Skip to main content

Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy

Abstract

Background

Advances in treatment for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) hold promise for children with these disorders. Accurate genetic diagnosis, early in the disease process, will allow these treatments to be most effective. Newborn screening (NBS) for SMA has been recommended in the United States, and a pilot DMD NBS program is underway in Hangzhou, China.

Data sources

A PubMed search, limited to the past 5 years, was conducted to identify: (1) therapeutic advancements for DMD/SMA approved by the United States Food and Drug Administration or the European Medicine Agency and (2) The status of NBS for DMD/SMA.

Results

We review the current state of approved treatments for DMD/SMA. We present recommendations regarding the future of NBS for these diseases, with a focus on the outcomes and challenges of SMA NBS in New York, USA, and the DMD NBS pilot program in Hangzhou, China.

Conclusions

Approved treatments for DMD and SMA may change the natural history of these diseases. Long-term studies of these treatments are underway. To avoid the known diagnostic delay associated with these disorders and provide optimal effectiveness of these treatments, early identification of patients through NBS will be necessary. Establishing comprehensive follow-up plans for positively identified patients will need to be in place for NBS programs to be successful.

This is a preview of subscription content, access via your institution.

References

  1. Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71:304–13.

    Article  CAS  PubMed  Google Scholar 

  2. 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;20:27–32.

    Article  PubMed  Google Scholar 

  3. Gregoretti C, Ottonello G, Chiarini Testa MB, Mastella C, Rava L, Bignamini E, et al. Survival of patients with spinal muscular atrophy type 1. Pediatrics. 2013;131:e1509–14.

    Article  PubMed  Google Scholar 

  4. United States Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm (2016). Accessed 8 Jan 2019.

  5. United States Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm534611.htm (2016). Accessed 8 Jan 2019.

  6. Ottesen EW. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy. Transl Neurosci. 2017;8:1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mendell JM. Precision genetic medicine for neuromuscular diseases. In: Proceedings of the world muscle society congress; 2018 Oct 3–6; Mendoza, Argentina.

  8. Mendell JM. Molecularly-based treatments for DMD. In: Proceedings of the fourth Qianjiang inherited birth defect (SMA/DMD) forum 2018 March 16; Hangzhou, China.

  9. Matthews E, Brassington R, Kuntzer T, Jichi F, Manzur AY. Corticosteroids for the treatment of Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2016;2016:CD003725.

    PubMed Central  Google Scholar 

  10. Griggs RC, Herr BE, Reha A, Elfring G, Atkinson L, Cwik V, et al. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013;48:27–31.

    Article  CAS  PubMed  Google Scholar 

  11. Koeks Z, Bladen CL, Salgado D, van Zwet E, Pogoryelova O, McMacken G, et al. Clinical outcomes in duchenne muscular dystrophy: a study of 5345 patients from the TREAT-NMD DMD global database. J Neuromuscul Dis. 2017;4:293–306.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Griggs RC, Miller JP, Greenberg CR, Fehlings DL, Pestronk A, Mendell JR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology. 2016;87:2123–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gloss D, Moxley RT 3rd, Ashwal S, Oskoui M. Practice guideline update summary: corticosteroid treatment of duchenne muscular dystrophy: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2016;86:465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Connolly AM, Florence JM, Zaidman CM, Golumbek PT, Mendell JR, Flanigan KM, et al. Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up. Muscle Nerve. 2016;54:681–9.

    Article  CAS  PubMed  Google Scholar 

  15. Connolly AM, Malkus EC, Mendell JR, Flanigan KM, Miller JP, Schierbecker JR, et al. Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy. Muscle Nerve. 2015;51:522–32.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Connolly AM, Schierbecker J, Renna R, Florence J. High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2002;12:917–25.

    Article  PubMed  Google Scholar 

  17. Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, Viswanathan V, et al. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 2011;77:444–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guglieri M, Bushby K, McDermott MP, Hart KA, Tawil R, Martens WB, et al. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy. Contemp Clin Trials. 2017;58:34–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Connolly A. Care of the boy with DMD in an era of molecularly-based treatments. In: Proceedings of the fourth Qianjiang inherited birth defect (SMA/DMD) forum; 2018, Mar 15–17; Hangzhou, China; 2018.

  20. Connolly AM, Zaidman CM, Golumbek PT, Cradock MM, Flanigan KM, Kuntz NL, et al. Twice weekly glucocorticosteroids in infants and young boys with duchenne muscular dystrophy. Muscle Nerve. 2019. https://doi.org/10.1002/mus.26441.

