (SMN) protein.
What the SMN Protein Actually Does
The SMN protein plays a housekeeping role inside cells. Its primary job is helping assemble tiny molecular machines called snRNPs, which cells need to process their genetic instructions correctly. Think of it as a quality-control worker on an assembly line: without it, the machinery that reads and edits genetic messages starts to malfunction.
Every cell in the body relies on this process, so a fair question is why motor neurons are hit hardest. The answer appears to involve two factors. First, motor neurons are unusually large, long-lived cells with high metabolic demands, making them more vulnerable when protein production dips. Second, low SMN levels seem to disproportionately disrupt the processing of a specific subset of genes that motor neurons depend on more than other cell types. Research on patient-derived motor neurons has shown that individual cells with lower SMN levels are more susceptible to damage, while artificially boosting SMN in those cells protects them.
How SMA Is Inherited
SMA follows an autosomal recessive inheritance pattern. That means a child needs to inherit a faulty SMN1 gene from both parents to develop the disease. If both parents are carriers, each pregnancy carries a 1 in 4 chance of producing a child with SMA, a 1 in 2 chance of producing another carrier, and a 1 in 4 chance the child inherits two working copies.
Carriers have one functional copy of SMN1 and one non-functional copy. They produce enough SMN protein to stay completely healthy and typically have no idea they carry the gene. With a carrier frequency of roughly 1 in 50 in the U.S. population, two carriers partnering is uncommon but far from rare. Carrier screening through a simple blood test is now available and increasingly offered during family planning.
The Backup Gene That Determines Severity
Humans have a near-duplicate of SMN1 called SMN2. This backup gene produces the same protein, but with one key flaw: only about 10 to 20% of the protein it makes is fully functional. The rest is truncated and quickly broken down by the cell. On its own, SMN2 can’t fully compensate for a missing SMN1, but having more copies of it helps.
The number of SMN2 copies a person carries varies from zero to eight, and this number is the single biggest factor determining how severe their SMA will be. More copies mean more functional protein trickling through, which slows the loss of motor neurons. This relationship is consistent enough that SMN2 copy number is used clinically to predict disease course, though it isn’t a perfect predictor. Some individuals with the same copy number still experience different levels of disability.
The Five Types of SMA
SMA is classified into types based on when symptoms appear and the highest physical milestone a person reaches. The types exist on a spectrum, and roughly 25% of patients don’t fit neatly into one category.
- Type 0 is the rarest and most severe form. Weakness begins before birth, and affected infants typically need breathing support immediately. Most do not survive beyond six months. These babies usually have just one copy of SMN2.
- Type 1 (Werdnig-Hoffmann disease) appears before six months of age. Infants have poor head control, weak muscle tone, and reduced reflexes. They never gain the ability to sit independently and generally develop respiratory failure before age two. Most have two SMN2 copies.
- Type 2 shows up before 18 months. Children can learn to sit on their own but never walk independently. Respiratory complications are common but progress more slowly than in type 1, and survival extends well beyond two years. These children typically carry three or four SMN2 copies.
- Type 3 (Kugelberg-Welander disease) can appear anywhere from 18 months through childhood. These individuals walk independently at some point in their lives, though many lose that ability later. Thinking and life expectancy are not affected. SMN2 copies usually number three or four.
- Type 4 is the mildest form, with onset in adulthood, often after age 30. People with type 4 remain able to walk and have a normal lifespan. They typically carry four to eight copies of SMN2.
How Motor Neuron Loss Affects the Body
The chain of events in SMA starts in the spinal cord. As motor neurons in the anterior horn degenerate, the muscles they control stop receiving signals. Without those signals, muscles weaken and gradually waste away. This process is irreversible for each neuron lost, which is why early intervention matters so much.
The muscles most critically affected are those involved in breathing and swallowing. In types 1 and 2, the combination of weak respiratory muscles and a stiffening chest wall leads to progressively poorer lung function. Coughing becomes ineffective, airway secretions build up, and recurring pneumonia becomes a serious risk. Respiratory failure is the leading cause of death in types 1 and 2. Limb weakness tends to be more pronounced in the legs than the arms, and the muscles closer to the trunk (shoulders, hips) are generally weaker than those in the hands and feet.
Non-5q Forms of SMA
A small fraction of SMA cases, roughly 5%, are not caused by SMN1 mutations at all. These are collectively called non-5q SMA, and at least 16 different genes have been linked to them. One example involves mutations in a gene called ASAH1, which can cause a form of spinal muscular atrophy sometimes accompanied by progressive epilepsy. These rare variants can look similar to classic SMA on the surface, with motor neuron loss and muscle weakness, but they involve entirely different biological pathways and require different diagnostic approaches.
Newborn Screening and Early Detection
Since 2018, newborn screening for SMA has expanded across the United States and now covers all 50 states plus Washington, D.C. The screening uses a blood spot taken shortly after birth to check for the SMN1 exon 7 deletion. This has been a major shift: before screening, most children weren’t diagnosed until symptoms were already obvious, by which point significant motor neuron loss had already occurred.
Early detection opens the door to treatment before irreversible damage sets in, but the system still has bottlenecks. While all specialty providers see newly referred infants within a week of a positive screen, about 39% report they cannot start treatment until three or more weeks after birth. Insurance approval processes are the most commonly cited reason for the delay. For infants with type 1 SMA, who can develop symptoms in the first weeks of life, even short delays can affect outcomes.