Spinal Muscular Atrophy (SMA): Clinical Characteristics, Molecular Mechanisms and Treatment

Gokhan Gorgisen (Author)

Release Date:

Spinal Muscular Atrophy (SMA) is an otosomal recessive genetic disorder characterized by the degeneration of motor neurons, leading to muscle weakness and atrophy. It is predominantly caused by mutations or deletions in the SMN1 gene, resulting in insufficient levels of functional SMN protein, which is crucial for motor neuron survival and function. The clinical presentation [...]

Media Type
    Buy from

    Price may vary by retailers

    Work TypeBook Chapter
    Published inMolecular Approaches in Medicine
    First Page153
    Last Page170
    DOIhttps://doi.org/10.69860/nobel.9786053359524.8
    Page Count18
    Copyright HolderNobel Tıp Kitabevleri
    Licensehttps://nobelpub.com/publish-with-us/copyright-and-licensing

    Spinal Muscular Atrophy (SMA) is an otosomal recessive genetic disorder characterized by the degeneration of motor neurons, leading to muscle weakness and atrophy. It is predominantly caused by mutations or deletions in the SMN1 gene, resulting in insufficient levels of functional SMN protein, which is crucial for motor neuron survival and function. The clinical presentation of SMA varies from severe infantile onset with early mortality (Type 0 and Type 1) to milder adult forms (Type 4). Phenotype of patients can be modified by SMN2 gene copy numbers. Molecular diagnosis of SMA involves genetic testing techniques like qPCR and MLPA to identify SMN1/2 gene mutations and deletions. Treatment options include FDA-approved therapies such as Nusinersen, Onasemnogene abeparvovec, and Risdiplam, which aim to increase SMN protein levels and improve patient outcomes, with early intervention being key to better prognosis.

    Gokhan Gorgisen (Author)
    Associate Professor, Van Yuzuncu Yil University
    https://orcid.org/0000-0001-6040-7863
    3Gökhan Görgişen is an Associate Professor at the Faculty of Medicine, Department of Medical Genetics at Van Yüzüncü Yıl University and cofounder of Genovan Genetics and Biotechnology R&D in Van, Turkey. With a robust background in medical genetics, he focuses on cancer biology, exploring mechanisms of oncogenesis, cancer cell signaling, and the implications of insulin receptor substrates in both cancer progression and diabetes. His research is pivotal in understanding molecular signaling pathways in cancer, and he is recognized for his innovative approach to cancer treatment and prevention and recipient of several research grants and prestigious awards including Prof Dr. Altan Günalp Research Award for his innovative works in the field of oncology.

    • Aasdev, A, R, S. S., Iyer, V.R., et al. (2024). Spinal muscular atrophy: Molecular mechanism of pathogenesis, diagnosis, therapeutics, and clinical trials in the Indian context. J Biosci., 49:36.

    • Angilletta, I., Ferrante, R., Giansante, R., et al. (2023). Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies. Int J Mol Sci., Oct 3, 24(19), 14873.

    • Angilletta, I., Ferrante, R., Giansante, R., et al. (2023). Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies., Int J Mol Sci., Oct 3, 24(19), 14873.

    • Arnold, W.D., Kassar, D., Kissel, J.T. (2015). Spinal muscular atrophy: Diagnosis and management in a new therapeutic era. Muscle Nerve, 51, 157–167

    • Audic, F., Barnerias, C. (2020). Spinal muscular atrophy (SMA) type I (WerdnigHoffmann disease). Arch. Pediatr., 27, 7S15–7S17

    • Burghes, A.H.M., Beattie, C.E. (2009). Spinal muscular atrophy: Why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci., 10, 597–609.

    • Burr, P., Reddivari, A.K.R. (2023). Spinal Muscle Atrophy. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA,

    • Butterfield, R.J. (2021). Spinal Muscular Atrophy Treatments, Newborn Screening, and the Creation of a Neurogenetics Urgency. Semin. Pediatr. Neurol., 38, 100899

    • Calucho, M., Bernal, S., Alı¢as, L., et al. (2018). Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation

    • Chiriboga, C.A. (2022). Pharmacotherapy for Spinal Muscular Atrophy in Babies and Children: A Review of Approved and Experimental Therapies. Paediatr. Drugs, 24, 585–602.

    • Chiriboga, C.A., Swoboda, K.J., Darras, B.T., et al. (2016a). Results from a phase 1 study of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy. Neurology, Mar 8, 86(10), 890-7.

    • Crawford, T.O., Swoboda, K.J., De Vivo, D.C., et al. (2023). Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle Nerve, 68, 157–170.

