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Spinal muscular atrophy

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Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in SMN1 (encoding survival motor neuron protein (SMN)). Reduced expression of SMN leads to loss of α-motor neurons, severe muscle weakness and often early death. Standard-of-care recommendations for multidisciplinary supportive care of SMA were established in the past few decades. However, improved understanding of the pathogenetic mechanisms of SMA has led to the development of different therapeutic approaches. Three treatments that increase SMN expression by distinct molecular mechanisms, administration routes and tissue biodistributions have received regulatory approval with others in clinical development. The advent of the new therapies is redefining standards of care as in many countries most patients are treated with one of the new therapies, leading to the identification of emerging new phenotypes of SMA and a renewed characterization of demographics owing to improved patient survival.

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Fig. 1: Schematic diagram of human SMN1 and SMN2 on chromosome 5.
Fig. 2: SMN complex composition and function.
Fig. 3: SMN2 copies and SMA types.
Fig. 4: Spinal cord, motor neurons, motor axons, neuromuscular junctions and muscle.
Fig. 5: Mechanism of action of approved SMA therapies.

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References

  1. Ogino, S., Leonard, D. G., Rennert, H., Ewens, W. J. & Wilson, R. B. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am. J. Med. Genet. 110, 301–307 (2002).

    PubMed  Google Scholar 

  2. Pearn, J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J. Med. Genet. 15, 409–413 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sugarman, E. A. et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur. J. Hum. Genet. 20, 27–32 (2012).

    PubMed  Google Scholar 

  4. Mailman, M. D. et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet. Med. 4, 20–26 (2002).

    CAS  PubMed  Google Scholar 

  5. Verhaart, I. E. C. et al. A multi-source approach to determine SMA incidence and research ready population. J. Neurol. 264, 1465–1473 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. Verhaart, I. E. C. et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J. Rare Dis. 12, 124 (2017). This comprehensive review describes current data on carrier frequency and prevalence of SMA, using the current classification. The incidence of SMA and new phenotypes is likely to emerge as newborn screening becomes more widely initiated and treatment is started very early after birth.

    PubMed  PubMed Central  Google Scholar 

  7. Hale, J. E. et al. Massachusetts’ findings from statewide newborn screening for spinal muscular atrophy. Int. J. Neonatal Screen. https://doi.org/10.3390/ijns7020026 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kay, D. M. et al. Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy. Genet. Med. 22, 1296–1302 (2020).

    CAS  PubMed  Google Scholar 

  9. Kariyawasam, D. S. T., Russell, J. S., Wiley, V., Alexander, I. E. & Farrar, M. A. The implementation of newborn screening for spinal muscular atrophy: the Australian experience. Genet. Med. 22, 557–565 (2020).

    PubMed  Google Scholar 

  10. Vill, K. et al. Newborn screening for spinal muscular atrophy in Germany: clinical results after 2 years. Orphanet J. Rare Dis. 16, 153 (2021). This report presents incidence data for SMA in Germany (~1 in 6,910 births), with nearly half of those with two copies of SMN2 having early features of the disease at the initial visit, and discusses the challenges of treating these patients based on their SMN2 copy number.

    PubMed  PubMed Central  Google Scholar 

  11. Prior, T. W. et al. Newborn and carrier screening for spinal muscular atrophy. Am. J. Med. Genet. A 152A, 1608–1616 (2010).

    CAS  PubMed  Google Scholar 

  12. Ogino, S., Wilson, R. B. & 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. 12, 1015–1023 (2004).

    CAS  PubMed  Google Scholar 

  13. Dangouloff, T., Vrscaj, E., Servais, L., Osredkar, D. & Group, S. N. W. S. Newborn screening programs for spinal muscular atrophy worldwide: where we stand and where to go. Neuromuscul. Disord. 31, 574–582 (2021).

    PubMed  Google Scholar 

  14. Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).

    CAS  PubMed  Google Scholar 

  15. Lorson, C. L. & Androphy, E. J. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum. Mol. Genet. 9, 259–265 (2000).

    CAS  PubMed  Google Scholar 

  16. Lorson, C. L., Hahnen, E., Androphy, E. J. & Wirth, B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA 96, 6307–6311 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Monani, U. R. et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8, 1177–1183 (1999).

    CAS  PubMed  Google Scholar 

  18. Lefebvre, S. et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16, 265–269 (1997).

    CAS  PubMed  Google Scholar 

  19. Wirth, B. Spinal muscular atrophy: in the challenge lies a solution. Trends Neurosci. 44, 306–322 (2021). This comprehensive review discusses the evolution over the past 25 years in the understanding of the pathobiology of SMA, genotype–phenotype relationships and treatment strategies.

    CAS  PubMed  Google Scholar 

  20. van der Steege, G. et al. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am. J. Hum. Genet. 59, 834–838 (1996).

