CNS Drugs

, Volume 33, Issue 3, pp 239–250 | Cite as

Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis

  • Abdelrahman Elshafay
  • Truong Hong Hieu
  • Mohamed Fahmy Doheim
  • Mahmoud Attia Mohamed Kassem
  • Mohammed Fathi ELdoadoa
  • Sarah Keturah Holloway
  • Heba Abo-elghar
  • Kenji Hirayama
  • Nguyen Tien HuyEmail author
Systematic Review



Spinal muscular atrophy (SMA) is a neuromuscular disorder classified into four types based on the age of onset of the disease. Early onset is correlated with a higher mortality rate, mainly due to respiratory complications. Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor that has shown positive results on SMA both in experimental and cohort studies.


This systematic review and meta-analysis aimed to investigate the efficacy and safety of VPA in patients with SMA.


Eleven databases were systematically searched on 30 May 2017 for clinical trials that reported the efficacy and safety of VPA in SMA patients. The primary outcome was the efficacy of VPA in terms of gross motor function and expression of both full-length spinal motor neuron (SMN) gene (FL-SMN) and exon 7-lacking SMN. The secondary outcome was the safety of VPA in terms of reported adverse effects. The protocol was registered at PROSPERO (CRD42017067203).


Five of the ten included studies were used in the meta-analysis (n = 126). The overall effect estimate, comparing pre- and post-VPA treatment, regardless of carnitine co-administration and design of the studies, showed significant improvement in gross motor function (standard mean difference [SMD] = 0.302, 95% confidence interval [CI] 0.048–0.556, P = 0.02) using the Hammersmith Functional Motor Scale (HFMS), Modified Hammersmith Functional Motor Scale (MHFMS), and MHFMS-Extend, with no significant heterogeneity. Similarly, in non-randomized controlled studies, the results indicated that there was a significant improvement detected (SMD = 0.335, 95% CI 0.041–0.628, P = 0.025), with no significant heterogeneity. Meanwhile, our results suggest that there was no significant improvement in treatment with co-administered carnitine (SMD = 0.28, 95% CI − 0.02 to 0.581, P = 0.067). No significant differences were found between pre- and post-VPA treatment co-administered with carnitine, in terms of the change in FL-SMN and exon 7-lacking SMN. Qualitative synthesis showed that other motor functions were not improved, while respiratory function test results were contradictory. Regarding the safety of the treatment, a double-blind, randomized, placebo-controlled trial reported no statistically significant differences for adverse events (AEs) between groups. Moreover, most of the included studies reported no serious AEs related to VPA use, although weight gain, gastrointestinal symptoms and respiratory symptoms were notable problems.


Our study suggests that VPA treatment results in an improvement in gross motor functions for SMA patients, but not in other assessments of motor function or, possibly, in respiratory function. Furthermore, VPA appears to be a relatively safe drug, although treatment may be associated with a wide range of AEs (including body weight increase, fatigue, fever, flu-like symptoms, irritability, and pain). Double-blind, randomized, controlled trials are required to confirm these findings.



This study was conducted (in part) at the Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine, Nagasaki University, Japan.

Compliance with Ethical Standards


No funding was received for preparation of this article.

Conflict of interests

All authors, AE, THH, MFD, MAMK, MFE, SKH, HA, KH, and NTH, declare no competing interests.

Supplementary material

40263_2019_606_MOESM1_ESM.pdf (99 kb)
Supplementary material 1 (PDF 98 kb)


