SpringerLink
Log in

Spinal muscular atrophy caused by compound heterozygous SMN1 mutations: two cases and literature review

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Spinal muscular atrophy (SMA) is a rare neuromuscular disease, which is characterized by the degeneration of motor neurons, leading to symmetrical muscle weakness and atrophy. Description of two novel SMN1 mutations (patient1: c.683T > A, p.Leu228Ter; patient2: c.347 T > C, p.Ile116 Thr). We reported two patients with SMN1 mutations with the clinical features, and provided a literature review of the previously reported 22 cases. Two SMA patients showed progressive proximal lower limb weakness and milder clinical symptom. In a total of 22 cases, the most commonly observed SMN1 gene alteration was missense mutation (55%), followed by splicing defect (27%), nonsense (9%) and frameshift (9%). We discuss the possible decisive role of these intragenic mutations in the phenotypic results, which enriched the SMN 1 fine mutation database.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

References

  1. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T (2018) Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord 28:103–115

    Article  PubMed  Google Scholar 

  2. Nurputra DK, Lai PS, Harahap NIF, Morikawa S, Yamamoto T, Nishimura N, Kubo Y, Takeuchi A, Saito T, Takeshima Y, Tohyama Y (2013) Spinal muscular atrophy: from gene discovery to clinical trials. Ann Hum Genet 77:435–463

    Article  CAS  PubMed  Google Scholar 

  3. Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller H (2017) Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis 12:124

    Article  PubMed  PubMed Central  Google Scholar 

  4. Arnold WD, Kassar D, Kissel JT (2015) Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 51:157–167

    Article  CAS  PubMed  Google Scholar 

  5. Lefebvre S, Bürglen 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 80:155–165

    Article  CAS  PubMed  Google Scholar 

  6. Lefebvre S, Burlet P, Viollet L, Bertrandy S, Huber C, Belser C, Munnich A (2002) A novel association of the SMN protein with two major non-ribosomal nucleolar proteins and its implication in spinal muscular atrophy. Hum Mol Genet 11:1017–1027

    Article  CAS  PubMed  Google Scholar 

  7. 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: Off J Am Coll Med Genet 4:20–26

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Singh RN (2007) Evolving concepts on human SMN pre-mRNA splicing. RNA Biol 4:7–10

    Article  CAS  PubMed  Google Scholar 

  10. Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR (2006) Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet 78:63–77

    Article  CAS  PubMed  Google Scholar 

  11. Elsheikh B, Prior T, Zhang X, Miller R, Kolb SJ, Moore D, Bradley W, Barohn R, Bryan W, Gelinas D, Iannaccone S, Leshner R, Mendell JR, Mendoza M, Russman B, Smith S, King W, Kissel JT (2009) An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy. Muscle Nerve 40:652–656

    Article  PubMed  Google Scholar 

  12. Qiu J, Wu L, Qu R, Jiang T, Bai J, Sheng L, Feng P, Sun J (2022) History of development of the life-saving drug Nusinersen in spinal muscular atrophy. Front Cell Neurosci 16:942976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

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

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bai J, Qu Y, Cao Y, Yang L, Ge L, ** Y, Wang H, Song F (2018) The SMN1 common variant c.22 dupA in Chinese patients causes spinal muscular atrophy by nonsense-mediated mRNA decay in humans. Gene 644:49–55

    Article  CAS  PubMed  Google Scholar 

  16. Kashima T, Manley JL (2003) A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet 34:460–463

    Article  CAS  PubMed  Google Scholar 

  17. Eggermann T, Eggermann K, Elbracht M, Zerres K, Rudnik-Schöneborn S (2008) A new splice site mutation in the SMN1 gene causes discrepant results in SMN1 deletion screening approaches, neuromuscular disorders. NMD 18:146–149

    PubMed  Google Scholar 

  18. Vezain M, Gérard B, Drunat S, Funalot B, Fehrenbach S, N’Guyen-Viet V, Vallat JM, Frébourg T, Tosi M, Martins A, Saugier-Veber P (2011) A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy. Hum Mutat 32:989–994

    Article  CAS  PubMed  Google Scholar 

  19. Bai J, Qu Y, Song F, Cao Y, Cheng M, Wang J, ** Y, Wang H (2021) Dual mechanism of a new SMN1 variant (c.835G > C, p.Gly279Arg) by interrupting exon 7 skip** and YG Oligomerization in Causation of spinal muscular atrophy. J Mol Neurosci 71:112–121

    Article  CAS  PubMed  Google Scholar 

  20. Fraidakis MJ, Drunat S, Maisonobe T, Gerard B, Pradat PF, Meininger V, Salachas F (2012) Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain. Neurology 78:551–556

    Article  CAS  PubMed  Google Scholar 

  21. Kirwin SM, Vinette KM, Gonzalez IL, Abdulwahed HA, Al-Sannaa N, Funanage VL (2013) A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA. Mol Genet Genom Med 1:113–117

    Article  CAS  Google Scholar 

  22. Qu YJ, Song F, Yang YL, ** YW, Bai JL (2011) Compound heterozygous mutation in two unrelated cases of Chinese spinal muscular atrophy patients. Chin Med J (Engl) 124:385–389