    PubMed  PubMed Central  Google Scholar 

  21. Echaniz-Laguna, A., Miniou, P., Bartholdi, D. & Melki, J. The promoters of the survival motor neuron gene (SMN) and its copy (SMNc) share common regulatory elements. Am. J. Hum. Genet. 64, 1365–1370 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jodelka, F. M., Ebert, A. D., Duelli, D. M. & Hastings, M. L. A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum. Mol. Genet. 19, 4906–4917 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Monani, U. R., McPherson, J. D. & Burghes, A. H. Promoter analysis of the human centromeric and telomeric survival motor neuron genes (SMNC and SMNT). Biochim. Biophys. Acta 1445, 330–336 (1999).

    CAS  PubMed  Google Scholar 

  24. Kernochan, L. E. et al. The role of histone acetylation in SMN gene expression. Hum. Mol. Genet. 14, 1171–1182 (2005).

    CAS  PubMed  Google Scholar 

  25. Farooq, F. et al. Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. J. Clin. Invest. 121, 3042–3050 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. McCormack, N. M. et al. A high-throughput genome-wide RNAi screen identifies modifiers of survival motor neuron protein. Cell Rep. 35, 109125 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Marasco, L. E. et al. Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy. Cell 185, 2057–2070.e15 (2022).

    PubMed  Google Scholar 

  28. Woo, C. J. et al. Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy. Proc. Natl Acad. Sci. USA 114, E1509–E1518 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. d’Ydewalle, C. et al. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron 93, 66–79 (2017).

    PubMed  Google Scholar 

  30. Ottesen, E. W., Seo, J., Singh, N. N. & Singh, R. N. A multilayered control of the human survival motor neuron gene expression by Alu elements. Front. Microbiol. 8, 2252 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Avila, A. M. et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117, 659–671 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chang, J. G. et al. Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl Acad. Sci. USA 98, 9808–9813 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Herzel, L., Ottoz, D. S. M., Alpert, T. & Neugebauer, K. M. Splicing and transcription touch base: co-transcriptional spliceosome assembly and function. Nat. Rev. Mol. Cell Biol. 18, 637–650 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pagliarini, V., Guerra, M., Di Rosa, V., Compagnucci, C. & Sette, C. Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in spinal muscular atrophy cells. J. Neurochem. 153, 264–275 (2020).

    CAS  PubMed  Google Scholar 

  35. Cartegni, L. & Krainer, A. R. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet. 30, 377–384 (2002).

    CAS  PubMed  Google Scholar 

  36. Kashima, T. & Manley, J. L. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet. 34, 460–463 (2003).

    CAS  PubMed  Google Scholar 

  37. Singh, R. N. & Singh, N. N. Mechanism of splicing regulation of spinal muscular atrophy genes. Adv. Neurobiol. 20, 31–61 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. Prior, T. W. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am. J. Hum. Genet. 85, 408–413 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu, X. et al. A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum. Mol. Genet. 26, 2768–2780 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Auslander, N. et al. The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases. Mol. Syst. Biol. 16, e9701 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ruggiu, M. et al. A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol. Cell Biol. 32, 126–138 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F. & 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. 70, 358–368 (2002).

    CAS  PubMed  Google Scholar 

  43. Calucho, M. 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. 28, 208–215 (2018). A detailed genotpe–phenotype analysis of the Spanish SMA population is presented, melded with a comprehensive literature review.

    PubMed  Google Scholar 

  44. Arkblad, E., Tulinius, M., Kroksmark, A. K., Henricsson, M. & Darin, N. A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy. Acta Paediatr. 98, 865–872 (2009).

    PubMed  Google Scholar 

  45. Prior, T. W., Swoboda, K. J., Scott, H. D. & Hejmanowski, A. Q. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am. J. Med. Genet. A 130A, 307–310 (2004).

    PubMed  Google Scholar 

  46. Oprea, G. E. et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320, 524–527 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Riessland, M. et al. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am. J. Hum. Genet. 100, 297–315 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kaifer, K. A. et al. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI Insight 2, e89970 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. Singh, R. N., Howell, M. D., Ottesen, E. W. & Singh, N. N. Diverse role of survival motor neuron protein. Biochim. Biophys. Acta Gene Regul. Mech. 1860, 299–315 (2017). This comprehensive review discusses the many roles of SMN protein in RNA metabolism.

    CAS  PubMed  Google Scholar 

  50. Le, T. T. et al. SMNΔ7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum. Mol. Genet. 14, 845–857 (2005).

    CAS  PubMed  Google Scholar 

  51. Burnett, B. G. et al. Regulation of SMN protein stability. Mol. Cell Biol. 29, 1107–1115 (2009).

    CAS  PubMed  Google Scholar 

  52. Cho, S. & Dreyfuss, G. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev. 24, 438–442 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kwon, D. Y. et al. The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein. Mol. Biol. Cell 24, 1863–1871 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Powis, R. A. et al. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight 1, e87908 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Riboldi, G. M. et al. Sumoylation regulates the assembly and activity of the SMN complex. Nat. Commun. 12, 5040 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Renvoise, B., Querol, G., Verrier, E. R., Burlet, P. & Lefebvre, S. A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies. J. Cell Sci. 125, 2862–2874 (2012).

