This site is intended for healthcare professionals
Spinal Muscular Atrophy


1. Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224(1):15–28.

2. Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81(3):355–368.

3. Lipnick SL, Agniel DM, Aggarwal R, Makhortova NR, Finlayson SG, Brocato A, et al. Systemic nature of spinal muscular atrophy revealed by studying insurance claims. PLoS One. 2019;14(3):e0213680.

4. Hamilton G, Gillingwater TH. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med. 2013;19(1):40–50.

5. Nash LA, Burns JK, Chardon JW, Kothary R, Parks RJ. Spinal Muscular Atrophy: More than a Disease of Motor Neurons? Curr Mol Med. 2016;16(9):779–792.

6. Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E. Long-term survival in Werdnig-Hoffmann disease. Am J Phys Med Rehabil. 2007;86(5):339–45 quiz 346–8, 379.

7. Rudnik-Schöneborn S, Stolz P, Varon R, Grohmann K, Schächtele M, Ketelsen U-P, et al. Long-Term Observations of Patients with Infantile Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1). Neuropediatrics. 2004;35(3):174–182.

8. Rudnik-Schöneborn S, Vogelgesang S, Armbrust S, Graul-Neumann L, Fusch C, Zerres K. Digital necroses and vascular thrombosis in severe spinal muscular atrophy. Muscle Nerve. 2010;42(1):144–147.

9. Wijngaarde CA, Blank AC, Stam M, Wadman RI, van den Berg LH, van der Pol WL. Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet J Rare Dis. 2017;12(1):67.

10. Parra J, Alias L, Also-Rallo E, Martínez-Hernández R, Senosiain R, Medina C, et al. Evaluation of fetal nuchal translucency in 98 pregnancies at risk for severe spinal muscular atrophy: possible relevance of the SMN2 copy number. J Matern Neonatal Med. 2012;25(8):1246–1249.

11. Rudnik-Schöneborn S, Heller R, Berg C, Betzler C, Grimm T, Eggermann T, et al. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J Med Genet. 2008;45(10):635–8.

12. Wadman RI, van Bruggen HW, Witkamp TD, Sparreboom-Kalaykova SI, Stam M, van den Berg LH, et al. Bulbar muscle MRI changes in patients with SMA with reduced mouth opening and dysphagia. Neurology. 2014;83(12):1060–6.

13. Wasserman HM, Hornung LN, Stenger PJ, Rutter MM, Wong BL, Rybalsky I, et al. Low bone mineral density and fractures are highly prevalent in pediatric patients with spinal muscular atrophy regardless of disease severity. Neuromuscul Disord. 2017;27(4):331–337.

14. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157–67.

15. Fujak A, Haaker G. Proximal spinal muscular atrophy: current orthopedic perspective. Appl Clin Genet. 2013;113.

16. Deguise M-O, Kothary R. New insights into SMA pathogenesis: immune dysfunction and neuroinflammation. Ann Clin Transl Neurol. 2017;4(7):522–530.

17. Crawford TO, Sladky JT, Hurko O, Besner-Johnston A, Kelley RI. Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol. 1999;45(3):337–43.

18. Vitte JM, Davoult B, Roblot N, Mayer M, Joshi V, Courageot S, et al. Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload. Am J Pathol. 2004;165(5):1731–41.

19. Tein I, Sloane AE, Donner EJ, Lehotay DC, Millington DS, Kelley RI. Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)? Pediatr Neurol. 1995;12(1):21–30.

20. Bowerman M, Swoboda KJ, Michalski J-P, Wang G-S, Reeks C, Beauvais A, et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol. 2012;72(2):256–68.

21. Lamarca NH, Golden L, John RM, Naini A, Vivo DC De, Sproule DM. Diabetic Ketoacidosis in an Adult Patient With Spinal Muscular Atrophy Type II: Further Evidence of Extraneural Pathology Due to Survival Motor Neuron 1 Mutation? J Child Neurol. 2013;28(11):1517–1520.

22. Deguise M, Baranello G, Mastella C, Beauvais A, Michaud J, Leone A, et al. Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Ann Clin Transl Neurol. 2019;6(8):acn3.50855.

23. Schreml J, Riessland M, Paterno M, Garbes L, Roßbach K, Ackermann B, et al. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. Eur J Hum Genet. 2013;21(6):643–52.

24. Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, et al. Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet. 2011;20(18):3578–3591.

25. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 2011;478(7367):123–126.

26. Sleigh JN, Gillingwater TH, Talbot K. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis Model Mech. 2011;4(4):457–67.

27. 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.

28. Gubitz A, Feng W, Dreyfuss G. The SMN complex. Exp Cell Res. 2004;296(1):51–56.

29. Pillai RS, Grimmler M, Meister G, Will CL, Lührmann R, Fischer U, et al. Unique Sm core structure of U7 snRNPs: assembly by a specialized SMN complex and the role of a new component, Lsm11, in histone RNA processing. Genes Dev. 2003;17(18):2321–33.

30. Custer SK, Todd AG, Singh NN, Androphy EJ. Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle protein α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy. Hum Mol Genet. 2013;22(20):4043–4052.

31. Rossoll W, Jablonka S, Andreassi C, Kröning A-K, Karle K, Monani UR, et al. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol. 2003;163(4):801–12.

32. Fallini C, Zhang H, Su Y, Silani V, Singer RH, Rossoll W, et al. The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci. 2011;31(10):3914–25.

33. Gabanella F, Pisani C, Borreca A, Farioli-Vecchioli S, Ciotti MT, Ingegnere T, et al. SMN affects membrane remodelling and anchoring of the protein synthesis machinery. J Cell Sci. 2016;129(4):804–816.

34. Simon CM, Dai Y, Van Alstyne M, Koutsioumpa C, Pagiazitis JG, Chalif JI, et al. Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy. Cell Rep. 2017;21(13):3767–3780.

35. Ruggiu M, McGovern VL, Lotti F, Saieva L, Li DK, Kariya S, et al. A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol Cell Biol. 2012;32(1):126–38.

36. Park G-H, Maeno-Hikichi Y, Awano T, Landmesser LT, Monani UR. Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J Neurosci. 2010;30(36):12005–19.

37. Gogliotti RG, Quinlan KA, Barlow CB, Heier CR, Heckman CJ, DiDonato CJ. Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction. J Neurosci. 2012;32(11):3818–3829.

38. Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, et al. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci. 2012;32(25):8703–15.

39. Kong L, Wang X, Choe DW, Polley M, Burnett BG, Bosch-Marce M, et al. Impaired Synaptic Vesicle Release and Immaturity of Neuromuscular Junctions in Spinal Muscular Atrophy Mice. J Neurosci. 2009;29(3):842–851.

40. Kariya S, Obis T, Garone C, Akay T, Sera F, Iwata S, et al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J Clin Invest. 2014;124(2):785–800.

41. Shorrock HK, Gillingwater TH, Groen EJN. Molecular Mechanisms Underlying Sensory-Motor Circuit Dysfunction in SMA. Front Mol Neurosci. 2019;12:59.

42. Iascone DM, Henderson CE, Lee JC. Spinal muscular atrophy: from tissue specificity to therapeutic strategies. F1000Prime Rep. 2015;7:04.

43. McGovern VL, Gavrilina TO, Beattie CE, Burghes AHM. Embryonic motor axon development in the severe SMA mouse. Hum Mol Genet. 2008;17(18):2900–9.

44. Kong L, Wang X, Choe DW, Polley M, Burnett BG, Bosch-Marcé M, et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J Neurosci. 2009;29(3):842–51.

45. Zhang Z, Pinto AM, Wan L, Wang W, Berg MG, Oliva I, et al. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2013;110(48):19348–53.

46. Mentis GZ, Blivis D, Liu W, Drobac E, Crowder ME, Kong L, et al. Early Functional Impairment of Sensory-Motor Connectivity in a Mouse Model of Spinal Muscular Atrophy. Neuron. 2011;69(3):453–467.

47. Ling KKY, Lin M-Y, Zingg B, Feng Z, Ko C-P. Synaptic Defects in the Spinal and Neuromuscular Circuitry in a Mouse Model of Spinal Muscular Atrophy. PLoS One. 2010;5(11):e15457.

48. Yonekawa T, Komaki H, Saito Y, Sugai K, Sasaki M. Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy. Brain Dev. 2013;35(2):165–171.

