sma Epidemiology

Picture a crime scene straight out of a detective’s novel: you are a detective called to investigate a missing person’s case and when you arrive, everything is a mess and you don’t know where to begin. You take a closer look around and notice that the criminal has left post-it notes everywhere, giving telling clues about where the missing person was taken. One post-it note leads to another, and eventually, you find the missing person and solve the case. 

It would be most peculiar for a real-life criminal to leave clues for detectives to solve a crime he committed, but in the medical world, diseases often do the same. In medicine, the “post-it notes” are biomarkers, giving physicians vital clues to the identity of a disease and its progression. In fact, by following the right biomarkers with care and diligence, researchers hope to eventually discover the cure of the disease, much like the solving of a crime. 

Although the process of developing new therapeutics for rare diseases may seem frustratingly slow, scientists are learning more and more about the characteristics of certain diseases that may soon prove to be the keys that unlock their cures. This is certainly the case for spinal muscular atrophy (SMA), a rare degenerative motor neuron disease. Through the combined efforts of researchers around the world, we now have identified a number of key biomarkers of the disease. A group of researchers from the Department of Neurology at the Ohio State University Wexner Medical Center in Columbus conducted a review of what we know about SMA biomarkers and published their findings in Biomarker Insights. We will proceed to discuss some of their findings in this article. 

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Survival Motor Neuron 2 Copy Number 

SMN2 is a paralog of SMN1, differing by only 2 exonic base changes. However, this slight difference dampens the ability of the body to produce functional, full-length survival motor neuron (SMN) messenger RNA (mRNA) and protein from the SMN2 gene. 

The importance of SMN2 copy number is simple: the greater the copy number of SMN2, the greater the amount of full-length SMN protein produced. Hence, the greater the SMN2 copy number, the milder the SMA phenotype. For example, a study shows that infants with a lower SMN2 copy number demonstrated lower motor function scores than those with a higher copy number. 

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This makes the SMN2 copy number a valuable prognostic biomarker. It is also important to note that the SMN2 copy number is usually detected alongside genetic testing, and since the copy number does not change, it is not used to track treatment response or disease progression.

As the importance of the SMN2 copy number becomes more and more evident, attempts have been made to incorporate the quantification of SMN2 into newborn screening. Currently, the majority of newborn screening already includes detecting SMN1 deletions for diagnostic purposes; studies suggest that expanding newborn screening to include the SMN2 copy number will help physicians more effectively decide on the appropriate therapeutic management. 

Survival Motor Neuron mRNA and Protein Levels

The importance of SMN mRNA and protein levels are likewise elegantly simple: the greater the SMN mRNA and protein levels, the greater the expression of the SMN2 gene (and its corresponding transcription and translation). Therefore, the greater the SMN mRNA and protein levels, the milder the SMA phenotype. 

Therapies have focused on increasing SMN protein levels, particularly in the nervous tissue. However, a barrier that researchers have had to overcome is the fact that SMN expression differs between various tissue types, making it difficult to measure. For example, a study involving postmortem tissues from patients with SMA found that SMN protein levels were at their peak prenatally, decreased 6.5-fold in the perinatal period, and remained low throughout adolescence. 

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The most common route for measuring SMN expression is through the blood (as opposed to, for example, the cerebrospinal fluid [CSF]) due to ease of access. For example, the therapeutic agent risdiplam has been shown to increase full-length SMN2 mRNA levels and SMN protein levels in whole blood. A study demonstrated that SMN protein levels in whole blood have a negative correlation with the severity of denervation as assessed through muscle electrophysiology. 

A disadvantage of SMN mRNA and protein levels as biomarkers is that they do not seem to change over time, meaning that they are not useful in tracking disease progression or patient response to treatment. In addition, because SMN levels differ between various tissue types, SMN measurements in the blood may not accurately reflect their levels in the nervous tissue or motor neurons. 


Neurofilaments (NFs) are released from the neurons in response to injury, causing an elevation of their levels in the blood and CSF. They, therefore, serve as a marker of active axonal loss and are useful for researchers studying axonal injury and degeneration. In the context of SMA, NFs are elevated in both the plasma and CSF, serving as an important biomarker for the monitoring of neurodegeneration. 

One caveat to this is that NFs are useful as biomarkers in SMA in infants, but less so in chronic SMA; NF levels are not elevated in adolescent and adult patients with SMA. Multiple studies have confirmed this. The general consensus is that NF proteins do not serve as useful biomarkers for SMA disease progression or treatment response in adolescent or adult patients with SMA. 

Importance of Biomarkers in SMA

The authors of the study highlighted a few more SMA biomarkers that are not covered in this article, including electrophysiological and imaging biomarkers that allow for more accurate therapeutic intervention and therefore better patient outcomes. However, the importance of all biomarkers is in their usefulness in developing new targeted SMA therapies. Put together, their potential is indeed limitless. The authors of the study conclude, “No single biomarker may necessarily be sufficient to monitor disease progression and treatment efficacy, but there is great potential in a combination of robust biomarkers that together allow for more accurate clinical assessment.” 


Pino MG, Rich KA, Kolb SJ. Update on biomarkers in spinal muscular atrophyBiomark Insights. 2021;16:11772719211035643. doi:10.1177/11772719211035643

Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408-413. doi:10.1016/j.ajhg.2009.08.002