    CAS  PubMed  Google Scholar 

  57. Han, K. J. et al. Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. Hum. Mol. Genet. 25, 1392–1405 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Grimmler, M. et al. Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs. EMBO Rep. 6, 70–76 (2005).

    CAS  PubMed  Google Scholar 

  59. Petri, S., Grimmler, M., Over, S., Fischer, U. & Gruss, O. J. Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cγ governs Cajal body localization and stability of the SMN complex. J. Cell Biol. 179, 451–465 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Coovert, D. D. et al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 6, 1205–1214 (1997).

    CAS  PubMed  Google Scholar 

  61. Zhang, H. et al. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J. Neurosci. 26, 8622–8632 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Donlin-Asp, P. G. et al. The survival of motor neuron protein acts as a molecular chaperone for mRNP assembly. Cell Rep. 18, 1660–1673 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Pellizzoni, L., Yong, J. & Dreyfuss, G. Essential role for the SMN complex in the specificity of snRNP assembly. Science 298, 1775–1779 (2002).

    CAS  PubMed  Google Scholar 

  64. Tisdale, S. et al. SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3’-end formation of histone mRNAs. Cell Rep. 5, 1187–1195 (2013).

    CAS  PubMed  Google Scholar 

  65. Winkler, C. et al. Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev. 19, 2320–2330 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang, Z. et al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133, 585–600 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Fallini, C., Donlin-Asp, P. G., Rouanet, J. P., Bassell, G. J. & Rossoll, W. Deficiency of the survival of motor neuron protein impairs mRNA localization and local translation in the growth cone of motor neurons. J. Neurosci. 36, 3811–3820 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rossoll, W. et al. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of β-actin mRNA in growth cones of motoneurons. J. Cell Biol. 163, 801–812 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Donlin-Asp, P. G., Bassell, G. J. & Rossoll, W. A role for the survival of motor neuron protein in mRNP assembly and transport. Curr. Opin. Neurobiol. 39, 53–61 (2016).

    CAS  PubMed  Google Scholar 

  70. Hao le, T. et al. HuD and the survival motor neuron protein interact in motoneurons and are essential for motoneuron development, function, and mRNA regulation. J. Neurosci. 37, 11559–11571 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Akten, B. et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc. Natl Acad. Sci. USA 108, 10337–10342 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Strasswimmer, J. et al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum. Mol. Genet. 8, 1219–1226 (1999).

    CAS  PubMed  Google Scholar 

  73. Lauria, F. et al. SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy. Nat. Cell Biol. 22, 1239–1251 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Torres-Benito, L. et al. NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorates spinal muscular atrophy in mice. Am. J. Hum. Genet. 105, 221–230 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Upadhyay, A. et al. Neurocalcin delta knockout impairs adult neurogenesis whereas half reduction is not pathological. Front. Mol. Neurosci. 12, 19 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wolff, L. et al. Plastin 3 in health and disease: a matter of balance. Cell Mol. Life Sci. 78, 5275–5301 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Miller, N., Shi, H., Zelikovich, A. S. & Ma, Y. C. Motor neuron mitochondrial dysfunction in spinal muscular atrophy. Hum. Mol. Genet. 25, 3395–3406 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Boyd, P. J. et al. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy. PLoS Genet. 13, e1006744 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Thelen, M. P., Wirth, B. & Kye, M. J. Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons. Acta Neuropathol. Commun. 8, 223 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ripolone, M. et al. Impaired muscle mitochondrial biogenesis and myogenesis in spinal muscular atrophy. JAMA Neurol. 72, 666–675 (2015).

    PubMed  PubMed Central  Google Scholar 

  81. Habets, L. E. et al. Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy. Brain https://doi.org/10.1093/brain/awab411 (2021).

    Article  PubMed Central  Google Scholar 

  82. Wadman, R. I. et al. A comparative study of SMN protein and mRNA in blood and fibroblasts in patients with spinal muscular atrophy and healthy controls. PLoS ONE 11, e0167087 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. Poirier, A. et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol. Res. Perspect. 6, e00447 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. Burlet, P. et al. The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy. Hum. Mol. Genet. 7, 1927–1933 (1998).

    CAS  PubMed  Google Scholar 

  85. Ramos, D. M. et al. Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. J. Clin. Invest. 129, 4817–4831 (2019). Human fetal and infant autopsy samples from both unaffected individuals and those with SMA were analysed for SMN protein and transcript levels. SMN protein expression is highest in late fetal and early postnatal development.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Gabanella, F., Carissimi, C., Usiello, A. & Pellizzoni, L. The activity of the spinal muscular atrophy protein is regulated during development and cellular differentiation. Hum. Mol. Genet. 14, 3629–3642 (2005).

    CAS  PubMed  Google Scholar 

  87. Ji, C. et al. Interaction of 7SK with the Smn complex modulates snRNP production. Nat. Commun. 12, 1278 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gavrilina, T. O. et al. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum. Mol. Genet. 17, 1063–1075 (2008).