49. Duman O, Uysal H, Skjei KL, Kizilay F, Karauzum S, Haspolat S. Sensorimotor polyneuropathy in patients with SMA type-1: Electroneuromyographic findings. Muscle Nerve. 2013;48(1):117–121.

50. Rudnik-Schöneborn S, Goebel HH, Schlote W, Molaian S, Omran H, Ketelsen U, et al. Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy. Neurology. 2003;60(6):983–7.

51. Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet. 2010;19(20):4059–71.

52. Michaud M, Arnoux T, Bielli S, Durand E, Rotrou Y, Jablonka S, et al. Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy. Neurobiol Dis. 2010;38(1):125–135.

53. Gombash SE, Cowley CJ, Fitzgerald JA, Iyer CC, Fried D, McGovern VL, et al. SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice. Hum Mol Genet. 2015;24(13):3847–3860.

54. Thomson AK, Somers E, Powis RA, Shorrock HK, Murphy K, Swoboda KJ, et al. Survival of motor neurone protein is required for normal postnatal development of the spleen. J Anat. 2017;230(2):337–346.

55. SMN1 - Survival motor neuron protein - Homo sapiens (Human) - SMN1 gene & protein. Accessed 12 November 2019.

56. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–165.

57. Bürglen L, Lefebvre S, Clermont O, Burlet P, Viollet L, Cruaud C, et al. Structure and Organization of the Human Survival Motor Neurone (SMN) Gene. Genomics. 1996;32(3):479–482.

58. Singh RN, Singh NN. Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes. Adv Neurobiol. 2018;20:31–61.

59. Burghes AHM, Beattie CE. Spinal Muscular Atrophy: Why do low levels of SMN make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597.

60. Rochette C, Gilbert N, Simard L. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet. 2001;108(3):255–266.

61. Howell MD, Singh NN, Singh RN. Advances in therapeutic development for spinal muscular atrophy. Future Med Chem. 2014;6(9):1081–99.

62. Butchbach MER. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front Mol Biosci. 2016;3:7.

63. Darras BT, De Vivo DC. Precious SMA natural history data: A benchmark to measure future treatment successes. Neurology. 2018;91(8):337–339.

64. Harada Y, Sutomo R, Sadewa AH, Akutsu T, Takeshima Y, Wada H, et al. Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. J Neurol. 2002;249(9):1211–1219.

65. Ruhno C, McGovern VL, Avenarius MR, Snyder PJ, Prior TW, Nery FC, et al. Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Hum Genet. 2019;138(3):241–256.

66. Bernal S, Alias L, Barcelo MJ, Also-Rallo E, Martinez-Hernandez R, Gamez J, et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet. 2010;47(9):640–642.

67. Wu X, Wang S-H, Sun J, Krainer AR, Hua Y, Prior TW. A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum Mol Genet. 2017;26(14):2768–2780.

68. AAN novartis zolgesma. n.d. “New AveXis Data at AAN Showed Long-Term Durability of Zolgensma® in Patients with Spinal Muscular Atrophy (SMA) Type 1 | Novartis.” Accessed October 7, 2019.

69. Pattali R, Mou Y, Li X-J. AAV9 Vector: a Novel modality in gene therapy for spinal muscular atrophy. Gene Ther. 2019;26(7–8):287–295.

70. Avila AM, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P, et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest. 2007;117(3):659–671.

71. Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A. 2001;98(17):9808–13.

72. Sumner CJ, Crawford TO. Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. J Clin Invest. 2018;128(8):3219–3227.

73. Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010;5(8):e12140.

74. Brahe C, Vitali T, Tiziano FD, Angelozzi C, Pinto AM, Borgo F, et al. Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Eur J Hum Genet. 2005;13(2):256–259.

75. Piepers S, Cobben J-M, Sodaar P, Jansen MD, Wadman RI, Meester-Delver A, et al. Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid. J Neurol Neurosurg Psychiatry. 2011;82(8):850–2.

76. Singh J, Salcius M, Liu S-W, Staker BL, Mishra R, Thurmond J, et al. DcpS as a therapeutic target for spinal muscular atrophy. ACS Chem Biol. 2008;3(11):711–22.

77. Van Meerbeke JP, Gibbs RM, Plasterer HL, Miao W, Feng Z, Lin M-Y, et al. The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum Mol Genet. 2013;22(20):4074–83.

