Human Genetics

, Volume 119, Issue 4, pp 422–428 | Cite as

Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number

  • B. Wirth
  • L. Brichta
  • B. Schrank
  • H. Lochmüller
  • S. Blick
  • A. Baasner
  • R. Heller
Original Investigation


Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by loss of the SMN1 gene. The clinical distinction between SMA type I to IV reflects different age of onset and disease severity. SMN2, a nearly identical copy gene of SMN1, produces only 10% of full-length SMN RNA/protein and is an excellent target for a potential therapy. Several clinical trials with drugs that increase the SMN2 expression such as valproic acid and phenylbutyrate are in progress. Solid natural history data for SMA are crucial to enable a correlation between genotype and phenotype as well as the outcome of therapy. We provide genotypic and phenotypic data from 115 SMA patients with type IIIa (age of onset <3 years), type IIIb (age of onset >3 years) and rare type IV (onset >30 years). While 62% of type IIIa patients carry two or three SMN2 copies, 65% of type IIIb patients carry four or five SMN2 copies. Three type IV SMA patients had four and one had six SMN2 copies. Our data support the disease-modifying role of SMN2 leading to later onset and a better prognosis. A statistically significant correlation for ≥4 SMN2 copies with SMA type IIIb or a milder phenotype suggests that SMN2 copy number can be used as a clinical prognostic indicator in SMA patients. The additional case of a foetus with homozygous SMN1 deletion and postnatal measurement of five SMN2 copies illustrates the role of genotypic information in making informed decisions on the management and therapy of such patients.


Spinal muscular atrophy (SMA) Survival motor neuron (SMN) Quantification of SMN2 Natural history 



We are grateful to all SMA families and clinicians who contributed to this work. We are grateful to Yun Li for statistical advice. This study has been supported by grants from the Deutsche Forschungsgemeinschaft, Families of SMA and Center for Molecular Medicine Cologne. HL is member of the German network on muscular dystrophies (MD-NET; 01GM0302), funded by the German Ministry of Education and Research.


