Spinal muscular atrophy: a perspective outlook

Background. Recent decades have witnessed a leap in understanding the molecular genetic bases of spinal muscular atrophy for a considerable improvement in diagnosis and treatment of this disease and development of innovative therapies for correcting genetic deficiencies. Given scarcity of etiotropic therapies for spinal muscular atrophy, traditional effective approaches remain relevant to target pathophysiological mechanisms of the disease progression and demand further development and improvement.

Objectives. Efficacy assessment of proactive therapy to spinal muscular atrophy based on electromyographic techniques using verifiable patient-specific functional scales.

Methods. The study is designed as a prospective cohort study conducted at the Republican Clinical Centre for Neurorehabilitation. We used a 15-year monitoring data on 95 children (66 boys and 29 girls) with genetically confirmed proximal spinal muscular atrophy. Patients were divided in two cohorts. The main cohort (65 children) received personalised therapy based on a proactive comprehensive stepwise approach to isolate a stem pathological pattern with clinical and electromyographic data. The comparison cohort (30 children) received conventional symptomatic therapy, including neurometabolic, cholinotropic drugs, classical massage and physiotherapy. In the study design, functional capacities and electromyographic data were estimated in a standardised time scheme with reference points («baseline», «1 year», «3 years», «5 years»).

Results. The proposed methodology for clinical and electromyographic data sampling at different points of the disease progression has yielded results. We registered a weaker pathological progression in the main cohort reflected by less pronounced motor deficiency and electromyographic pathology compared to the comparison group receiving conventional symptomatic therapy.

Conclusion. Dynamic monitoring of clinical and neurological disorders using modern assessment scales and extended electromyography of morbid motor markers enables a personalised proactive clinically justified treatment to suppress complications and manifestation of pathology.

1. Zabnenkova V.V., Dadali E.L., Polyakov A.V. Proximal spinal muscular atrophy types I–IV: Specific features of molecular genetic diagnosis. Neuromuscular Diseases. 2013; 3: 27–31 (In Russ., English abstract). DOI: 10.17650/2222-8721-2013-0-3-27-31

2. Kovalchuk M.O., Nikitin S.S. Research of neuromuscular pathology in Russia. Background and perspectives. Neuromuscular Diseases. 2015; 5(2): 55–58 (In Russ., English abstract). DOI: 10.17650/2222-87212015-5-2-55-58

3. Hamilton G., Gillingwater T.H. Spinal muscular atrophy: going beyond the motor neuron. Trends. Mol. Med. 2013; 19(1): 40–50. DOI: 10.1016/j.molmed.2012.11.002

4. Dubowitz V. Spinal Muscular Atrophy Revisited. Neuromuscul. Disord. 2019; 29(6): 413–414. DOI: 10.1016/j.nmd.2019.06.008

5. Gregoretti C., Ottonello G., Chiarini Testa M.B., Mastella C., Ravà L., Bignamini E., et al. Survival of patients with spinal muscular atrophy type 1. Pediatrics. 2013; 131(5): e1509–1514. DOI: 10.1542/peds.2012-2278

6. Vaidya S., Boes S. Measuring quality of life in children with spinal muscular atrophy: a systematic literature review. Qual. Life. Res. 2018; 27(12): 3087–3094. DOI: 10.1007/s11136-018-1945-x

7. Kaufmann P., McDermott M.P., Darras B.T., Finkel R.S., Sproule D.M., Kang P.B., et al.; Muscle Study Group (MSG); Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR). Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012; 79(18): 1889–1897. DOI: 10.1212/WNL.0b013e318271f7e4

8. Groenestijn A.C., Kruitwagen-van Reenen E.T., Visser-Meily J.M., Berg L.H., Schröder C.D. Associations between psychological factors and health-related quality of life and global quality of life in patients with ALS: a systematic review. Health Qual. Life Outcomes. 2016; 14(1): 107. DOI: 10.1186/s12955-0160507-6

9. Ross L.F., Kwon J.M. Spinal Muscular Atrophy: Past, Present, and Future. Neoreviews. 2019; 20(8): e437e451. DOI: 10.1542/neo.20-8-e437

10. Lorson C.L., Rindt H., Shababi M. Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum. Mol. Genet. 2010; 19(R1): R111–118. DOI: 10.1093/hmg/ddq147

11. Serra-Juhe C., Tizzano E.F. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur. J. Hum. Genet. 2019; 27(12): 1774–1782. DOI: 10.1038/s41431-019-0415-4

12. Mendell J.R., Al-Zaidy S., Shell R., Arnold W.D., Rodino-Klapac L.R., Prior T.W., et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 2017; 377(18): 1713–1722. DOI: 10.1056/NEJMoa1706198

13. Singh N.N., Lee B.M., DiDonato C.J., Singh R.N. Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy. Future. Med. Chem. 2015; 7(13): 1793–1808. DOI: 10.4155/fmc.15.101

14. Finkel R.S., Farwell W. Therapy for Spinal Muscular Atrophy. N. Engl. J. Med. 2018; 378(5): 487–488. DOI: 10.1056/NEJMc1715769

15. Darras B.T., Mammas I.N., Spandidos D.A. Spinal muscular atrophy, pediatric virology and gene therapy: A challenge of modern weakness and hope. Exp. Ther. Med. 2018;15(4): 3671–3672. DOI: 10.3892/etm.2018.5883

16. Finkel R.S., Mercuri E., Meyer O.H., Simonds A.K., Schroth M.K., Graham R.J., et al.; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018; 28(3): 197–207. DOI: 10.1016/j.nmd.2017.11.004

17. Saffari A., Weiler M., Hoffmann G.F., Ziegler A. Gene therapies for neuromuscular diseases. Nervenarzt. 2019; 90(8): 809–816. DOI: 10.1007/s00115-0190761-z.

18. Pulst S.M. Antisense therapies for neurological diseases. Nervenarzt. 2019; 90(8): 781–786. DOI: 10.1007/s00115-019-0724-4

19. High K.A., Roncarolo M.G. Gene Therapy. N. Engl. J. Med. 2019; 381(5): 455–464. DOI: 10.1056/NEJMra1706910