78. Singh, Ravindra N., and Natalia N. Singh. 2018a. “Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.” In Adv Neurobiol. 2018;20:31-61.

79. Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a Critical Exon of Human Survival Motor Neuron Is Regulated by a Unique Silencer Element Located in the Last Intron. Mol Cell Biol. 2006;26(4):1333–1346.

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

81. Neil EE, Bisaccia EK. Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy. J Pediatr Pharmacol Ther. 2019;24(3):194–203.

82. Gidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol. 2019;61(1):19–24.

83. 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):625–635.

84. Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, et al. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019;33(9):919–932.

85. Cheung AK, Hurley B, Kerrigan R, Shu L, Chin DN, Shen Y, et al. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(24):11021–11036.

86. Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, et al. SMN2 splice modulators enhance U1–pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015;11(7):511–517.

87. Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2 ) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(15):6501–6517.

88. Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, et al. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science (80- ). 2014;345(6197):688–693.

89. Sivaramakrishnan M, McCarthy KD, Campagne S, Huber S, Meier S, Augustin A, et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun. 2017;8(1):1476.

90. Poirier A, Weetall M, Heinig K, Bucheli F, Schoenlein K, Alsenz J, et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol Res Perspect. 2018;6(6):e00447.

91. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120–2133.

92. Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, et al. Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;12(1):124.

93. Verhaart IEC, Robertson A, Jones CC, Cook SF, Lochmüller H. Spinal muscular atrophy: a global view on the burden of illness and clinical trial readiness. Neuromuscul Disord. 2017;27:S30.

94. Al Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, Al-Freihi H, et al. A Community Survey of Neurological Disorders in Saudi Arabia: The Thugbah Study. Neuroepidemiology. 1993;12(3):164–178.

95. Verhaart IEC, Robertson A, Leary R, McMacken G, König K, Kirschner J, et al. A multi-source approach to determine SMA incidence and research ready population. J Neurol. 2017;264(7):1465–1473.

96. Ogino S, Wilson RB. Spinal muscular atrophy: Molecular genetics and diagnostics. Expert Rev Mol Diagn. 2004;4(1):15–29.

97. Ogino S, Leonard DGB, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002;110(4):301–307.

98. Klug C, Schreiber-Katz O, Thiele S, Schorling E, Zowe J, Reilich P, et al. Disease burden of spinal muscular atrophy in Germany. Orphanet J Rare Dis. 2016;11(1):58.

99. 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.

100. Finkel RS, Sejersen T, Mercuri E. 218th ENMC International Workshop: Revisiting the consensus on standards of care in SMA Naarden, The Netherlands, 19–21 February 2016. Neuromuscul Disord. 2017;27:596–605.

101. MacLeod MJ, Taylor JE, Lunt PW, Mathew CG, Robb SA. Prenatal onset spinal muscular atrophy. Eur J Paediatr Neurol. 1999;3(2):65–72.

102. Bertoli S, De Amicis R, Mastella C, Pieri G, Giaquinto E, Battezzati A, et al. Spinal Muscular Atrophy, types I and II: What are the differences inbody composition and resting energy expenditure? Clin Nutr. 2017;36(6):1674–1680.

103. Mercuri E. The evolving natural history of SMA types II and III. 2016.

104. Ramsey D, Scoto M, Mayhew A, Main M, Mazzone ES, Montes J, et al. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PLoS One. 2017;12(2):e0172346.

105. TREAT-NMD SMA Europe. Briefing Document to the Clinical Trial Readiness in Spinal Muscular Atrophy (SMA) SMA Europe, TREAT-NMD and European Medicines Agency meeting. 2016;59.

106. Serra-Juhe C, Tizzano EF. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur J Hum Genet. 2019;1–9.

107. Wirth B, Brichta L, Schrank B, Lochmüller H, Blick S, Baasner A, et al. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet. 2006;119(4):422–428.

108. Bowerman M, Swoboda KJ, Michalski J-P, Wang G-S, Reeks C, Beauvais A, et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol. 2012;72(2):256–268.

109. Karasick D, Karasick S, Mapp E. Gastrointestinal radiologic manifestations of proximal spinal muscular atrophy (Kugelberg-Welander syndrome). J Natl Med Assoc. 1982;74(5):475–8.