    CAS  PubMed  Google Scholar 

  89. Van Alstyne, M. et al. Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit. Nat. Neurosci. 24, 930–940 (2021). This study examined overexpression of SMN in a mouse model of SMA via AAV9–SMN gene transduction and identified chronic development of sensory and motor impairment.

    PubMed  PubMed Central  Google Scholar 

  90. Thomsen, G. et al. Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Nat. Med. 27, 1701–1711 (2021).

    CAS  PubMed  Google Scholar 

  91. Ling, K. K., 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 5, e15457 (2010).

    PubMed  PubMed Central  Google Scholar 

  92. Mentis, G. Z. et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69, 453–467 (2011). Experiments in a mouse model for SMA support the authors’ proposal that SMA is a poly-neuronal network disorder, not purely a disease of motor neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Fletcher, E. V. et al. Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nat. Neurosci. 20, 905–916 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kong, L. et al. Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abb6871 (2021). Human autopsy samples from infants with SMA type 1 were studied for axonal development and demonstrated features of developmental arrest, followed by neurodegeneration, suggesting that there is a narrow therapeutic window to rescue the motor neurons after birth.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kariya, S. et al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 17, 2552–2569 (2008). Studies on the neuromuscular junction in a mouse model of severe SMA demonstrated early presynaptic morphological changes and functional impairment.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Murray, L. M. et al. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 17, 949–962 (2008).

    CAS  PubMed  Google Scholar 

  97. Kong, L. et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J. Neurosci. 29, 842–851 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee, Y. I., Mikesh, M., Smith, I., Rimer, M. & Thompson, W. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. Dev. Biol. 356, 432–444 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Buettner, J. M. et al. Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models. iScience 24, 103376 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Rodriguez-Muela, N. et al. Single-cell analysis of SMN reveals its broader role in neuromuscular disease. Cell Rep. 18, 1484–1498 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ling, K. K., Gibbs, R. M., Feng, Z. & Ko, C. P. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Hum. Mol. Genet. 21, 185–195 (2012).

    PubMed  Google Scholar 

  102. Darras, B. T. et al. Neurofilament as a potential biomarker for spinal muscular atrophy. Ann. Clin. Transl. Neurol. 6, 932–944 (2019). This study identified elevated plasma phosphorylated neurofilament heavy chain levels in children with SMA compared with typically developing children, which declined under treatment with nusinersen, suggesting that this could serve as an informative prognostic and predictive biomarker.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Simon, C. M. et al. Converging mechanisms of p53 activation drive motor neuron degeneration in spinal muscular atrophy. Cell Rep. 21, 3767–3780 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Van Alstyne, M. et al. Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy. Genes Dev. 32, 1045–1059 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. Genabai, N. K. et al. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy. Hum. Mol. Genet. 24, 6986–7004 (2015).

    PubMed  PubMed Central  Google Scholar 

  106. Pilato, C. M. et al. Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling. Hum. Mol. Genet. 28, 3282–3292 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Fayzullina, S. & Martin, L. J. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA). PLoS ONE 9, e93329 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. Jangi, M. et al. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage. Proc. Natl Acad. Sci. USA 114, E2347–E2356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ng, S. Y. et al. Genome-wide RNA-Seq of human motor neurons implicates selective ER stress activation in spinal muscular atrophy. Cell Stem Cell 17, 569–584 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Govoni, A., Gagliardi, D., Comi, G. P. & Corti, S. Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy. Mol. Neurobiol. 55, 6307–6318 (2018).

    CAS  PubMed  Google Scholar 

  111. Hamilton, G. & Gillingwater, T. H. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol. Med. 19, 40–50 (2013).

    CAS  PubMed  Google Scholar 

  112. Yeo, C. J. J. & Darras, B. T. Overturning the paradigm of spinal muscular atrophy as just a motor neuron disease. Pediatr. Neurol. 109, 12–19 (2020). The authors discuss SMA as a systemic disease, beyond a motor neuron disorder, and the implications for needing to consider targeting non-neuronal tissues with SMN-enhancing drugs.

    PubMed  Google Scholar 

  113. Hernandez-Gerez, E., Dall’Angelo, S., Collinson, J. M., Fleming, I. N. & Parson, S. H. Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA. Ann. Clin. Transl. Neurol. 7, 1580–1593 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Somers, E. et al. Vascular defects and spinal cord hypoxia in spinal muscular atrophy. Ann. Neurol. 79, 217–230 (2016).

    CAS  PubMed  Google Scholar 

  115. Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kray, K. M., McGovern, V. L., Chugh, D., Arnold, W. D. & Burghes, A. H. M. Dual SMN inducing therapies can rescue survival and motor unit function in symptomatic 7SMA mice. Neurobiol. Dis. 159, 105488 (2021).

