Spinal Muscular Atrophy (SMA)


Spinal muscular atrophy (SMA) is a rare genetic disorder. The traditional types of SMA are caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene located on chromosome 5 that result in a lack of SMN proteins.1 A second gene, called SMN2, also produces SMN proteins but they are usually truncated and only 10%-20% are viable.1 Without enough SMN protein, which is integral to the health and growth of motor neurons,2 the cells begin to die and lead to progressive loss of motor function.

The number of SMN2 genes a patient has is variable and contributes, along with the efficiency of the SMN protein from the SMN2 genes, to the severity of the disease. The SMA subtypes range from SMA type 0, which manifests prenatally and is the most severe, to SMA type 4 where symptom onset generally occurs in adulthood and is the least severe. Since SMA is a rare disease, estimates for spinal muscular atrophy epidemiology vary from study to study and throughout the world.

SMA Incidence/Birth Prevalence

Given that SMA is a genetic disorder, the incidence of the disease is more accurately related to the birth prevalence or number of children born with SMA during a given period of time.1 Many studies from around the world have attempted to estimate the birth prevalence of SMA. A spinal muscular atrophy prevalence review article from 2017 found a global average of approximately 8 children with SMA per 100,000 births, although estimates ranged from 5 to 24.1

A number of factors may affect the estimates found.1 Studies were performed in different countries from around the world and could indicate regional differences in SMA prevalence due to those specific gene pools. Some countries have higher rates of parental consanguinity than others. Many of the studies were only performed in small regions of their respective countries and therefore sampled smaller populations. Smaller sample sizes combined with the rarity of SMA could lead to large changes in the prevalence estimates. Differences in the time periods of the studies, available diagnostic technologies, clinical classifications used for diagnosis, and the state of the health care systems in the countries can also affect the ability to diagnose SMA, affecting estimates.

An analysis performed in the UK using death certificates and hospital admissions from 2008 to 2016 found an average birth prevalence of 6.2 per 100,000.3

Another study, focused on data from European countries in the period of 2011-2015, found a median incidence of 11.9 per 100,000.4 The study used the number of genetic confirmations of SMA at European laboratories to make their estimates. Depending on the country, the incidence estimates varied between 6.3 and 26.7 per 100,000.4

Studies have also been performed in the US. A study from 2012 using genetic confirmation of patients estimated the disease incidence to be 1 in 11,000 (~9.1 per 100,000).5

Newborn screening data in the state of New York over a one-year period starting in October 2018 yielded 8 children with SMA out of 225,093 newborns screened (a prevalence of ~3.6 per 100,000).6 These numbers were much lower than expected based on previous study estimates. The authors attributed the differences to the earlier estimates being based on small European population studies, clinical diagnosis without genetic confirmations, changes through the years in the diagnostic and classification systems used to identify SMA and its types, and also possible sample bias.6

As of April 2021, 36 states in the US have adopted newborn screenings for SMA.7 As more states and countries move toward standard newborn screening, estimates of birth prevalence will continue to become more accurate and may highlight regional differences in prevalence. Other countries have recently reported some initial findings of their newborn screenings, as well, which seem to indicate this possibility. Taiwan found a total of 7 out of 120,267 newborns (~5.8 per 100,000),8 Australia identified 9 out of 103,903 (~8.7 per 100,000),9 and Germany discovered 22 out of 165,525 (~13.3 per 100,000).10

SMA Prevalence

Over the years, several studies focusing on spinal muscular atrophy epidemiology have also attempted to estimate the population prevalence of SMA or the number of patients alive during a given time period. Many of the studies were performed before the identification of the SMN1 gene mutation in 19951 and relied on clinical diagnosis rather than genetic confirmation. There was some degree of variability between studies for the estimated prevalence of patients living with all forms of SMA around the world. A review paper published in 2017 found studies with some estimates being as low as 0.74 per 100,00 and as high as 13.26 per 100,000.1

Prevalence by SMA Type

The population prevalence and the birth prevalence of patients with SMA also vary by type. The 2017 review article further divided prevalence and birth prevalence rates by SMA types. Using data from 17 studies, the review found the live-birth estimate of SMA type 1 to be 6 per 100,000.1 Further analysis resulted in birth prevalence estimates for types 1, 2, and 3 of 5.5, 1.9, and 1.7 per 100,000, respectively. 

These results were similar to an earlier paper that estimated the numbers to be 5.83, 2.66, and 1.20 per 100,000.12 From these 2 studies, roughly 60% of SMA newborns have SMA type 1 while types 2 and 3 make up the remaining 40%. SMA type 0 and type 4 are very rare and are estimated to account for 1% or fewer SMA cases.12

While SMA type 1 makes up the majority of newborn SMA, the overall prevalence of SMA type 1 patients in the population is much lower. Studies have shown a prevalence of 0.04 to 0.28 per 100,000.1 The much lower prevalence is most likely due to the high mortality rate of patients with this form. The population prevalence of type 3 has been estimated to be higher than type 2, again most likely due to those patients’ longer life expectancy.

With the development of several disease-modifying therapies such as onasemnogene abeparvovec (Zolgensma), nusinersen (Spinraza), and risdiplam (Evrysdi) and increases in newborn screening for earlier diagnosis, life expectancy for patients is expected to increase in the future, which will increase the population prevalence and impact future studies in spinal muscular atrophy epidemiology.

Reviewed by Michael Sapko, MD on 7/1/2021

References

  1. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;12(1):124. doi:10.1186/s13023-017-0671-8 
  2. Chaytow H, Huang Y-T, Gillingwater TH, Faller KME. The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci. 2018;75(21):3877-3894. doi:10.1007/s00018-018-2849-1
  3. Spinal muscular atrophy type 1: NCARDRS data briefing. Gov.uk. Accessed April 15, 2021. 
  4. Verhaart IEC, Robertson A, Leary R, et al. A multi-source approach to determine SMA incidence and research ready population. J Neurol. 2017;264(7):1465-1473. doi:10.1007/s00415-017-8549-1 
  5. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. doi:10.1038/ejhg.2011.134
  6. Kay DM, Stevens CF, Parker A, et al. Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy. Genet Med. 2020;22(8):1296-1302. doi: 10.1038/s41436-020-0824-3
  7. McCall S. Newborn screening for spinal muscular atrophy – cure SMA. CureSMA.org. Published October 21, 2019. Accessed April 15, 2021. 
  8. Chien Y-H, Chiang S-C, Weng W-C, et al. Presymptomatic diagnosis of spinal muscular atrophy through newborn screening. J Pediatr. 2017;190:124-129.e1. 
  9. Kariyawasam DST, Russell JS, Wiley V, Alexander IE, Farrar MA. The implementation of newborn screening for spinal muscular atrophy: the Australian experience. Genet Med. 2020;22(3):557-565. doi: 10.1016/j.jpeds.2017.06.042
  10. Vill K, Kölbel H, Schwartz O, et al. One year of newborn screening for SMA – results of a German pilot project. J Neuromuscul Dis. 2019;6(4):503-515. doi:10.3233/JND-190428
  11. Ogino S, Wilson RB, Gold B. New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations. Eur J Hum Genet. 2004;12(12):1015-1023.
  12. Mercuri E. Proximal spinal muscular atrophy type 4. Orphanet. Updated January 2021. Accessed April 15, 2021.
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