110. Ionasescu V, Christensen J, Hart M. Intestinal pseudo-obstruction in adult spinal muscular atrophy. Muscle Nerve. 1994;17(8):946–948.

111. 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):103–115.

112. Recommended Uniform Screening Panel | Official web site of the U.S. Health Resources & Services Administration.

113. Feldkötter 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.

114. Gómez-Curet I, Robinson KG, Funanage VL, Crawford TO, Scavina M, Wang W. Robust quantification of the SMN gene copy number by real-time TaqMan PCR. Neurogenetics. 2007;8(4):271–278.

115. Arkblad EL, Darin N, Berg K, Kimber E, Brandberg G, Lindberg C, et al. Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy. Neuromuscul Disord. 2006;16(12):830–838.

116. van der Steege G, Grootscholten PM, van der Vlies P, Draaijers TG, Osinga J, Cobben JM, et al. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet (London, England). 1995;345(8955):985–6.

117. López-Bastida J, Peña-Longobardo LM, Aranda-Reneo I, Tizzano E, Sefton M, Oliva-Moreno J. Social/economic costs and health-related quality of life in patients with spinal muscular atrophy (SMA) in Spain. Orphanet J Rare Dis. 2017;12(1):141.

118. Tetafort A, Couray-Targe S, Harmand S, Ansolabehere X, Maurel F, Hammes F. Assessing The Real-World Hospital Economic Burden Of Spinal Muscular Atrophy (SMA) In France. Value Heal. 2017;20(9):A553.

119. 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):1027–1049.

120. 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.

121. Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. J Neuromuscul Dis. 2018;5(2):145–158.

122. 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):1723–1732.

123. Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, et al. Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology. 2019;92(21):e2492–e2506.

124. ZOLGENSMA | FDA. Accessed 31 October 2019.

125. Spinraza 12 mg solution for injection - Summary of Product Characteristics (SmPC) - (emc). Accessed 31 October 2019.

126. De Vivo D, Bertini E, Hwu W, Foster R, Bhan I, Gheuens S, et al. B.05 Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim results from the Phase 2 NURTURE study. Can J Neurol Sci / J Can des Sci Neurol. 2018;45(s2):S12–S13.

127. EVRYSDI™ Prescribing Information. 2020. Available at: (accessed August 2020).

128. Sturm S, Günther A , Jaber B , Jordan P , Al Kotbi  N , Parkar N, et al. A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 2019;85(1):181-193.

129. Roche, 2018. PRIME designation granted by European Medicines Agency for Roche’s risdiplam for treatment of spinal muscular atrophy (SMA) [Media Release]. Available at: (accessed August 2020).

130. Roche, 2020. FDA approves Roche’s Evrysdi (risdiplam) for treatment of spinal muscular atrophy (SMA) in adults and children 2 months and older [Media Release]. Available at: (accessed August 2020).

131. Cytokinetics 2019. Cytokinetics granted European orphan designation for reldesemtiv for the treatment of spinal muscular ATR [press release]. Available at: (accessed August 2020).

132. Charnas L, Voltz E, Pfister C, Peters T, Hartmann A, Berghs-Clairmont C, et al. Safety and efficacy findings in the first-in-human trial (FIH) of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results. Neuromuscul Disord. 2017;27:S207–S208.

133. Cytokinetics. Cytokinetics Announces Data From Phase 2 Clinical Study of Reldesemtiv in Patients With Spinal Muscular Atrophy Presented at the 2018 Annual Cure SMA Conference | Cytokinetics, Inc. annual cure SMA conference, Dallas. 2018.

134. Long K, Webster M, Chen KS, Howell K, Paushkin S, Khairallah R, et al. Inhibition of myostatin activation by SRK-015 promotes muscle strength in a multiple mouse models of SMA. 21st Annu Spinal Muscular Atrophy Res Meet 2017; Orlando, Florida; 2017. 2017;21774.

135. Spinal Muscular Atrophy - Research | Muscular Dystrophy Association. Accessed 12 November 2019.

136. Kariyawasam DST, D’Silva A, Lin C, Ryan MM, Farrar MA. Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy. Front Neurol. 2019;10:898.