    Article  PubMed  Google Scholar 

  21. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009;8:918–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74:637–47.

    Article  CAS  PubMed  Google Scholar 

  23. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79:257–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dent KM, Dunn DM, von Niederhausern AC, Aoyagi AT, Kerr L, Bromberg MB, et al. Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort. Am J Med Genet A. 2005;134:295–8.

    Article  CAS  PubMed  Google Scholar 

  25. Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50:477–87.

    Article  CAS  PubMed  Google Scholar 

  26. McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1489–98.

    Article  CAS  PubMed  Google Scholar 

  27. European Medical Agencies. Tranlarna (ataluren): an overview of Translarna and why it is authorised in the EU. https://www.ema.europa.eu/en/medicines/human/EPAR/translarna (2018). Accessed 8 Jan 2019.

  28. Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S, et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med. 2010;363:1429–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Salva MZ, Himeda CL, Tai PW, Nishiuchi E, Gregorevic P, Allen JM, et al. Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol Ther. 2007;15:320–9.

    Article  CAS  PubMed  Google Scholar 

  30. Inacio P. Sarepta’s gene therapy improves muscle function in 4 boys with DMD, phase 1/2 trial shows. https://musculardystrophynews.com/2018/10/12/sarepta-dmd-gene-therapy-improves-muscle-function-4-boys-trial/ (2018). Accessed 8 Jan 2019.

  31. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–65.

    Article  CAS  PubMed  Google Scholar 

  32. Parente V, Corti S. Advances in spinal muscular atrophy therapeutics. Ther Adv Neurol Disord. 2018;11:1756285618754501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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;377:1723–32.

    Article  CAS  PubMed  Google Scholar 

  34. Biogen. New data presented at MDA clinical conference show benefit in motor function for infants, teens, and young adults treated with Spinraza (Nusinersen). http://investors.biogen.com/news-releases/news-release-details/new-data-presented-mda-clinical-conference-show-benefit-motor (2018). Accessed 8 Jan 2019.

  35. Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011;20:681–93.

    Article  CAS  PubMed  Google Scholar 

  36. Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med. 2010;2:35ra42.

    Article  CAS  PubMed  Google Scholar 

  37. 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;377:1713–22.

    Article  CAS  PubMed  Google Scholar 

  38. 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;54:179–85.

    PubMed  Google Scholar 

  39. Novartis. Novartis announces FDA filing acceptance and priority review of AVXS-101, a one-time treatment designed to address the genetic root cause of SMA Type 1. https://www.novartis.com/news/media-releases/novartis-announces-fda-filing-acceptance-and-priority-review-avxs-101-one-time-treatment-designed-address-genetic-root-cause-sma-type-1(2018). Accessed 8 Jan 2019.

  40. Gatheridge MA, Kwon JM, Mendell JM, Scheuerbrandt G, Moat SJ, Eyskens F, et al. Identifying non-duchenne muscular dystrophy-positive and false negative results in prior duchenne muscular dystrophy newborn screening programs: a review. JAMA Neurol. 2015;2015:1–7.

    Google Scholar 

  41. Laing N KB, Waddell L, Kreissl M, Douglas L, Wiley V. Newborn screening for duchenne muscular dystrophy in Australia. Abstract presented at: HGSA 2015. In: Proceedings of the human genetics society of Australasia annual scientific meeting, 8–11 Aug 2015, Perth, Australia.

  42. Ke Q, Zhao ZY, Griggs R, Wiley V, Connolly A, Kwon J, et al. Newborn screening for Duchenne muscular dystrophy in China: follow-up diagnosis and subsequent treatment. World J Pediatr. 2017;13:197–201.

    Article  CAS  PubMed  Google Scholar 

  43. Zhou Z. Updates in Zhejiang DMD NBS. In: Proceedings of the fourth Qianjiang inherited birth defect (SMA/DMD) forum; 16–17 Mar 2018; Hangzhou, China; 2018.

  44. Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17:347–61.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17:251–67.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, et al. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018;17:445–55.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kwon JM, Abdel-Hamid HZ, Al-Zaidy SA, Mendell JR, Kennedy A, Kinnett K, et al. Clinical follow-up for duchenne muscular dystrophy newborn screening: a proposal. Muscle Nerve. 2016;54:186–91.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Cure SMA. New York to implement newborn screening for sma October 1st. http://www.curesma.org/news/newyork-nbs-2018.html (2018). Accessed 8 Jan 2019.

