Current Genetic Medicine Reports

, Volume 7, Issue 3, pp 162–167 | Cite as

Spinal Muscular Atrophy (SMA) in the Therapeutic Era

  • Melissa GibbonsEmail author
  • Anne Stratton
  • Julie Parsons
Counseling and Testing (C Reiser and C Walton, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Counseling and Testing


Purpose of Review

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in the SMN1 gene. It is relatively common worldwide, affecting approximately 1 in 11,000 live births, and about 1 in every 54 individuals is a carrier. The FDA-approved nusinersen (Spinraza) in December 2016 and onasmenogene abeparvovec (Zolgensma) in May 2019 for treatment of SMA after clinical trials showed slowed progression, improved motor function, and improved survival in treated infants and children. This review is aimed at educating medical professionals to facilitate a better understanding of SMA genetics, care recommendations, current and future therapies, and the avenues for early diagnosis.

Recent Findings

With the advent of disease-modifying treatment for SMA, the prognosis and outcomes for patients are changing rapidly. Treatment response is time sensitive, and it is important to diagnose as early as possible and counsel families so prompt decisions regarding treatment can be made. An updated consensus statement on standards of care was published in 2018.


Understanding the historical phenotypes, genetics and treatment options are critical to provide comprehensive counseling to families, allowing them to make informed decisions. Improved education of providers and advances in screening recommendations and create the opportunity for earlier diagnosis and treatment, further improving the outlook for this disease.


Spinal muscular atrophy SMA Gene therapy Genetic counseling 


Compliance with Ethical Standards

Conflict of Interest

Anne Stratton reports membership on the Medical Advisory Board for Cure SMA (a nonpaid volunteer position) since 2015.

Julie Parsons reports serving as the principle investigator on clinical trials for Biogen, AveXis, Cytokinetics, Scholar Rock, and Genentech Roche, outside of the submitted work.