    CAS  PubMed  Google Scholar 

  117. Zhou, H. et al. Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy. J. Cachexia Sarcopenia Muscle 11, 768–782 (2020). Adding myostatin inhibition to antisense oligonucleotide-mediated SMN enhancement in a mouse model of severe SMA generated a synergistic increase in survival, muscle mass, NMJ and motor function, and sensory neurons. These animal data support a combinatorial treatment for SMA.

    PubMed  PubMed Central  Google Scholar 

  118. Barrett, D. et al. A randomized phase 1 safety, pharmacokinetic and pharmacodynamic study of the novel myostatin inhibitor apitegromab (SRK-015): a potential treatment for spinal muscular atrophy. Adv. Ther. 38, 3203–3222 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kizina, K. et al. Cognitive impairment in adult patients with 5q-associated spinal muscular atrophy. Brain Sci. https://doi.org/10.3390/brainsci11091184 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Masson, R., Brusa, C., Scoto, M. & Baranello, G. Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review. Dev. Med. Child Neurol. 63, 527–536 (2021).

    PubMed  Google Scholar 

  121. Schorling, D. C. et al. Discrepancy in redetermination of SMN2 copy numbers in children with SMA. Neurology 93, 267–269 (2019).

    PubMed  Google Scholar 

  122. Boemer, F. et al. Newborn screening for SMA in Southern Belgium. Neuromuscul. Disord. 29, 343–349 (2019).

    PubMed  Google Scholar 

  123. Zhao, S. et al. Next generation sequencing is a highly reliable method to analyze exon 7 deletion of survival motor neuron 1 (SMN1) gene. Sci. Rep. 12, 223 (2022).

    PubMed  PubMed Central  Google Scholar 

  124. Gregg, A. R. et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 23, 1793–1806 (2021).

    PubMed  Google Scholar 

  125. Aharoni, S. et al. Impact of a national population-based carrier-screening program on spinal muscular atrophy births. Neuromuscul. Disord. 30, 970–974 (2020).

    PubMed  Google Scholar 

  126. Sun, Y., Kong, X., Zhao, Z. & Zhao, X. Mutation analysis of 419 family and prenatal diagnosis of 339 cases of spinal muscular atrophy in China. BMC Med. Genet. 21, 133 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Almeida-Porada, G. et al. In utero gene therapy consensus statement from the IFeTIS. Mol. Ther. 27, 705–707 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03761849 (2022).

  129. De Vivo, D. C. et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul. Disord. 29, 842–856 (2019). Nusinersen is the first of the three SMN-enhancing drugs to demonstrate a marked improvement in survival and function when treatment is started shortly after birth, in the presymptomatic or early symptomatic state of SMA.

    PubMed  PubMed Central  Google Scholar 

  130. Strauss, K. A. et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the phase III SPR1NT trial. Nat. Med. https://doi.org/10.1038/s41591-022-01866-4 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Strauss, K. A. et al. Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the phase III SPR1NT trial. Nat. Med. https://doi.org/10.1038/s41591-022-01867-3 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Wang, C. H. et al. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22, 1027–1049 (2007).

    PubMed  Google Scholar 

  133. Finkel, R. S. 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. 28, 197–207 (2018). This revision of the standard-of-care guidelines for SMA provides a template for the comprehensive management of patients with SMA.

    PubMed  Google Scholar 

  134. Mercuri, E. et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul. Disord. 28, 103–115 (2018). This revision of the standard-of-care guidelines for SMA provides a template for the comprehensive management of patients with SMA.

    PubMed  Google Scholar 

  135. Glanzman, A. M. et al. Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr. Phys. Ther. 23, 322–326 (2011).

    PubMed  Google Scholar 

  136. Haataja, L. et al. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J. Pediatr. 135, 153–161 (1999).

    CAS  PubMed  Google Scholar 

  137. Glanzman, A. M. et al. Validation of the expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J. Child Neurol. 26, 1499–1507 (2011).

    PubMed  Google Scholar 

  138. Mazzone, E. S. et al. Revised upper limb module for spinal muscular atrophy: development of a new module. Muscle Nerve 55, 869–874 (2017).

    PubMed  Google Scholar 

  139. Coratti, G. et al. Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscul. Disord. https://doi.org/10.1016/j.nmd.2021.10.009 (2021).

    Article  PubMed  Google Scholar 

  140. Coratti, G. et al. Clinical variability in spinal muscular atrophy type III. Ann. Neurol. 88, 1109–1117 (2020).

    CAS  PubMed  Google Scholar 

  141. Coratti, G. et al. Age related treatment effect in type II spinal muscular atrophy pediatric patients treated with nusinersen. Neuromuscul. Disord. 31, 596–602 (2021).

    PubMed  Google Scholar 

  142. Coratti, G. et al. Age and baseline values predict 12 and 24-month functional changes in type 2 SMA. Neuromuscul. Disord. 30, 756–764 (2020).

    PubMed  Google Scholar 

  143. Coratti, G. et al. Different trajectories in upper limb and gross motor function in spinal muscular atrophy. Muscle Nerve 64, 552–559 (2021).

