1932

Abstract

Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of cause SMA, and the copy number of the nearly identical copy gene inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of genes, the disease's phenotype–genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively.This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-102319-103602
2020-08-31
2024-04-22
Loading full text...

Full text loading...

/deliver/fulltext/genom/21/1/annurev-genom-102319-103602.html?itemId=/content/journals/10.1146/annurev-genom-102319-103602&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Ackermann B, Krober S, Torres-Benito L, Borgmann A, Peters M et al. 2013. Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum. Mol. Genet. 22:1328–47
    [Google Scholar]
  2. 2. 
    Acsadi G, Lee I, Li X, Khaidakov M, Pecinova A et al. 2009. Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy. J. Neurosci. Res. 87:2748–56
    [Google Scholar]
  3. 3. 
    Akten B, Kye MJ, Hao LT, Wertz MH, Singh S et al. 2011. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. PNAS 108:10337–42
    [Google Scholar]
  4. 4. 
    Al-Zaidy SA, Kolb SJ, Lowes L, Alfano LN, Shell R et al. 2019. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J. Neuromuscul. Dis. 6:307–17
    [Google Scholar]
  5. 5. 
    Al-Zaidy SA, Pickard AS, Kotha K, Alfano LN, Lowes L et al. 2019. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr. Pulmonol. 54:179–85
    [Google Scholar]
  6. 6. 
    Alias L, Bernal S, Fuentes-Prior P, Barcelo MJ, Also E et al. 2009. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum. Genet. 125:29–39
    [Google Scholar]
  7. 7. 
    Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK et al. 2018. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 57:729–34
    [Google Scholar]
  8. 8. 
    Andrews JA, Shefner JM. 2019. Clinical neurophysiology of anterior horn cell disorders. Handb. Clin. Neurol. 161:317–26
    [Google Scholar]
  9. 9. 
    Araki S, Hayashi M, Tamagawa K, Saito M, Kato S et al. 2003. Neuropathological analysis in spinal muscular atrophy type II. Acta Neuropathol 106:441–48
    [Google Scholar]
  10. 10. 
    Arkblad E, Tulinius M, Kroksmark AK, Henricsson M, Darin N 2009. A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy. Acta Paediatr 98:865–72
    [Google Scholar]
  11. 11. 
    Arnold WD, Simard LR, Rutkove SB, Kolb SJ 2017. Development and testing of biomarkers in spinal muscular atrophy. See Ref. 164 383–97
  12. 12. 
    Baloh RH, Rakowicz W, Gardner R, Pestronk A 2007. Frequent atrophic groups with mixed-type myofibers is distinctive to motor neuron syndromes. Muscle Nerve 36:107–10
    [Google Scholar]
  13. 13. 
    Berger A, Mayr JA, Meierhofer D, Fotschl U, Bittner R et al. 2003. Severe depletion of mitochondrial DNA in spinal muscular atrophy. Acta Neuropathol 105:245–51
    [Google Scholar]
  14. 14. 
    Bertini E, Burghes A, Bushby K, Estournet-Mathiaud B, Finkel RS et al. 2005. 134th ENMC international workshop: outcome measures and treatment of spinal muscular atrophy, 11–13 February 2005, Naarden, the Netherlands. Neuromuscul. Disord. 15:802–16
    [Google Scholar]
  15. 15. 
    Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J et al. 2017. Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 16:513–22
    [Google Scholar]
  16. 16. 
    Bertrandy S, Burlet P, Clermont O, Huber C, Fondrat C et al. 1999. The RNA-binding properties of SMN: deletion analysis of the zebrafish orthologue defines domains conserved in evolution. Hum. Mol. Genet. 8:775–82
    [Google Scholar]
  17. 17. 
    Boido M, Vercelli A. 2016. Neuromuscular junctions as key contributors and therapeutic targets in spinal muscular atrophy. Front. Neuroanat. 10:6
    [Google Scholar]
  18. 18. 
    Bowerman M, Becker CG, Yanez-Munoz RJ, Ning K, Wood MJA et al. 2017. Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Dis. Models Mech. 10:943–54
    [Google Scholar]
  19. 19. 
    Bowerman M, Murray LM, Beauvais A, Pinheiro B, Kothary R 2012. A critical Smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul. Disord. 22:263–76
    [Google Scholar]
  20. 20. 
    Bowerman M, Shafey D, Kothary R 2007. Smn depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity. J. Mol. Neurosci. 32:120–31
    [Google Scholar]
  21. 21. 
    Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H et al. 2003. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum. Mol. Genet. 12:2481–89
    [Google Scholar]
  22. 22. 