Melissa Gibbons reports membership on the Advisory Board for Sarepta and honoraria for speaking engagements at AveXis and France Foundation.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 2010;12(3):145–52.CrossRefGoogle Scholar
  2. 2.
    Russman BS. Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol. 2007;22(8):946–51.CrossRefGoogle Scholar
  3. 3.
    Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228–37.CrossRefGoogle Scholar
  4. 4.
    Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979–84.CrossRefGoogle Scholar
  5. 5.
    Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, 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.CrossRefGoogle Scholar
  6. 6.
    Rochette CF, Surh LC, Ray PN, McAndrew PE, Prior TW, Burghes AH, et al. Molecular diagnosis of non-deletion SMA patients using quantitative PCR of SMN exon 7. Neurogenetics. 1997;1(2):141–7.CrossRefGoogle Scholar
  7. 7.
    Prior TW, Professional P, Guidelines C. Carrier screening for spinal muscular atrophy. Genet Med. 2008;10(11):840–2.CrossRefGoogle Scholar
  8. 8.
    Calucho M, Bernal S, Alias L, March F, Vencesla A, Rodriguez-Alvarez FJ, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28(3):208–15.CrossRefGoogle Scholar
  9. 9.
    • Rao VK, Kapp D, Schroth M. Gene therapy for spinal muscular atrophy: an emerging treatment option for a devastating disease. J Manag Care Spec Pharm. 2018;24(12-a Suppl):S3–S16 Review of current treatments in SMA and considerations for implementation of treatments in the healthcare system.Google Scholar
  10. 10.
    Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002;4(1):20–6.CrossRefGoogle Scholar
  11. 11.
    Crawford TO, Paushkin SV, Kobayashi DT, Forrest SJ, Joyce CL, Finkel RS, et al. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012;7(4):e33572.CrossRefGoogle Scholar
  12. 12.
    Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408–13.CrossRefGoogle Scholar
  13. 13.
    Arkblad E, Tulinius M, Kroksmark AK, Henricsson M, Darin N. A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy. Acta Paediatr. 2009;98(5):865–72.CrossRefGoogle Scholar
  14. 14.
    Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358–68.CrossRefGoogle Scholar
  15. 15.
    Feng Y, Ge X, Meng L, Scull J, Li J, Tian X, et al. The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med. 2017;19(8):936–44.CrossRefGoogle Scholar
  16. 16.
    Tiziano FD, Pinto AM, Fiori S, Lomastro R, Messina S, Bruno C, et al. SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR. Eur J Hum Genet. 2010;18(1):52–8.CrossRefGoogle Scholar
  17. 17.
    • Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103–15 2018 Care Considerations part one. CrossRefGoogle Scholar
  18. 18.
    • Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197–207 2018 Care Considerations part two. CrossRefGoogle Scholar
  19. 19.
    Khatri IA, Chaudhry US, Seikaly MG, Browne RH, Iannaccone ST. Low bone mineral density in spinal muscular atrophy. J Clin Neuromuscul Dis. 2008;10(1):11–7.CrossRefGoogle Scholar
  20. 20.
    Lykken EA, Shyng C, Edwards RJ, Rozenberg A, Gray SJ. Recent progress and considerations for AAV gene therapies targeting the central nervous system. J Neurodev Disord. 2018;10(1):16.CrossRefGoogle Scholar
  21. 21.
    Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713–22.CrossRefGoogle Scholar
  22. 22.
    • Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82(6):883–91 Natural history of SMA.CrossRefGoogle Scholar
  23. 23.
    • Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810–7 Natural history of SMA.CrossRefGoogle Scholar
  24. 24.
    Al-Zaidy S, Pickard AS, Kotha K, Alfano LN, Lowes L, Paul G, et al. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019;54(2):179–85.Google Scholar
  25. 25.
    FDA:Zolgensma. (2019). Accessed June 10, 2019.
  26. 26.
    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017–26.CrossRefGoogle Scholar
  27. 27.
    Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–32.CrossRefGoogle Scholar
  28. 28.
    Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625–35.CrossRefGoogle Scholar
  29. 29.
    Mercuri E, Baranello G, Kirschner J. SUNFISH part 1. Risdiplam (RG7916) treatment results in a sustained increase of SMN protein levels and improvement in motor function in patients with type 2 or 3 SMA. In: 23rd International Annual Congress of the World Muscle Society; 2018.Google Scholar
  30. 30.
    Baranell G, Servais L, Day J. FIREFISH: Risdiplam (RG7916) improves motor function in babies with type 1 SMA. In: 23rd International Annual Congress of the World Muscle Society; 2019.Google Scholar
  31. 31.
    Charmas L. Safety and efficacy findings in the first-in-human trial of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results. In: 21st Annual Spinal Muscular Atrophy Researcher Meeting; 2017.Google Scholar
  32. 32.
    Cure SMA. Cytokinetics presents data from the phase 2 clinical trial of reldesemtiv (CK-2127107) in patients with SMA at the 2018 Annual SMA Conference. (2018). Accessed May 12, 2019.
  33. 33.
    Long KK, O’Shea KM, Khairallah RJ, Howell K, Paushkin S, Chen KS, et al. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum Mol Genet. 2019;28(7):1076–89.CrossRefGoogle Scholar
  34. 34.
    Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027–49.CrossRefGoogle Scholar
  35. 35.
    Chali F, Desseille C, Houdebine L, Benoit E, Rouquet T, Bariohay B, et al. Long-term exercise-specific neuroprotection in spinal muscular atrophy-like mice. J Physiol. 2016;594(7):1931–52.CrossRefGoogle Scholar
  36. 36.
    Committee on G. Committee opinion no. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):e35–40.CrossRefGoogle Scholar
  37. 37.
    • Committee on G. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41–55 Current carrier screening recommendations for SMA.CrossRefGoogle Scholar
  38. 38.
    Hendrickson BC, Donohoe C, Akmaev VR, Sugarman EA, Labrousse P, Boguslavskiy L, et al. Differences in SMN1 allele frequencies among ethnic groups within North America. J Med Genet. 2009;46(9):641–4.CrossRefGoogle Scholar
  39. 39.
    • Luo M, Liu L, Peter I, Zhu J, Scott SA, Zhao G, Eversley C, Kornreich R, Desnick RJ, Edelmann L An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet Med 2014;16(2):149–156. Discussion of the utility of enhanced carrier screening. Google Scholar
  40. 40.
    Dahdouh EM, Balayla J, Audibert F, Genetics C, Wilson RD, Audibert F, et al. Technical update: preimplantation genetic diagnosis and screening. J Obstet Gynaecol Can. 2015;37(5):451–63.CrossRefGoogle Scholar
  41. 41.
    Ghi T, Sotiriadis A, Calda P, Da Silva Costa F, Raine-Fenning N, Alfirevic Z, et al. ISUOG Practice Guidelines: invasive procedures for prenatal diagnosis. Ultrasound Obstet Gynecol. 2016;48(2):256–68.CrossRefGoogle Scholar
  42. 42.
    Alfirevic Z, Navaratnam K, Mujezinovic F. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2017;(9):CD003252.Google Scholar
  43. 43.
    Cure SMA: HHS Secretary, Alex Azar, recommends nationwide newborn screening for SMA: Accessed May 12, 2019.
  44. 44.
    Knapkova M, Hall K, Loeber G. Reliability of neonatal screening results. Int J Neonatal Screening [Internet] MDPI AG. 2018;4:28. Available from:. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.University of Colorado Anschutz Medical Campus/Children’s Hospital ColoradoAuroraUSA

Personalised recommendations