    PubMed  PubMed Central  Google Scholar 

  144. Pera, M. C. et al. Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Ann. Clin. Transl. Neurol. 8, 1622–1634 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Pera, M. C. et al. Revised upper limb module for spinal muscular atrophy: 12 month changes. Muscle Nerve 59, 426–430 (2019).

    PubMed  Google Scholar 

  146. Yeo, C. J. J., Simmons, Z., De Vivo, D. C. & Darras, B. T. Ethical perspectives on treatment options with spinal muscular atrophy patients. Ann. Neurol. 91, 305–316 (2022).

    PubMed  PubMed Central  Google Scholar 

  147. Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017). This study presents the positive results of nusinersen treatment in patients with early-infantile onset SMA, with improved survival and motor function. and a favourable safety profile. This study provided the most convincing data in support of gaining regulatory approval for this drug.

    CAS  PubMed  Google Scholar 

  148. Mercuri, E. et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med. 378, 625–635 (2018). This study presents the positive results of nusinersen treatment in patients with late-infantile onset SMA, with improved motor function and a favourable safety profile. It provides support for the application for regulatory approval.

    CAS  PubMed  Google Scholar 

  149. Tiberi, E. et al. Nusinersen in type 0 spinal muscular atrophy: should we treat? Ann. Clin. Transl. Neurol. https://doi.org/10.1002/acn3.51126 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Pane, M. et al. Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data. Ann. Neurol. 86, 443–451 (2019).

    CAS  PubMed  Google Scholar 

  151. Aragon-Gawinska, K. et al. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study. Neurology 91, e1312–e1318 (2018).

    CAS  PubMed  Google Scholar 

  152. Pechmann, A. et al. Treatment with nusinersen – challenges regarding the indication for children with SMA type 1. J. Neuromuscul. Dis. 7, 41–46 (2020).

    PubMed  Google Scholar 

  153. Szabo, L. et al. Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: real world data from Hungarian patients. Eur. J. Paediatr. Neurol. 27, 37–42 (2020).

    PubMed  Google Scholar 

  154. Audic, F. et al. Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study. Orphanet J. Rare Dis. 15, 148 (2020).

    PubMed  PubMed Central  Google Scholar 

  155. Gomez-Garcia de la Banda, M. et al. Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen. Pediatr. Pulmonol. 56, 299–306 (2021).

    PubMed  Google Scholar 

  156. Jochmann, E. et al. Experiences from treating seven adult 5q spinal muscular atrophy patients with nusinersen. Ther. Adv. Neurol. Disord. 13, 1756286420907803 (2020).

    PubMed  PubMed Central  Google Scholar 

  157. Maggi, L. et al. Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. J. Neurol. Neurosurg. Psychiatry 91, 1166–1174 (2020).

    PubMed  Google Scholar 

  158. Hagenacker, T. et al. Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol. 19, 317–325 (2020). Real-world data from Germany for adults with SMA who were treated with nusinersen, which demonstrated a positive response in motor function and acceptable tolerability of the related lumbar punctures necessary to administer the drug.

    CAS  PubMed  Google Scholar 

  159. Walter, M. C. et al. Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3 – a prospective observational study. J. Neuromuscul. Dis. 6, 453–465 (2019).

    PubMed  PubMed Central  Google Scholar 

  160. Kessler, T. et al. Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy. J. Neurochem. https://doi.org/10.1111/jnc.14953 (2020).

    Article  PubMed  Google Scholar 

  161. Yeo, C. J. J., Simeone, S. D., Townsend, E. L., Zhang, R. Z. & Swoboda, K. J. Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy. J. Neuromuscul. Dis. https://doi.org/10.3233/JND-190453 (2020).

    Article  PubMed  Google Scholar 

  162. Osmanovic, A. et al. Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy. J. Neurol. 267, 2398–2407 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. De Wel, B. et al. Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4. J. Neurol. https://doi.org/10.1007/s00415-020-10223-9 (2020).

    Article  PubMed  Google Scholar 

  164. Kizina, K. et al. Fatigue in adults with spinal muscular atrophy under treatment with nusinersen. Sci. Rep. 10, 11069 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Moshe-Lilie, O. et al. Nusinersen in adult patients with spinal muscular atrophy: observations from a single center. Neurology 95, e413–e416 (2020).

    PubMed  Google Scholar 

  166. Konersman, C. G. et al. Nusinersen treatment of older children and adults with spinal muscular atrophy. Neuromuscul. Disord. 31, 183–193 (2021).

    PubMed  Google Scholar 

  167. Mendonca, R. H. et al. Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience. J. Neuromuscul. Dis. 8, 101–108 (2021).

    PubMed  Google Scholar 

  168. Duong, T. et al. Nusinersen treatment in adults with spinal muscular atrophy. Neurol. Clin. Pract. https://doi.org/10.1212/cpj.0000000000001033 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Veerapandiyan, A. et al. Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience. Muscle Nerve 61, 222–226 (2020).