    Burlet P, Burglen L, Clermont O, Lefebvre S, Viollet L et al. 1996. Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. J. Med. Genet. 33:281–83
    [Google Scholar]
  23. 23. 
    Bussaglia E, Clermont O, Tizzano E, Lefebvre S, Burglen L et al. 1995. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat. Genet. 11:335–37
    [Google Scholar]
  24. 24. 
    Calucho M, Bernal S, Alias L, March F, Vencesla A et al. 2018. 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. 28:208–15
    [Google Scholar]
  25. 25. 
    Cartegni L, Krainer AR. 2002. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet 30:377–84
    [Google Scholar]
  26. 26. 
    Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J et al. 2016. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 86:890–97
    [Google Scholar]
  27. 27. 
    Chou SM, Wang HS. 1997. Aberrant glycosylation/phosphorylation in chromatolytic motoneurons of Werdnig-Hoffmann disease. J. Neurol. Sci. 152:198–209
    [Google Scholar]
  28. 28. 
    Cifuentes-Diaz C, Frugier T, Tiziano FD, Lacene E, Roblot N et al. 2001. Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J. Cell Biol. 152:1107–14
    [Google Scholar]
  29. 29. 
    Cifuentes-Diaz C, Nicole S, Velasco ME, Borra-Cebrian C, Panozzo C et al. 2002. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Hum. Mol. Genet. 11:1439–47
    [Google Scholar]
  30. 30. 
    Cioni JM, Lin JQ, Holtermann AV, Koppers M, Jakobs MAH et al. 2019. Late endosomes act as mRNA translation platforms and sustain mitochondria in axons. Cell 176:56–72.e15
    [Google Scholar]
  31. 31. 
    Clermont O, Burlet P, Benit P, Chanterau D, Saugier-Veber P et al. 2004. Molecular analysis of SMA patients without homozygous SMN1 deletions using a new strategy for identification of SMN1 subtle mutations. Hum. Mutat. 24:417–27
    [Google Scholar]
  32. 32. 
    Cooper DN, Ball EV, Stenson PD, Phillips AD, Evans K et al. 2019. Human Gene Mutation Database Accessed Oct. 22, 2019. http://www.hgmd.cf.ac.uk
  33. 33. 
    Crawford TO, Pardo CA. 1996. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 3:97–110
    [Google Scholar]
  34. 34. 
    d'Ydewalle C, Ramos DM, Pyles NJ, Ng SY, Gorz M et al. 2017. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron 93:66–79
    [Google Scholar]
  35. 35. 
    Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J et al. 2019. Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology 92:e2492–506
    [Google Scholar]
  36. 36. 
    Darras BT, Crawford TO, Finkel RS, Mercuri E, De Vivo DC et al. 2019. Neurofilament as a potential biomarker for spinal muscular atrophy. Ann. Clin. Transl. Neurol. 6:932–44
    [Google Scholar]
  37. 37. 
    De Sanctis R, Coratti G, Pasternak A, Montes J, Pane M et al. 2016. Developmental milestones in type I spinal muscular atrophy. Neuromuscul. Disord. 26:754–59
    [Google Scholar]
  38. 38. 
    De Vivo DC, Topaloglu H, Swoboda KJ, Bertini E, Hwu W-L et al. 2019. Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim efficacy and safety results from the phase 2 NURTURE study (S25.001). Neurology 92:S25.001
    [Google Scholar]
  39. 39. 
    Dennis MY, Harshman L, Nelson BJ, Penn O, Cantsilieris S et al. 2017. The evolution and population diversity of human-specific segmental duplications. Nat. Ecol. Evol. 1:0069
    [Google Scholar]
  40. 40. 
    Dimitriadi M, Derdowski A, Kalloo G, Maginnis MS, O'Hern P et al. 2016. Decreased function of survival motor neuron protein impairs endocytic pathways. PNAS 113:E4377–86
    [Google Scholar]
  41. 41. 
    Dimitriadi M, Sleigh JN, Walker A, Chang HC, Sen A et al. 2010. Conserved genes act as modifiers of invertebrate SMN loss of function defects. PLOS Genet 6:e1001172
    [Google Scholar]
  42. 42. 
    Doktor TK, Hua Y, Andersen HS, Broner S, Liu YH et al. 2017. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res 45:395–416
    [Google Scholar]
  43. 43. 
    Dubowitz V. 1999. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Eur. J. Paediatr. Neurol. 3:49–51
    [Google Scholar]
  44. 44. 
    Duque SI, Arnold WD, Odermatt P, Li X, Porensky PN et al. 2015. A large animal model of spinal muscular atrophy and correction of phenotype. Ann. Neurol. 77:399–414
    [Google Scholar]
  45. 45. 