  1. Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, Villanova M, Bertini E, Pini A, Neri G, Brahe C (2004) Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet 12:59–65CrossRefPubMedGoogle Scholar
  2. Brahe C, Zappata S, Velona I, Bertini E, Servidei S, Tonali P, Neri G (1993) Presymptomatic diagnosis of SMA III by genotype analysis. Am J Med Genet 45:408–411CrossRefPubMedGoogle Scholar
  3. Brahe C, Servidei S, Zappata S, Ricci E, Tonali P, Neri G (1995) Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 346:741–742CrossRefPubMedGoogle Scholar
  4. Brahe C, Vitali T, Tiziano FD, Angelozzi C, Pinto AM, Borgo F, Moscato U, Bertini E, Mercuri E, Neri G (2005) Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Eur J Hum Genet 13:256–259CrossRefPubMedGoogle Scholar
  5. Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B (2003) Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet 12:2481–2489CrossRefPubMedGoogle Scholar
  6. Brichta L, Haug K, Sun Y, Stier S, Klockgether T, Wirth B (2004) Pilot study of in-vivo effects of valproic acid on SMN gene expression in SMA carriers. Eur J Hum Genet 1(Suppl 1):5Google Scholar
  7. Burghes AH (1997) When is a deletion not a deletion? When it is converted. Am J Hum Genet 61:9–15PubMedCrossRefGoogle Scholar
  8. Clermont O, Burlet P, Lefebvre S, Burglen L, Munnich A, Melki J (1995) SMN gene deletions in adult-onset spinal muscular atrophy. Lancet 346:1712–1713CrossRefPubMedGoogle Scholar
  9. Cobben JM, van der Steege G, Grootscholten P, de Visser M, Scheffer H, Buys CH (1995) Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet 57:805–808PubMedGoogle Scholar
  10. Cusin V, Clermont O, Gerard B, Chantereau D, Elion J (2003) Prevalence of SMN1 deletion and duplication in carrier and normal populations: implication for genetic counselling. J Med Genet 40:E39CrossRefPubMedGoogle Scholar
  11. DiDonato CJ, Ingraham SE, Mendell JR, Prior TW, Lenard S, Moxley RT III, Florence J, Burghes AH (1997) Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity? Ann Neurol 41:230–237CrossRefPubMedGoogle Scholar
  12. 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 70:358–368CrossRefPubMedGoogle Scholar
  13. Gennarelli M, Lucarelli M, Capon F, Pizzuti A, Merlini L, Angelini C, Novelli G, Dallapiccola B (1995) Survival motor neuron gene transcript analysis in muscles from spinal muscular atrophy patients. Biochem Biophys Res Commun 213:342–348CrossRefPubMedGoogle Scholar
  14. Hahnen E, Forkert R, Marke C, Rudnik-Schoneborn S, Schonling J, Zerres K, Wirth B (1995) Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum Mol Genet 4:1927–1933PubMedCrossRefGoogle Scholar
  15. 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 59:1057–1065PubMedGoogle Scholar
  16. Helmken C, Hofmann Y, Schoenen F, Oprea G, Raschke H, Rudnik-Schoneborn S, Zerres K, Wirth B (2003) Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. Hum Genet 114:11–21CrossRefPubMedGoogle Scholar
  17. Kerr DA, Nery JP, Traystman RJ, Chau BN, Hardwick JM (2000) Survival motor neuron protein modulates neuron-specific apoptosis. Proc Natl Acad Sci USA 97:13312–13317CrossRefPubMedGoogle Scholar
  18. Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GJ, Burghes AH (2005) SMNDelta7, 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 14:845–857CrossRefPubMedGoogle Scholar
  19. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165CrossRefPubMedGoogle Scholar
  20. Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AH, Prior TW (2002) Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 4:20–26PubMedCrossRefGoogle Scholar
  21. Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossol W, Prior TW, Morris GE, Burghes AH (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 9:333–339CrossRefPubMedGoogle Scholar
  22. Munsat TL, Davies KE (1992) International SMA consortium meeting. (26–28 June 1992, Bonn, Germany). Neuromuscul Disord 2:423–428PubMedCrossRefGoogle Scholar
  23. Ogino S, Gao S, Leonard DG, Paessler M, Wilson RB (2003) Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1. Eur J Hum Genet 11:275–277CrossRefPubMedGoogle Scholar
  24. Pearn J (1978) Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet 15:409–413PubMedCrossRefGoogle Scholar
  25. Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ (2004) Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet 130A:307–310CrossRefPubMedGoogle Scholar
  26. Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP, Fischbeck KH (2003) Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol 54:647–654CrossRefPubMedGoogle Scholar
  27. van der Steege G, Grootscholten PM, Cobben JM, Zappata S, Scheffer H, den Dunnen JT, van Ommen GJ, Brahe C, Buys CH (1996) Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am J Hum Genet 59:834–838PubMedGoogle Scholar
  28. Vitali T, Sossi V, Tiziano F, Zappata S, Giuli A, Paravatou-Petsotas M, Neri G, Brahe C (1999) Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients. Hum Mol Genet 8:2525–2532CrossRefPubMedGoogle Scholar
  29. Vyas S, Bechade C, Riveau B, Downward J, Triller A (2002) Involvement of survival motor neuron (SMN) protein in cell death. Hum Mol Genet 11:2751–2764CrossRefPubMedGoogle Scholar
  30. Wang CH, Xu J, Carter TA, Ross BM, Dominski MK, Bellcross CA, Penchaszadeh GK, Munsat TL, Gilliam TC (1996) Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. Hum Mol Genet 5:359–365CrossRefPubMedGoogle Scholar
  31. 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 15:228–237CrossRefPubMedGoogle Scholar
  32. Wirth B (2002) Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. Amyotroph Lateral Scler Other Motor Neuron Disord 3:87–95CrossRefPubMedGoogle Scholar
  33. Wirth B, Hahnen E, Morgan K, DiDonato CJ, Dadze A, Rudnik-Schoneborn S, Simard LR, Zerres K, Burghes AH (1995) Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. Hum Mol Genet 4:1273–1284PubMedCrossRefGoogle Scholar
  34. Wirth B, Schmidt T, Hahnen E, Rudnik-Schoneborn S, Krawczak M, Muller-Myhsok B, Schonling J, Zerres K (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 61:1102–1111CrossRefPubMedGoogle Scholar
  35. Wirth B, Herz M, Wetter A, Moskau S, Hahnen E, Rudnik-Schoneborn S, Wienker T, Zerres K (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 64:1340–1356CrossRefPubMedGoogle Scholar
  36. 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 52:518–523PubMedGoogle Scholar
  37. Zerres K, Rudnik-Schoneborn S, Forkert R, Wirth B (1995) Genetic basis of adult-onset spinal muscular atrophy. Lancet 346:1162CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • B. Wirth
    • 1
    • 2
    • 3
  • L. Brichta
    • 1
    • 2
  • B. Schrank
    • 4
  • H. Lochmüller
    • 5
  • S. Blick
    • 1
  • A. Baasner
    • 1
  • R. Heller
    • 1
  1. 1.Institute of Human GeneticsUniversity of CologneCologneGermany
  2. 2.Institute of GeneticsUniversity of CologneCologneGermany
  3. 3.Center for Molecular Medicine CologneUniversity of CologneCologneGermany
  4. 4.Stiftung Deutsche Klinik für DiagnostikWiesbadenGermany
  5. 5.Department of NeurologyFriedrich-Baur-InstitutMünchenGermany

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