    PubMed  Google Scholar 

  170. Jedrzejowska, M. Advances in newborn screening and presymptomatic diagnosis of spinal muscular atrophy. Degener. Neurol. Neuromuscul. Dis. 10, 39–47 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Biogen. First quarter 2021: Financial results and business update. Biogen https://investors.biogen.com/static-files/a957e5ba-325f-4a37-bfc8-43cecfc64620 (2021).

  172. Coratti, G. et al. Motor function in type 2 and 3 SMA patients treated with nusinersen: a critical review and meta-analysis. Orphanet J. Rare Dis. 16, 430 (2021).

    PubMed  PubMed Central  Google Scholar 

  173. Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017). This is the first of the studies of onasemnogene abeparvovec, demonstrating improved survival and motor function compared with historic controls, and a favourable safety profile. This phase I study was largely responsible for gaining regulatory approval for this drug.

    CAS  PubMed  Google Scholar 

  174. Mendell, J. R. et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2021.1272 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Day, J. W. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 20, 284–293 (2021).

    CAS  PubMed  Google Scholar 

  176. Mercuri, E. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 20, 832–841 (2021).

    CAS  PubMed  Google Scholar 

  177. Friese, J. et al. Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec – a single centre experience. J. Neuromuscul. Dis. 8, 209–216 (2021).

    PubMed  PubMed Central  Google Scholar 

  178. Chand, D. H. et al. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series. J. Pediatr. 231, 265–268 (2021).

    CAS  PubMed  Google Scholar 

  179. Matesanz, S. E. et al. Clinical course in a patient with spinal muscular atrophy type 0 treated with nusinersen and onasemnogene abeparvovec. J. Child Neurol. 35, 717–723 (2020).

    PubMed  Google Scholar 

  180. Weiss, C. et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc. Health 6, 17–27 (2022).

    CAS  PubMed  Google Scholar 

  181. Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2021).

    CAS  PubMed  Google Scholar 

  182. Baranello, G. et al. Risdiplam in type 1 spinal muscular atrophy. N. Engl. J. Med. 384, 915–923 (2021).

    CAS  PubMed  Google Scholar 

  183. Darras, B. T. et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N. Engl. J. Med. 385, 427–435 (2021). This study of risdiplam in patients with early-infantile onset SMA type 1 demonstrated improved survival and motor function, and a favourable safety profile, and supported gaining regulatory approval for this drug.

    CAS  PubMed  Google Scholar 

  184. Mercuri, E. et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 21, 42–52 (2022). This study presents the positive results of risdiplam treatment in patients with late-infantile onset SMA type 2, with improved motor function and a favourable safety profile. It provided support for the application for regulatory approval.

    CAS  PubMed  Google Scholar 

  185. Glascock, J. et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J. Neuromuscul. Dis. 7, 97–100 (2020). This survey of SMA clinicians resulted in an algorithm for approaching treatment decisions for young infants with SMA identified by newborn screening. This updated expert opinion document recommended treatment as soon as feasible for all patients with two, three or four copies of SMN2.

    PubMed  PubMed Central  Google Scholar 

  186. Bach, J. R., Vega, J., Majors, J. & Friedman, A. Spinal muscular atrophy type 1 quality of life. Am. J. Phys. Med. Rehabil. 82, 137–142 (2003).

    PubMed  Google Scholar 

  187. de Oliveira, C. M. & Araujo, A. P. Self-reported quality of life has no correlation with functional status in children and adolescents with spinal muscular atrophy. Eur. J. Paediatr. Neurol. 15, 36–39 (2011).

    PubMed  Google Scholar 

  188. Kruitwagen-Van Reenen, E. T. et al. Correlates of health related quality of life in adult patients with spinal muscular atrophy. Muscle Nerve 54, 850–855 (2016).

    PubMed  Google Scholar 

  189. Jeppesen, J., Madsen, A., Marquardt, J. & Rahbek, J. Living and ageing with spinal muscular atrophy type 2: observations among an unexplored patient population. Dev. Neurorehabil. 13, 10–18 (2010).

    PubMed  Google Scholar 

  190. Iannaccone, S. T. et al. The PedsQL in pediatric patients with spinal muscular atrophy: feasibility, reliability, and validity of the pediatric quality of life inventory generic core scales and neuromuscular module. Neuromuscul. Disord. 19, 805–812 (2009).

    PubMed  PubMed Central  Google Scholar 

  191. Landfeldt, E. et al. Quality of life of patients with spinal muscular atrophy: a systematic review. Eur. J. Paediatr. Neurol. 23, 347–356 (2019).

    PubMed  Google Scholar 

  192. Gunther, R. et al. Patient-reported prevalence of non-motor symptoms is low in adult patients suffering from 5q spinal muscular atrophy. Front. Neurol. 10, 1098 (2019).

    PubMed  PubMed Central  Google Scholar 

  193. Messina, S. et al. A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy. Neuromuscul. Disord. 29, 940–950 (2019).