    Duque SI, Joussemet B, Riviere C, Marais T, Dubreil L et al. 2009. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17:1187–96
    [Google Scholar]
  46. 46. 
    Edens BM, Ajroud-Driss S, Ma L, Ma YC 2015. Molecular mechanisms and animal models of spinal muscular atrophy. Biochim. Biophys. Acta 1852:685–92
    [Google Scholar]
  47. 47. 
    Federici T, Taub JS, Baum GR, Gray SJ, Grieger JC et al. 2012. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 19:852–59
    [Google Scholar]
  48. 48. 
    Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B 2002. 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. 70:358–68
    [Google Scholar]
  49. 49. 
    Feng Z, Ling KK, Zhao X, Zhou C, Karp G et al. 2016. Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset. Hum. Mol. Genet. 25:964–75
    [Google Scholar]
  50. 50. 
    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J et al. 2016. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388:3017–26
    [Google Scholar]
  51. 51. 
    Finkel RS, Crawford TO, Swoboda KJ, Kaufmann P, Juhasz P et al. 2012. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLOS ONE 7:e35462
    [Google Scholar]
  52. 52. 
    Finkel RS, Day JW, Darras BT, Kuntz NL, Connolly AM et al. 2019. Phase 1 study of intrathecal administration of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2) (STRONG) (P1.6-059). Neurology 92:P1.6–059
    [Google Scholar]
  53. 53. 
    Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL et al. 2017. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377:1723–32
    [Google Scholar]
  54. 54. 
    Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK et al. 2018. 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
    [Google Scholar]
  55. 55. 
    Foust KD, Wang X, McGovern VL, Braun L, Bevan AK et al. 2010. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotechnol. 28:271–74
    [Google Scholar]
  56. 56. 
    Frugier T, Tiziano FD, Cifuentes-Diaz C, Miniou P, Roblot N et al. 2000. Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy. Hum. Mol. Genet. 9:849–58
    [Google Scholar]
  57. 57. 
    Gabanella F, Butchbach ME, Saieva L, Carissimi C, Burghes AH, Pellizzoni L 2007. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLOS ONE 2:e921
    [Google Scholar]
  58. 58. 
    Gennarelli M, Lucarelli M, Capon F, Pizzuti A, Merlini L et al. 1995. Survival motor neuron gene transcript analysis in muscles from spinal muscular atrophy patients. Biochem. Biophys. Res. Commun. 213:342–48
    [Google Scholar]
  59. 59. 
    Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B et al. 2018. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J. Neuromuscul. Dis. 5:145–58
    [Google Scholar]
  60. 60. 
    Gogliotti RG, Quinlan KA, Barlow CB, Heier CR, Heckman CJ, Didonato CJ 2012. 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. 32:3818–29
    [Google Scholar]
  61. 61. 
    Groen EJN, Perenthaler E, Courtney NL, Jordan CY, Shorrock HK et al. 2018. Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 27:2851–62
    [Google Scholar]
  62. 62. 
    Groen EJN, Talbot K, Gillingwater TH 2018. Advances in therapy for spinal muscular atrophy: promises and challenges. Nat. Rev. Neurol. 14:214–24
    [Google Scholar]
  63. 63. 
    Grotto S, Cuisset JM, Marret S, Drunat S, Faure P et al. 2016. Type 0 spinal muscular atrophy: further delineation of prenatal and postnatal features in 16 patients. J. Neuromuscul. Dis. 3:487–95
    [Google Scholar]
  64. 64. 
    Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A et al. 2016. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J. Child Neurol. 31:899–906
    [Google Scholar]
  65. 65. 
    Hahnen E, Schonling J, Rudnik-Schoneborn S, Zerres K, Wirth B 1996. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am. J. Hum. Genet. 59:1057–65
    [Google Scholar]
  66. 66. 
    Hamilton G, Gillingwater TH. 2013. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol. Med. 19:40–50
    [Google Scholar]
  67. 67. 
    Heesen L, Peitz M, Torres-Benito L, Holker I, Hupperich K et al. 2016. Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals. Cell Mol. Life Sci. 73:2089–104
    [Google Scholar]
  68. 68. 
    Helmken C, Hofmann Y, Schoenen F, Oprea G, Raschke H et al. 2003. Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-β1. Hum. Genet. 114:11–21
    [Google Scholar]
  69. 69. 
    Hofmann Y, Lorson CL, Stamm S, Androphy EJ, Wirth B 2000. Htra2-β1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). PNAS 97:9618–23
    [Google Scholar]
  70. 70. 
