spinal muscular atrophy

Astronomers and geneticists have something in common—the desire to visualize things the naked eye cannot see. As astronomers look up into the heavens and beyond, geneticists look down at lab specimens in an attempt to unveil the code for all living things: DNA. 

It has been said that “Band-Aids don’t fix bullet holes,” but too often this is the case in medicine. When physicians are preoccupied with treating the symptoms of a disease rather than its cause, they are playing a game of catch-up, especially in the case of rare diseases such as spinal muscular atrophy (SMA). 

Read more about SMA etiology

Continue Reading

However, geneticists are making it possible for us to see SMA as never before—in stunning detail that can provide the basis for new targeted treatments capable of cutting off the illness at its very roots. A team of Spanish researchers conducted a review of the importance of “digging” into the genetics of SMA and published their findings in the International Journal of Molecular Sciences. In this article, we take a look at some of their thoughts regarding SMA genetics and its effect on therapeutic developments today. 

The SMN1 and SMN2 Genes

We begin with what we do know about SMA at the genetic level. It is caused by a loss of the survival motor neuron 1 (SMN1) gene in the 5q13 locus. Almost all cases can be explained by homozygous deletion or gene conversion. Another gene, SMN2, is an almost equal centromeric paralog gene. We know that SMN2 originates from SMN1 and that the genomic organization of the 2 genes is identical. 

The authors of the study explained, “The SMA genomic region is highly polymorphic and dynamic, which is prone to unequal rearrangements leading to deletions, duplications or gene conversions.” Therefore, partial deletions of SMN genes can occur, as can structural variants characterized as hybrid SMN1-SMN2 genes. Variants form when part of the SMN2 gene fuses with the SMN1 gene during gene conversion events and intrachromosomal deletions. 

Another important point to note regarding SMN genes is their copy number. Interestingly, studies have found that 54.7% of Africans carry 3 or more SMN1 genes and that 2 SMN1 variants occur in silent carriers among the Ashkenazi Jewish population. “Therefore, an accurately deep characterization of the SMA region is relevant not only for the detection of SMN1 and SMN2 copy number, but also for the different structural variants described,” the authors of the study wrote. 

Prognostic Implications 

Studies have proposed that the count number of SMN2 is an incredibly useful prognostic tool that physicians can use to predict disease course and plan appropriate treatment. A large-scale study involving a total of 3459 patients with SMA showed that a higher count number of SMN2 leads to a milder SMA phenotype. Other studies have even proposed using the SMN2 count number to quantify disease severity. This suggestion is based on the fact that, despite some differences in the outcome of studies looking into the genetics behind SMA, all agree on one thing: the higher the SMN2 count number, the less severe the SMA phenotype.

Why is this the case? Scientists have theorized that it is because a higher SMN2 count number means that the body is producing a greater volume of SMN functional genes to compensate for the SMN1 deficiency, thus leading to better clinical outcomes. 

Read more about SMA prognosis

However, this correlation is not absolute, and some studies have observed patients whose outcomes were either better or worse than expected. In addition to the SMN2 count number, SMN1 intragenic variants can be a useful prognostic indicator. Researchers have identified more than 80 pathogenic variants of the SMN1 gene in heterozygous individuals, located mainly at the Tudor and C-terminal domains. It has been observed that missense mutations in the Tudor domain are generally associated with a more severe SMA phenotype, whereas mutations in the C-terminal domain are largely associated with a phenotype that is worse than expected.

Genetic-Based Therapies 

In their review, the authors highlighted 3 therapies approved by both the US Food and Drug Administration and the European Medicines Agency. All rely on a genetic confirmation of SMA for patients to be eligible for treatment. 

The first 2 therapies are nusinersen and risdiplam. Both are designed to bind to SMN2 pre-RNA specifically to increase the volume of functional SMN protein. Because the therapies target SMN2, it would be useful to have as much information about existing SMN2 as possible: its copy number, variants, and structure. The third therapy, onasemnogene abeparvovec-xioi, is a gene replacement therapy that uses a viral vector (AAV9) to restore the expression of normal SMN1. 

In medical practice today, neonates undergo a host of screening tests, sometimes including one for SMA. The authors of this study recommend that when SMA is identified in a patient, further investigations should be undertaken to determine the SMN2 count number, variants, and structural changes whenever possible because research indicates that all these factors may influence the effectiveness of SMN2 modulators. 

Digging Deeper

It is encouraging that in the past few years medicine has been moving in the direction of using genetic discoveries as a basis for formulating new therapies. In the title of their review, the authors underscore the importance of “digging into the genetics of SMA genes.” Indeed, more “digging” is warranted in the years to come if genetically based therapies for SMA are to become more fully developed. 


Costa-Roger M, Blasco-Pérez L, Cuscó I, Tizzano EF. The importance of digging into the genetics of SMN genes in the therapeutic scenario of spinal muscular atrophy. Int J Mol Sci. Published online August 21, 2021. doi:10.3390/ijms22169029

Butchbach MER. Genomic variability in the survival motor neuron genes (SMN1 and SMN2): implications for spinal muscular atrophy phenotype and therapeutics development. Int J Mol Sci. 2021;22(15):7896. doi:10.3390/ijms22157896