    • Custer, S.K., Todd, A.G., Singh, N.N., et al. (2013). Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle proteina α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy. Hum. Mol. Genet., 22, 4043–4052.

    • Day, J.W., Howell, K., Place, A., et al. (2022). Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatr., 22, 632.

    • De Vivo, D.C., Bertini, E., Swoboda, K.J., at al. (2019). 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

    • Emmady, P.D., Bodle, J. (2022) Werdnig Hoffmann disease. StatPearls

    • Fallini, C., Zhang, H., Su, Y., et al. (2011). The Survival of Motor Neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J. Neurosci., 31, 3914–3925.

    • Farrar, M.A., Park, S.B., Vucic, S., et al. (2017). Emerging therapies and challenges in spinal muscular atrophy. Ann. Neurol., 81:355–68.

    • Finkel, R., Bertini, E., Muntoni, F., et al. (2015). 209th ENMC international workshop: outcome measures and clinical trial readiness in spinal muscular atrophy. 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscul. Disord. 25, 593–602.

    • Finkel, R.S., Chiriboga, C.A., Vajsar, et al. (2021). Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc. Health, 5, 491–500.

    • Finkel, R.S., Chiriboga, C.A., Vajsar, J., et al. (2016). Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet, 388, 3017–3026.

    • Foust, K.D., Nurre, E., Montgomery, C.L., et al. (2009). Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol., 27, 59–65.

    • Glascock, J., Sampson, J., Haidet-Phillips, A., et al. (2018). Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. J. Neuromuscul. Dis., 5, 145–158

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

    • Harada, Y., Sutomo, R., Sadewa, A.H., et al. (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.

    • Hjartarson, H.T., Nathorst-Boos, K., Sejersen, T. (2022) Disease Modifying Therapies for the Management of Children with Spinal Muscular Atrophy (5q SMA): An Update on the Emerging Evidence. Drug Des. Dev. Ther., 16, 1865– 1883.

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

    • Jedrzejowska, M. (2020). Advances in Newborn Screening and Presymptomatic Diagnosis of Spinal Muscular Atrophy. Degener. Neurol. Neuromuscul. Dis., 10, 39–47.

    • Kakazu, J., Walker, N.L., Babin, K.C., et al. (2021). Risdiplam for the Use of Spinal Muscular Atrophy. Orthop Rev (Pavia)., Jul 12, 13(2), 25579.

    • Kaufmann, P., McDermott, M.P., Darras, B.T., et al. (2011). Observational study of spinal muscular atrophy type 2 and 3: Functional outcomes over 1 year. Arch. Neurol., 68, 779–786

    • Kotulska, K., Jozwiak, S. Jedrzejowska, M., et al. (2022). Newborn screening and gene therapy in SMA: Challenges related to vaccinations. Front Neurol., Nov 23, 13, 890860.

    • Li, H., Custer, S.K., Gilson, T., et al. (2015). α-COP binding to the survival motor neuron protein SMN is required for neuronal process outgrowth. Hum. Mol. Genet., 24, 7295–7307.

    • López-Cortés, A., Echeverría-Garcés, G., Ramos-Medina, M.J. (2022) Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy. Biology (Basel)., Jun 10;11(6):894.

    • Lowes, L.P., Alfano, L.N., Arnold, W.D., et al. (2019) Impact of Age and Motor Function in a Phase 1/2A Study of Infants with SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatr. Neurol., 98, 39–45.

    • Lunn, M.R.,Wang, C.H. (2008). Spinal muscular atrophy. Lancet, 371, 2120–2133

    • Luo, M., Liu, L., Peter, I., et al. (2014). An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet. Med., 16, 149–156.

    • Mahajan, R. (2019). Onasemnogene Abeparvovec for Spinal Muscular Atrophy: The Costlier Drug Ever. Int. J. Appl. Basic Med. Res., 9, 127–128.

    • Markati, T., Fisher, G., Ramdas, S., et al. (2022). Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA). Expert Opin Investig Drugs., May, 31(5), 451-461.

    • Mendell, J.R., Al-Zaidy, S., Shell, R., et al. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N. Engl. J. Med., 377, 1713–1722

    • Mercuri, E., Pera, M.C., Scoto, M., et al. (2020) Spinal muscular atrophy—Insights and challenges in the treatment era. Nat. Rev. Neurol., 16, 706–715.

    • Mercuri, E., Sumner, C.J., Muntoni, F. et al. (2022). Spinal muscular atrophy. Nat. Rev. Dis. Primers, 8, 52.

    • Messina, S., Sframeli, M., (2020). New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J Clin Med., Jul 13, 9(7), 2222.