    Hofmann Y, Wirth B. 2002. hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-β1. Hum. Mol. Genet. 11:2037–49
    [Google Scholar]
  71. 71. 
    Hosseinibarkooie S, Peters M, Torres-Benito L, Rastetter RH, Hupperich K et al. 2016. The power of human protective modifiers: PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype. Am. J. Hum. Genet. 99:647–65
    [Google Scholar]
  72. 72. 
    Hosseinibarkooie S, Schneider S, Wirth B 2017. Advances in understanding the role of disease-associated proteins in spinal muscular atrophy. Expert Rev. Proteom. 14:581–92
    [Google Scholar]
  73. 73. 
    Hoy SM. 2018. Nusinersen: a review in 5q spinal muscular atrophy. CNS Drugs 32:689–96
    [Google Scholar]
  74. 74. 
    Hoy SM. 2019. Onasemnogene abeparvovec: first global approval. Drugs 79:1255–62
    [Google Scholar]
  75. 75. 
    Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM et al. 2000. A mouse model for spinal muscular atrophy. Nat. Genet. 24:66–70
    [Google Scholar]
  76. 76. 
    Hua Y, Liu YH, Sahashi K, Rigo F, Bennett CF, Krainer AR 2015. Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 29:288–97
    [Google Scholar]
  77. 77. 
    Hua Y, Sahashi K, Hung G, Rigo F, Passini MA et al. 2010. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–44
    [Google Scholar]
  78. 78. 
    Hua Y, Sahashi K, Rigo F, Hung G, Horev G et al. 2011. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478:123–26
    [Google Scholar]
  79. 79. 
    Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR 2007. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLOS Biol 5:e73
    [Google Scholar]
  80. 80. 
    Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR 2008. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet. 82:834–48
    [Google Scholar]
  81. 81. 
    Hwee DT, Kennedy AR, Hartman JJ, Ryans J, Durham N et al. 2015. The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. J. Pharmacol. Exp. Ther. 353:159–68
    [Google Scholar]
  82. 82. 
    Iyer CC, McGovern VL, Murray JD, Gombash SE, Zaworski PG et al. 2015. Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNΔ7 mouse model of SMA. Hum. Mol. Genet. 24:6160–73
    [Google Scholar]
  83. 83. 
    Jablonka S, Beck M, Lechner BD, Mayer C, Sendtner M 2007. Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy. J. Cell Biol. 179:139–49
    [Google Scholar]
  84. 84. 
    Janzen E, Mendoza-Ferreira N, Hosseinibarkooie S, Schneider S, Hupperich K et al. 2018. CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis. Brain 141:2343–61
    [Google Scholar]
  85. 85. 
    Jedrzejowska M, Gos M, Zimowski JG, Kostera-Pruszczyk A, Ryniewicz B, Hausmanowa-Petrusewicz I 2014. Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients. Neuromuscul. Disord. 24:617–23
    [Google Scholar]
  86. 86. 
    Kaczmarek A, Schneider S, Wirth B, Riessland M 2015. Investigational therapies for the treatment of spinal muscular atrophy. Expert Opin. Investig. Drugs 24:867–81
    [Google Scholar]
  87. 87. 
    Kaifer KA, Villalón E, Osman EY, Glascock JJ, Arnold LL et al. 2017. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI Insight 2:e89970
    [Google Scholar]
  88. 88. 
    Kariya S, Obis T, Garone C, Akay T, Sera F et al. 2014. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J. Clin. Investig. 124:785–800
    [Google Scholar]
  89. 89. 
    Kashima T, Manley JL. 2003. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet. 34:460–63
    [Google Scholar]
  90. 90. 
    Kaufmann P, McDermott MP, Darras BT, Finkel RS, Kang P et al. 2011. Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch. Neurol. 68:779–86
    [Google Scholar]
  91. 91. 
    Kaufmann P, McDermott MP, Darras BT, Finkel RS, Sproule DM et al. 2012. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology 79:1889–97
    [Google Scholar]
  92. 92. 
    Kelter AR, Herchenbach J, Wirth B 2000. The transcription factor-like nuclear regulator (TFNR) contains a novel 55-amino-acid motif repeated nine times and maps closely to SMN1. Genomics 70:315–26
    [Google Scholar]
  93. 93. 
    Kobayashi DT, Shi J, Stephen L, Ballard KL, Dewey R et al. 2013. SMA-MAP: a plasma protein panel for spinal muscular atrophy. PLOS ONE 8:e60113
    [Google Scholar]
  94. 94. 
    Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD et al. 2016. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann. Clin. Transl. Neurol. 3:132–45
    [Google Scholar]
  95. 95. 
    Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD et al. 2017. Natural history of infantile-onset spinal muscular atrophy. Ann. Neurol. 82:883–91
    [Google Scholar]
  96. 96. 
    Kubo Y, Nishio H, Saito K 2015. A new method for SMN1 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed by sequencing. J. Hum. Genet. 60:233–39
    [Google Scholar]
  97. 97. 
    Kuru S, Sakai M, Konagaya M, Yoshida M, Hashizume Y, Saito K 2009. An autopsy case of spinal muscular atrophy type III (Kugelberg-Welander disease). Neuropathology 29:63–67
    [Google Scholar]
  98. 98. 
    Kye MJ, Niederst ED, Wertz MH, Goncalves Ido C, Akten B et al. 2014. SMN regulates axonal local translation via miR-183/mTOR pathway. Hum. Mol. Genet. 23:6318–31
    [Google Scholar]
  99. 99. 
    Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR et al. 2005. 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. 14:845–57
    [Google Scholar]
  100. 100. 
    Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P et al. 1995. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–65
    [Google Scholar]
  101. 101. 
    Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O et al. 1997. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16:265–69
    [Google Scholar]
  102. 102. 
    Lewelt A, Krosschell KJ, Scott C, Sakonju A, Kissel JT et al. 2010. Compound muscle action potential and motor function in children with spinal muscular atrophy. Muscle Nerve 42:703–8
    [Google Scholar]
  103. 103. 
    Liu Q, Dreyfuss G. 1996. A novel nuclear structure containing the survival of motor neurons protein. EMBO J 15:3555–65
    [Google Scholar]
  104. 104. 
    Liu Q, Fischer U, Wang F, Dreyfuss G 1997. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90:1013–21
    [Google Scholar]
  105. 105. 
    Long KK, O'Shea KM, Khairallah RJ, Howell K, Paushkin S et al. 2019. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum. Mol. Genet. 28:1076–89
    [Google Scholar]
  106. 106. 
    Lorson CL, Hahnen E, Androphy EJ, Wirth B 1999. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. PNAS 96:6307–11
    [Google Scholar]
  107. 107. 
    Lotti F, Imlach WL, Saieva L, Beck ES, Hao LT et al. 2012. An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151:440–54
    [Google Scholar]
  108. 108. 
    Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS et al. 2002. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet. Med. 4:20–26
    [Google Scholar]
  109. 109. 
    Malone DC, Dean R, Arjunji R, Jensen I, Cyr P et al. 2019. Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients. J. Market Access Health Policy 7:1601484
    [Google Scholar]
  110. 110. 
    Martinez-Hernandez R, Bernal S, Also-Rallo E, Alias L, Barcelo MJ et al. 2013. Synaptic defects in type I spinal muscular atrophy in human development. J. Pathol. 229:49–61
    [Google Scholar]
  111. 111. 
    McWhorter ML, Monani UR, Burghes AH, Beattie CE 2003. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J. Cell Biol. 162:919–31
    [Google Scholar]
  112. 112. 
    Mende Y, Jakubik M, Riessland M, Schoenen F, Rossbach K et al. 2010. Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and has no impact on full-length SMN/Smn splicing. Hum. Mol. Genet. 19:2154–67
    [Google Scholar]
  113. 113. 
    Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR et al. 2017. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377:1713–22
    [Google Scholar]
  114. 114. 
    Mendell JR, Lehman KJ, McColly M, Lowes LP, Alfano LN et al. 2019. AVXS-101 gene-replacement therapy (GRT) in spinal muscular atrophy type 1 (SMA1): long-term follow-up from the phase 1 clinical trial (S25.006). Neurology 92:S25.006
    [Google Scholar]
  115. 115. 
    Mentis GZ, Blivis D, Liu W, Drobac E, Crowder ME et al. 2011. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69:453–67
    [Google Scholar]
  116. 116. 
    Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C et al. 2018. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med. 378:625–35
    [Google Scholar]
  117. 117. 
    Mercuri E, Finkel R, Montes J, Mazzone ES, Sormani MP et al. 2016. Patterns of disease progression in type 2 and 3 SMA: implications for clinical trials. Neuromuscul. Disord. 26:126–31
    [Google Scholar]
  118. 118. 
    Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J et al. 2018. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul. Disord. 28:103–15
    [Google Scholar]
  119. 119. 
    Mercuri E, Kirschner J, Baranello G, Servais L, Goemans N et al. 2017. Clinical studies of RG7916 in patients with spinal muscular atrophy: SUNFISH part 1 study update. Neuromuscul. Disord. 27:S209
    [Google Scholar]
  120. 120. 