  49. Kraszewski JN, Kay DM, Stevens CF, Koval C, Haser B, Ortiz V, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20:608–13.

    Article  PubMed  Google Scholar 

  50. Ciafaloni E, Fox DJ, Pandya S, Westfield CP, Puzhankara S, Romitti PA, et al. Delayed diagnosis in duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr. 2009;155:380–5.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lin CW, Kalb SJ, Yeh WS. Delay in diagnosis of spinal muscular atrophy: a systematic literature review. Pediatr Neurol. 2015;53:293–300.

    Article  PubMed  Google Scholar 

  52. Wang DN, Wang ZQ, Yan L, He J, Lin MT, Chen WJ, et al. Clinical and mutational characteristics of Duchenne muscular dystrophy patients based on a comprehensive database in South China. Neuromuscul Disord. 2017;27:715–22.

    Article  PubMed  Google Scholar 

  53. Chung J, Smith AL, Hughes SC, Niizawa G, Abdel-Hamid HZ, Naylor EW, et al. Twenty-year follow-up of newborn screening for patients with muscular dystrophy. Muscle Nerve. 2016;53:570–8.

    Article  PubMed  Google Scholar 

  54. Xu EX. Professor Shi-Wen Wu: One City, One Doctor-building up the national DMD registry network. Ann Transl Med. 2015;3:204.

    PubMed  PubMed Central  Google Scholar 

  55. Liu Y, Zhong L, Yuan S, van de Klundert J. Why patients prefer high-level healthcare facilities: a qualitative study using focus groups in rural and urban China. BMJ Glob Health. 2018;3:e000854.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Campbell A, Uren M. “The invisibles”… Disability in China in the 21st century. Int J Spec Educ. 2011;26:12–24.

    Google Scholar 

Download references

Funding

There was no funding associated with this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

QK: acquisition of data and interpretation of data; drafting/revising the article critically for important intellectual content; final approval of the version to be published; ZZ, JRM, MB, VW, JMK, LNA, AMC, CJ, HP, EC, QM: revising the article critically for important intellectual contact; final approval of the version to be published; RCG: conceptualization, acquisition of data and interpretation of data; drafting/revising the article critically for important intellectual contact; final approval of the version to be published; MAG: acquisition of data and interpretation of data; drafting/revising the article critically for important intellectual contact; final approval of the version to be published.

Corresponding author

Correspondence to Michele A. Gatheridge.

Ethics declarations

Ethical approval

Ethical approval was not obtained since this is a literature review article.

Conflict of interest

Q. Ke, Z. Zhao, M. Baker, V. Wiley, J. M. Kwon, L. N. Alfano, C. Jay, E. Ciafaloni, M. Qi, M. A. Gatheridge: no financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article; J. R. Mendell: Dr. Mendell is a Consultant for Sarepta Therapeutics, Avexis (Novartis) therapeutics, and Exonics. He receives consulting fees but no salary. He is reimbursed for presenting clinical trials that pertain to the products sponsored by these companies. He also serves on the Scientific Advisory Boards of the companies. He has no interests from or investments in products that he tests in clinical trials; A. M. Connolly: Dr. Connolly is site principal investigator for multiple studies funded by industry (Sarepta, Avexis, Biogen, PTC Therapeutics, Pfizer, BMS, Fibrogen, Italafarma and NS Pharma). In the last 2 years, Dr. Connolly has served on advisory boards for Sarepta, Avexis, Genetech-Roche, Acceleron, Astelles, Mallincrodt, and SMA Foundation. She is also on the DMSB for Catabasis. Dr. Connolly does not have stock in any company; H. Polari: employee of PerkinElmer Inc; R. C. Griggs: Dr. Griggs has received a research grant support from Marathon, PTC and Sarepta Pharmaceuticals for work related to Duchenne muscular dystrophy. He is also supported by the U.S. National Institutes of Health, the Muscular Dystrophy Association and the Parent Project for Muscular Dystrophy for research on Duchenne muscular dystrophy. He consults for Solid Bioscience.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ke, Q., Zhao, ZY., Mendell, J.R. et al. Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy. World J Pediatr 15, 219–225 (2019). https://doi.org/10.1007/s12519-019-00242-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-019-00242-6

Keywords

  • Duchene muscular dystrophy
  • Spinal muscular atrophy
  • Newborn screening
  • Neuromuscular disorders
  • Neurology