    • Monine, M., Norris, D., Wang, Y., et al. (2021). A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration. J. Pharmacokinet. Pharmacodyn., 48, 639–654

    • of 2834 reported cases. Neuromuscul. Disord., 28, 208–215.

    • Pagliardini, S., Giavazzi, A., Setola, V. (2000). Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord. Hum. Mol. Genet. 9(1):47-56.

    • Paik, J., (2022). Risdiplam: A Review in Spinal Muscular Atrophy. CNS Drugs., Apr, 36(4), 401-410.

    • Panagiotou, P., Kanaka-Gantenbein, C., Kaditis, A.G. (2022) Changes in Ventilatory Support Requirements of Spinal Muscular Atrophy (SMA) Patients Post Gene-Based Therapies. Children, 9, 1207.

    • Phan, H.C., Taylor, J.L., Hannon, H., et al. (2015). Newborn screening for spinal muscular atrophy: Anticipating an imminent need. Semin. Perinatol., 39, 217–229

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

    • Ratni, H., Ebeling, M., Baird, 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, 6501–6517

    • Renvoisé, B., Quérol, G., Verrier, E.R., et al. (2012). A role for protein phosphatase PP1 in SMN complex formation and subnuclear localization to Cajal bodies. J. Cell Sci., 125, 2862–2874.

    • Rossoll, W., Jablonka, S., Andreassi, C., 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, 801–812.

    • Stabley, D.L., Holbrook, J., Scavina, M., et al. (2021) Detection of SMN1 to SMN2 gene conversion events and partial SMN1 gene deletions using array digital PCR. Neurogenetics, 22, 53–64

    • Strauss, K.A., Farrar, M.A., Muntoni, F., et al. (2022). Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy:

    • Takarada, T., Ar Rochmah, M., Harahap, N.I.F., et al. (2017). SMA mutations in SMN Tudor and C-terminal domains destabilize the protein. Brain Dev., 39, 606–612.

    • The Phase III SPR1NT trial. Nat. Med., 28, 1390–1397.

    • Torres-Benito, L., Neher, M.F., Cano, R.,et al. (2011). SMN requirement for synaptic vesicle, active zone and microtubule postnatal organization in motor nerve terminals. PLoS ONE, 6, e26164

    • Verhaart, I.E.C., Robertson, A. Wilson, I. et al. (2017a). Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy—A literature review. Orphanet J. Rare Dis., 12, 124.

    • Verhaart, I.E.C., Robertson, A., Leary, R.A. et al. (2017b). Multi-source approach to determine SMA incidence and research ready population. J. Neurol, 264, 1465– 1473

    • Vijzelaar, R., Snetselaar, R., Clausen, M., et al. (2019). The frequency of SMN gene variants lacking exon 7 and 8 is highly population dependent. PLoS One, 14, e0220211

    • Von Gontard, A., Zerres, K., Backes, M., et al. (2002) Intelligence and cognitive function in children and adolescents with spinal muscular atrophy. Neuromuscul. Disord., 12, 130–136.

    • Wadman, R.I., Van der Pol, W.L., Bosboom, W.M., et al. (2019). Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst. Rev., 12, CD006281.

    • Weber, T. (2021). Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions. Front. Immunol., 12, 658399

    • Will, C.L., Lührmann, R. (2011). Spliceosome structure and function. Cold Spring Harb. Perspect. Biol. Jul 1;3(7):a003707.

    • Wirth, B. (2021). Spinal muscular atrophy: in the challenge lies a solution. Trends Neurosci., 44, 306–322

    • Wirth, B., Karakaya, M., Kye, M.J., et al. (2020). Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu. Rev. Genom. Hum. Genet., 21, 231–261

    • Yamamoto, T., Sato, H., Lai, P.S., et al. (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.

    onix_3.0::thothThoth ONIX 3.0
    onix_3.0::project_museProject MUSE ONIX 3.0
    onix_3.0::oapenOAPEN ONIX 3.0
    onix_3.0::jstorJSTOR ONIX 3.0
    onix_3.0::google_booksGoogle Books ONIX 3.0
    onix_3.0::overdriveOverDrive ONIX 3.0
    onix_2.1::ebsco_hostEBSCO Host ONIX 2.1
    csv::thothThoth CSV
    json::thothThoth JSON
    kbart::oclcOCLC KBART
    bibtex::thothThoth BibTeX
    doideposit::crossrefCrossRef DOI deposit
    onix_2.1::proquest_ebraryProQuest Ebrary ONIX 2.1
    marc21record::thothThoth MARC 21 Record
    marc21markup::thothThoth MARC 21 Markup
    marc21xml::thothThoth MARC 21 XML

    Share This Chapter!