    Merette C, Brzustowicz LM, Daniels RJ, Davies KE, Gilliam TC et al. 1994. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy. Genomics 21:27–33
    [Google Scholar]
  121. 121. 
    Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V et al. 2015. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. Mol. Ther. 23:477–87
    [Google Scholar]
  122. 122. 
    Miller N, Shi H, Zelikovich AS, Ma YC 2016. Motor neuron mitochondrial dysfunction in spinal muscular atrophy. Hum. Mol. Genet. 25:3395–406
    [Google Scholar]
  123. 123. 
    Mills KR. 2005. The basics of electromyography. J. Neurol. Neurosurg. Psychiatry 76:Suppl. 2ii32–35
    [Google Scholar]
  124. 124. 
    Miyajima H, Miyaso H, Okumura M, Kurisu J, Imaizumi K 2002. Identification of a cis-acting element for the regulation of SMN exon 7 splicing. J. Biol. Chem. 277:23271–77
    [Google Scholar]
  125. 125. 
    Monani UR. 2005. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48:885–96
    [Google Scholar]
  126. 126. 
    Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C et al. 2000. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn−/− mice and results in a mouse with spinal muscular atrophy. Hum. Mol. Genet. 9:333–39
    [Google Scholar]
  127. 127. 
    Munsat TL, Davies KE. 1992. International SMA Consortium meeting (26–28 June 1992, Bonn, Germany). Neuromuscul. Disord. 2:423–28
    [Google Scholar]
  128. 128. 
    Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X et al. 2014. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345:688–93
    [Google Scholar]
  129. 129. 
    Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S et al. 2008. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320:524–27
    [Google Scholar]
  130. 130. 
    Oskoui M, Darras BT, De Vivo DC 2017. Spinal muscular atrophy: 125 years later and on the verge of a cure. See Ref. 164, pp. 3–19
  131. 131. 
    Palacino J, Swalley SE, Song C, Cheung AK, Shu L et al. 2015. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat. Chem. Biol. 11:511–17
    [Google Scholar]
  132. 132. 
    Parente V, Corti S. 2018. Advances in spinal muscular atrophy therapeutics. Ther. Adv. Neurol. Disord. 11: https://doi.org/10.1177/1756285618754501
    [Crossref] [Google Scholar]
  133. 133. 
    Parsons DW, McAndrew PE, Monani UR, Mendell JR, Burghes AH, Prior TW 1996. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum. Mol. Genet. 5:1727–32
    [Google Scholar]
  134. 134. 
    Passini MA, Bu J, Richards AM, Treleaven CM, Sullivan JA et al. 2014. Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy. Hum. Gene Ther. 25:619–30
    [Google Scholar]
  135. 135. 
    Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G 1998. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 95:615–24
    [Google Scholar]
  136. 136. 
    Pirruccello-Straub M, Jackson J, Wawersik S, Webster MT, Salta L et al. 2018. Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci. Rep. 8:2292
    [Google Scholar]
  137. 137. 
    Poirier A, Weetall M, Heinig K, Bucheli F, Schoenlein K et al. 2018. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol. Res. Perspect. 6:e00447
    [Google Scholar]
  138. 138. 
    Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC et al. 2009. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am. J. Hum. Genet. 85:408–13
    [Google Scholar]
  139. 139. 
    Ramos DM, d'Ydewalle C, Gabbeta V, Dakka A, Klein SK et al. 2019. Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. J. Clin. Investig. 129:4817–83
    [Google Scholar]
  140. 140. 
    Ratni H, Ebeling M, Baird J, Bendels S, Bylund J et al. 2018. 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. 61:6501–17
    [Google Scholar]
  141. 141. 
    Ratni H, Karp GM, Weetall M, Naryshkin NA, Paushkin SV et al. 2016. Specific correction of alternative survival motor neuron 2 splicing by small molecules: discovery of a potential novel medicine to treat spinal muscular atrophy. J. Med. Chem. 59:6086–100
    [Google Scholar]
  142. 142. 
    Riessland M, Kaczmarek A, Schneider S, Swoboda KJ, Lohr H et al. 2017. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am. J. Hum. Genet. 100:297–315
    [Google Scholar]
  143. 143. 
    Rigo F, Hua Y, Krainer AR, Bennett CF 2012. Antisense-based therapy for the treatment of spinal muscular atrophy. J. Cell Biol. 199:21–25
    [Google Scholar]
  144. 144. 
    Rochette CF, Gilbert N, Simard LR 2001. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum. Genet 108:255–66
    [Google Scholar]
  145. 145. 
    Rossoll W, Jablonka S, Andreassi C, Kroning AK, Karle K et al. 2003. 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. 163:801–12
    [Google Scholar]
  146. 146. 
    Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z et al. 1995. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167–78
    [Google Scholar]
  147. 147. 
    Rudnik-Schöneborn S, Hausmanowa-Petrusewicz I, Borkowska J, Zerres K 2001. The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III. Eur. Neurol. 45:174–81
    [Google Scholar]
  148. 148. 
    Rudnik-Schöneborn S, Heller R, Berg C, Betzler C, Grimm T et al. 2008. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J. Med. Genet. 45:635–38
    [Google Scholar]
  149. 149. 
    Rudnik-Schöneborn S, Lutzenrath S, Borkowska J, Karwanska A, Hausmanowa-Petrusewicz I, Zerres K 1998. Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I–III from the point of view of progression and severity. Eur. Neurol. 39:154–62
    [Google Scholar]
  150. 150. 
    Ruiz R, Casanas JJ, Torres-Benito L, Cano R, Tabares L 2010. Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice. J. Neurosci. 30:849–57
    [Google Scholar]
  151. 151. 
    Rutkove SB, Shefner JM, Gregas M, Butler H, Caracciolo J et al. 2010. Characterizing spinal muscular atrophy with electrical impedance myography. Muscle Nerve 42:915–21
    [Google Scholar]
  152. 152. 
    Sanchez G, Dury AY, Murray LM, Biondi O, Tadesse H et al. 2013. A novel function for the survival motoneuron protein as a translational regulator. Hum. Mol. Genet. 22:668–84
    [Google Scholar]
  153. 153. 
    Schmutz J, Martin J, Terry A, Couronne O, Grimwood J et al. 2004. The DNA sequence and comparative analysis of human chromosome 5. Nature 431:268–74
    [Google Scholar]
  154. 154. 
    Schorling DC, Becker J, Pechmann A, Langer T, Wirth B, Kirschner J 2019. Discrepancy in redetermination of SMN2 copy numbers in children with SMA. Neurology 93:267–69
    [Google Scholar]
  155. 155. 
    Schrank B, Gotz R, Gunnersen JM, Ure JM, Toyka KV et al. 1997. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. PNAS 94:9920–25
    [Google Scholar]
  156. 156. 
    Sen A, Dimlich DN, Guruharsha KG, Kankel MW, Hori K et al. 2013. Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy. PNAS 110:E2371–80
    [Google Scholar]
  157. 157. 
    Seo J, Singh NN, Ottesen EW, Lee BM, Singh RN 2016. A novel human-specific splice isoform alters the critical C-terminus of Survival Motor Neuron protein. Sci. Rep. 6:30778
    [Google Scholar]
  158. 158. 
    Singh NK, Singh NN, Androphy EJ, Singh RN 2006. 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. 26:1333–46
    [Google Scholar]
  159. 159. 
    Singh RN, Howell MD, Ottesen EW, Singh NN 2017. Diverse role of survival motor neuron protein. Biochim. Biophys. Acta Gene Regul. Mech. 1860:299–315
    [Google Scholar]
  160. 160. 
    Singh RN, Singh NN. 2018. Mechanism of splicing regulation of spinal muscular atrophy genes. Adv. Neurobiol. 20:31–61
    [Google Scholar]
  161. 161. 
    Skordis LA, Dunckley MG, Yue B, Eperon IC, Muntoni F 2003. Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. PNAS 100:4114–19
    [Google Scholar]
  162. 162. 
    Sleigh JN, Gillingwater TH, Talbot K 2011. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis. Models Mech. 4:457–67
    [Google Scholar]
  163. 163. 
    Snyder BR, Gray SJ, Quach ET, Huang JW, Leung CH et al. 2011. Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Hum. Gene Ther. 22:1129–35
    [Google Scholar]
  164. 164. 
    Sumner CJ, Paushkin S, Ko C-P 2017. Spinal Muscular Atrophy: Disease Mechanisms and Therapy London: Academic
  165. 165. 
    Sun Y, Grimmler M, Schwarzer V, Schoenen F, Fischer U, Wirth B 2005. Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum. Mutat. 25:64–71
    [Google Scholar]
  166. 166. 
    Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, Aebischer J et al. 2012. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology 62:2346–52
    [Google Scholar]
  167. 167. 
    Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC et al. 2005. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann. Neurol. 57:704–12
    [Google Scholar]
  168. 168. 
    Tisdale S, Pellizzoni L. 2015. Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J. Neurosci. 35:8691–700
    [Google Scholar]
  169. 169. 
    Torres-Benito L, Schneider S, Rombo R, Ling KK, Grysko V et al. 2019. NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorates spinal muscular atrophy in mice. Am. J. Hum. Genet. 105:221–30
    [Google Scholar]
  170. 170. 