    CAS  PubMed  Google Scholar 

  23. Qu YJ, Bai JL, Cao YY, Zhang WH, Wang H, ** YW, Song F (2016) A rare variant (c.863G > T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy. Eur J Hum Genet 24:864–870

    Article  CAS  PubMed  Google Scholar 

  24. Ronchi D, Previtali SC, Sora MG, Barera G, Del Menico B, Corti S, Bresolin N, Comi GP (2015) Novel splice-site mutation in SMN1 associated with a very severe SMA-I phenotype. J Mol Neurosci 56:212–215

    Article  CAS  PubMed  Google Scholar 

  25. Wijaya YOS, Ar Rohmah M, Niba ETE, Morisada N, Noguchi Y, Hidaka Y, Ozasa S, Inoue T, Shimazu T, Takahashi Y, Tozawa T, Chiyonobu T, Inoue T, Shiroshita T, Yokoyama A, Okamoto K, Awano H, Takeshima Y, Saito T, Saito K, Nishio H, Shinohara M (2021) Phenotypes of SMA patients retaining SMN1 with intragenic mutation. Brain Dev 43:745–758

    Article  CAS  PubMed  Google Scholar 

  26. Yamamoto T, Sato H, Lai PS, Nurputra DK, Harahap NI, Morikawa S, Nishimura N, Kurashige T, Ohshita T, Nakajima H, Yamada H, Nishida Y, Toda S, Takanashi J, Takeuchi A, Tohyama Y, Kubo Y, Saito K, Takeshima Y, Matsuo M, Nishio H (2014) Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients. Brain Dev 36:914–920

    Article  PubMed  Google Scholar 

  27. Takarada T, Ar Rochmah M, Harahap NIF, Shinohara M, Saito T, Saito K, Lai PS, Bouike Y, Takeshima Y, Awano H, Morioka I, Iijima K, Nishio H, Takeuchi A (2017) SMA mutations in SMN Tudor and C-terminal domains destabilize the protein. Brain Dev 39:606–612

    Article  PubMed  Google Scholar 

  28. Kolb SJ, Kissel JT (2015) Spinal muscular atrophy. Neurol Clin 33:831–846

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zerres K, Rudnik-Schöneborn 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

    Article  CAS  PubMed  Google Scholar 

  30. Zerres K, Rudnik-Schöneborn S (1995) Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 52:518–523

    Article  CAS  PubMed  Google Scholar 

  31. Xu Y, **ao B, Liu Y, Qu XX, Dai MY, Ying XM, Jiang WT, Zhang JM, Liu XQ, Chen YW, Ji X (2020) Identification of novel SMN1 subtle mutations using an allelic-specific RT-PCR. Neuromuscul Disord 30:219–226

    Article  PubMed  Google Scholar 

  32. Zeng J, Lin Y, Yan A, Ke L, Zhu Z, Lan F (2011) Establishment of a molecular diagnostic system for spinal muscular atrophy experience from a clinical laboratory in China. J Mol Diagn 13:41–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yu-** Q, Juan D, Er-zhen L, **-li B, Yu-wei J, Hong W, Fang S (2012) Subtle mutations in the SMN1 gene in Chinese patients with SMA: p.Arg288Met mutation causing SMN1 transcript exclusion of exon7. BMC Med Genet 13:86

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bai JL, Qu YJ, Cao YY, Li EZ, Wang LW, Li Y, Zhu YL, Zhang WH, ** YW, Wang H, Song F (2014) Subtle mutation detection of SMN1 gene in Chinese spinal muscular atrophy patients: implication of molecular diagnostic procedure for SMN1 gene mutations. Genetic Test Mol Biomark 18:546–551

    Article  CAS  Google Scholar 

  35. Kimizu, Tomokazu et al (2021) Spinal Muscular Atrophy: Diagnosis, Incidence, and Newborn Screening in Japan. International journal of neonatal screening 7(3):45. https://doi.org/10.3390/ijns7030045

  36. Raimer, Amanda C et al (2020) Temperature-sensitive spinal muscular atrophy-causing point mutations lead to SMN instability, locomotor defects and premature lethality in Drosophila. Disease models & mechanisms 13(5):dmm043307. https://doi.org/10.1242/dmm.043307

  37. Zhang H, **ng L, Singer RH, Bassell GJ (2007) QNQKE targeting motif for the SMN-Gemin multiprotein complexin neurons. J Neurosci Res 85:2657–2667

    Article  CAS  PubMed  Google Scholar 

  38. Martin R, Gupta K, Ninan NS, Perry K, Van Duyne GD (2012) The survival motor neuron protein forms soluble glycine zipper oligomers. Structure (London, England: 1993) 20:1929–1939

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Neurology, Sheng**g Hospital of China Medical University, Shenyang, Liaoning, 110000, China

    Yuewei Chi, Yue Qiao & Ying Ma

Authors
  1. Yuewei Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. YC: subject design and writing—original draft. YQ: investigation. YM: conceptualization, supervision, and funding acquisition—reviewing and editing. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Ying Ma.

Ethics declarations

Ethical approval

None.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chi, Y., Qiao, Y. & Ma, Y. Spinal muscular atrophy caused by compound heterozygous SMN1 mutations: two cases and literature review. Neurol Sci (2024). https://doi.org/10.1007/s10072-024-07651-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10072-024-07651-0

Keywords

Search

Navigation