    PubMed  Google Scholar 

  194. Messina, S. et al. Health-related quality of life and functional changes in DMD: a 12-month longitudinal cohort study. Neuromuscul. Disord. 26, 189–196 (2016).

    PubMed  PubMed Central  Google Scholar 

  195. Mercuri, E. et al. Patient and parent oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in SMA. Rome, 13 July 2019. Neuromuscul. Disord. 30, 431–436 (2020). This workshop report summarizes the current state for patient-reported outcome measures for patients with SMA, highlighting those metrics of clinical utility and the gaps and limitations that need to be addressed.

    PubMed  Google Scholar 

  196. Pasternak, A. et al. Rasch analysis of the pediatric evaluation of disability inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy. Muscle Nerve 54, 1097–1107 (2016).

    PubMed  Google Scholar 

  197. Sansone, V. A. et al. The spinal muscular atrophy health index: Italian validation of a disease-specific outcome measure. Neuromuscul. Disord. 31, 409–418 (2021).

    PubMed  Google Scholar 

  198. Bartels, B. et al. Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests. BMC Neurol. 19, 21 (2019).

    PubMed  PubMed Central  Google Scholar 

  199. Dunaway Young, S. et al. Perceived fatigue in spinal muscular atrophy: a pilot study. J. Neuromuscul. Dis. 6, 109–117 (2019).

    PubMed  Google Scholar 

  200. Montes, J. et al. Fatigue leads to gait changes in spinal muscular atrophy. Muscle Nerve 43, 485–488 (2011).

    PubMed  Google Scholar 

  201. Darras, B. T., Markowitz, J. A., Monani, U. R., De Vivo, D. C. in Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach (eds Darras, B. T., Jones, H. R. Jr, Ryan, M. M. & De Vivo, D. C.) 117–145 (Elsevier, 2015).

  202. Jedrzejowska, M. et al. Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients. Neuromuscul. Disord. 24, 617–623 (2014).

    PubMed  Google Scholar 

  203. Douglas, A. G. & Wood, M. J. Splicing therapy for neuromuscular disease. Mol. Cell. Neurosci. 56, 169–185 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Gubitz, A. K., Feng, W. & Dreyfuss, G. The SMN complex. Exp. Cell Res. 296, 51–56 (2004).

    CAS  PubMed  Google Scholar 

  205. Khalil, M. et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat. Commun. 11, 812 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Reinert, M. C. et al. Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000749 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Wurster, C. D. et al. Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J. Neurol. 267, 36–44 (2020).

    CAS  PubMed  Google Scholar 

  208. Chen, I. An antisense oligonucleotide splicing modulator to treat spinal muscular atrophy. Nature Portfolio Milestones http://www.nature.com/articles/d42859-019-00090-4 (2019).

  209. Sivaramakrishnan, M. et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat. Commun. 8, 1476 (2017).

    PubMed  PubMed Central  Google Scholar 

  210. Tretiakova, A. P. et al. Realizing the promise of gene therapy through collaboration and partnering: Pfizer’s view. Nature Portfolio Sponsor Feature http://www.nature.com/articles/d42473-018-00307-6 (2021).

  211. Li, C. & Samulski, R. J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 21, 255–272 (2020).

    CAS  PubMed  Google Scholar 

  212. Schorling, D. C., Pechmann, A. & Kirschner, J. Advances in treatment of spinal muscular atrophy – new phenotypes, new challenges, new implications for care. J. Neuromuscul. Dis. 7, 1–13 (2020).

    PubMed  PubMed Central  Google Scholar 

  213. Montes, J. et al. Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy. Muscle Nerve 60, 409–414 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Paediatric Neurology, Università Cattolica del Sacro Cuore, Rome, Italy

    Eugenio Mercuri

  2. Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Eugenio Mercuri

  3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Charlotte J. Sumner

  4. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Charlotte J. Sumner

  5. Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK

    Francesco Muntoni

  6. NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK

    Francesco Muntoni

  7. Department of Neurology, Neuromuscular Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Basil T. Darras

  8. Center for Experimental Neurotherapeutics, Department of Paediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Richard S. Finkel

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Contributions

Introduction (E.M.); Epidemiology (B.T.D.); Mechanisms/pathophysiology (B.T.D., C.J.S. and F.M.); Diagnosis, screening and prevention (F.M., E.M. and R.S.F.); Management (R.S.F. and E.M.); Quality of life (B.T.D. and E.M.); Outlook (E.M., C.J.S., F.M., B.T.D. and R.S.F.); Overview of Primer (E.M. and F.M.).

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Correspondence to Eugenio Mercuri.

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Competing interests

E.M., C.J.S., F.M., B.T.D. and R.S.F. are all principal investigators for clinical studies and consultants for Roche, Biogen, Novartis and Scholar Rock.

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Mercuri, E., Sumner, C.J., Muntoni, F. et al. Spinal muscular atrophy. Nat Rev Dis Primers 8, 52 (2022). https://doi.org/10.1038/s41572-022-00380-8

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