    Tsai LK, Chen CL, Ting CH, Lin-Chao S, Hwu WL et al. 2014. Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice. Mol. Ther. 22:1450–59
    [Google Scholar]
  171. 171. 
    Van Alstyne M, Lotti F, Dal Mas A, Area-Gomez E, Pellizzoni L 2018. Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development. Biochem. Biophys. Res. Commun. 506:463–70
    [Google Scholar]
  172. 172. 
    van der Steege G, Grootscholten PM, Cobben JM, Zappata S, Scheffer H et al. 1996. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am. J. Hum. Genet. 59:834–38
    [Google Scholar]
  173. 173. 
    Verhaart IEC, Robertson A, Leary R, McMacken G, Konig K et al. 2017. A multi-source approach to determine SMA incidence and research ready population. J. Neurol. 264:1465–73
    [Google Scholar]
  174. 174. 
    Vidal-Folch N, Milosevic D, Majumdar R, Gavrilov D, Matern D et al. 2017. A droplet digital PCR method for severe combined immunodeficiency newborn screening. J. Mol. Diagn. 19:755–65
    [Google Scholar]
  175. 175. 
    Vill K, Kölbel H, Schwartz O, Blaschek A, Olgemöller B et al. 2019. One year of newborn screening for SMA – results of a German pilot project. J. Neuromuscul. Dis. 6:503–15
    [Google Scholar]
  176. 176. 
    Villalón E, Kline RA, Smith CE, Lorson ZC, Osman EY et al. 2019. AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy. Hum. Mol. Genet. 28:3742–54
    [Google Scholar]
  177. 177. 
    Vitte JM, Davoult B, Roblot N, Mayer M, Joshi V et al. 2004. Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload. Am. J. Pathol. 165:1731–41
    [Google Scholar]
  178. 178. 
    Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A et al. 2007. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22:1027–49
    [Google Scholar]
  179. 179. 
    Winkler C, Eggert C, Gradl D, Meister G, Giegerich M et al. 2005. Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev 19:2320–30
    [Google Scholar]
  180. 180. 
    Wirth B. 2000. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum. Mutat. 15:228–37
    [Google Scholar]
  181. 181. 
    Wirth B, Brichta L, Schrank B, Lochmuller H, Blick S et al. 2006. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum. Genet. 119:422–28
    [Google Scholar]
  182. 182. 
    Wirth B, Garbes L, Riessland M 2013. How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches. Curr. Opin. Genet. Dev. 23:330–38
    [Google Scholar]
  183. 183. 
    Wirth B, Herz M, Wetter A, Moskau S, Hahnen E et al. 1999. Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am. J. Hum. Genet. 64:1340–56
    [Google Scholar]
  184. 184. 
    Wirth B, Mendoza-Ferreira N, Torres-Benito L 2017. Spinal muscular atrophy disease modifiers. See Ref. 164 191–210
  185. 185. 
    Wirth B, Schmidt T, Hahnen E, Rudnik-Schoneborn S, Krawczak M et al. 1997. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling. Am. J. Hum. Genet. 61:1102–11
    [Google Scholar]
  186. 186. 
    Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G et al. 2014. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. J. Clin. Investig. 124:1821–34
    [Google Scholar]
  187. 187. 
    Woo CJ, Maier VK, Davey R, Brennan J, Li G et al. 2017. Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy. PNAS 114:E1509–18
    [Google Scholar]
  188. 188. 
    Zalneraitis EL, Halperin JJ, Grunnet ML, Russman BS, Peress N 1991. Muscle biopsy and the clinical course of infantile spinal muscular atrophy. J. Child Neurol. 6:324–28
    [Google Scholar]
  189. 189. 
    Zerres K, Rudnik-Schoneborn S. 1995. Natural history in proximal spinal muscular atrophy: clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch. Neurol. 52:518–23
    [Google Scholar]
  190. 190. 
    Zerres K, Rudnik-Schoneborn S, Forkert R, Wirth B 1995. Genetic basis of adult-onset spinal muscular atrophy. Lancet 346:1162
    [Google Scholar]
  191. 191. 
    Zerres K, Rudnik-Schoneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-Petrusewicz I 1997. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J. Neurol. Sci. 146:67–72
    [Google Scholar]
  192. 192. 
    Zhang Z, Pinto AM, Wan L, Wang W, Berg MG et al. 2013. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. PNAS 110:19348–53
    [Google Scholar]
/content/journals/10.1146/annurev-genom-102319-103602
Loading
/content/journals/10.1146/annurev-genom-102319-103602
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error