  1. 1.
    Tizzano EF, Zafeiriou D. Prenatal aspects in spinal muscular atrophy: from early detection to early presymptomatic intervention. Eur J Paediatr Neurol 2018;22(6):944–50.Google Scholar
  2. 2.
    Govoni A, et al. Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy. Mol Neurobiol. 2018;55(8):6307–18.Google Scholar
  3. 3.
    Verhaart IEC, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy—a literature review. Orphanet J Rare Dis. 2017;12(1):124.Google Scholar
  4. 4.
    Mostacciuolo ML, et al. Epidemiology of spinal muscular atrophies in a sample of the Italian population. Neuroepidemiology. 1992;11(1):34–8.Google Scholar
  5. 5.
    Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228–37.Google Scholar
  6. 6.
    Howell MD, Singh NN, Singh RN. Advances in therapeutic development for spinal muscular atrophy. Future Med Chem. 2014;6(9):1081–99.Google Scholar
  7. 7.
    Russman BS. Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol. 2007;22(8):946–51.Google Scholar
  8. 8.
    Arnold WD, Burghes AHM. Spinal muscular atrophy: development and implementation of potential treatments. Ann Neurol. 2013;74(3):348–62.Google Scholar
  9. 9.
    Lefebvre S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65.Google Scholar
  10. 10.
    Melki J, et al. Prenatal prediction of Werdnig-Hoffmann disease using linked polymorphic DNA probes. J Med Genet. 1992;29(3):171–4.Google Scholar
  11. 11.
    Brzustowicz L, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2–13.3. Nature. 1990;344(6266):540.Google Scholar
  12. 12.
    Hahnen E, et al. 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. 1995;4(10):1927–33.Google Scholar
  13. 13.
    Finkel RS, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017–26.Google Scholar
  14. 14.
    Corey DR. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat Neurosci. 2017;20(4):497.Google Scholar
  15. 15.
    Kernochan LE, et al. The role of histone acetylation in SMN gene expression. Hum Mol Genet. 2005;14(9):1171–82.Google Scholar
  16. 16.
    Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695–714.Google Scholar
  17. 17.
    Balfour JA, Bryson HM. Valproic acid. CNS Drugs. 1994;2(2):144–73.Google Scholar
  18. 18.
    Löscher W. Basic pharmacology of valproate. CNS Drugs. 2002;16(10):669–94.Google Scholar
  19. 19.
    Sumner CJ, et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol Off J Am Neurol Assoc Child Neurol Soc. 2003;54(5):647–54.Google Scholar
  20. 20.
    Brichta L, et al. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet. 2003;12(19):2481–9.Google Scholar
  21. 21.
    Tsai L-K, et al. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy. Neurobiol Dis. 2006;24(2):286–95.Google Scholar
  22. 22.
    Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. 2006;67(3):500–1.Google Scholar
  23. 23.
    Tsai LK, et al. Valproic acid treatment in six patients with spinal muscular atrophy. Eur J Neurol. 2007;14(12):e8–9.Google Scholar
  24. 24.
    Liberati A, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;21(339):b2700.Google Scholar
  25. 25.
    Fleiss JL, Levin B, Paik MC. Statistical methods for rates and proportions, 3rd edn. Hoboken: John Wiley & Sons; 2013.Google Scholar
  26. 26.
    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33(1):159–74.Google Scholar
  27. 27.
    Higgins JPT, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.Google Scholar
  28. 28.
    Sterne JAC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.Google Scholar
  29. 29.
    Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions, vol. 4. New York: Wiley; 2011.Google Scholar
  30. 30.
    Wan X, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14(1):135.Google Scholar
  31. 31.
    Balk EM, et al. AHRQ methods for effective health care. In: Empirical assessment of within-arm correlation imputation in trials of continuous outcomes. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012.Google Scholar
  32. 32.
    Brichta L, et al. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann Neurol. 2006;59(6):970–5.Google Scholar
  33. 33.
    Darbar IA, et al. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol. 2011;11(1):36.Google Scholar
  34. 34.
    Kissel JT, et al. SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle Nerve. 2014;49(2):187–92.Google Scholar
  35. 35.
    Kissel JT, et al. SMA carni-VAL trial part II: a prospective, single-armed trial of l-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011;6(7):e21296.Google Scholar
  36. 36.
    Piepers S, et al. Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid. J Neurol Neurosurg Psychiatry. 2011;82(8):850–2.Google Scholar
  37. 37.
    Renusch SR, et al. Spinal Muscular Atrophy biomarker measurements from blood samples in a clinical trial of valproic acid in ambulatory adults. J Neuromuscul Dis. 2015;2(2):119–30.Google Scholar
  38. 38.
    Saito T, et al. A Study of valproic acid for patients with spinal muscular atrophy. Neurol Clin Neurosci. 2015;3(2):49–57.Google Scholar
  39. 39.
    Swoboda KJ, et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010;5(8):e12140.Google Scholar
  40. 40.
    Swoboda KJ, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One. 2009;4(5):e5268.Google Scholar
  41. 41.
    Krosschell KJ, et al. Clinical trial of l-carnitine and valproic acid in spinal muscular atrophy type I. Muscle Nerve. 2018;57(2):193–9.Google Scholar
  42. 42.
    Krosschell KJ, et al. Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy. Muscle Nerve. 2011;44(2):246–51.Google Scholar
  43. 43.
    Sumner CJ, et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol. 2003;54(5):647–54.Google Scholar
  44. 44.
    Sugai F, et al. Benefit of valproic acid in suppressing disease progression of ALS model mice. Eur J Neurosci. 2004;20(11):3179–83.Google Scholar
  45. 45.
    Bezkorovainy A. Carnosine, carnitine, and Vladimir Gulevich. J Chem Educ. 1974;51:652–4.Google Scholar
  46. 46.
    Winter BK, Fiskum G, Gallo LL. Effects of l-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock. Br J Cancer. 1995;72:1173–9.Google Scholar
  47. 47.
    Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47:101–11.Google Scholar
  48. 48.
    Silva MF, Aires CC, Luis PB. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation. A review. J Inherit Metabol Dis. 2008;31:205–16.Google Scholar
  49. 49.
    Kang S-W, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil. 2000;79(3):222–7.Google Scholar
  50. 50.
    Crawford TO, et al. Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol. 1999;45(3):337–43.Google Scholar
  51. 51.
    Tein I, et al. Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)? Pediatr Neurol. 1995;12(1):21–30.Google Scholar
  52. 52.
    Coulter D. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet. 1984;323(8378):689.Google Scholar
  53. 53.
    Garbes L, et al. VPA response in SMA is suppressed by the fatty acid translocase CD36. Hum Mol Genet. 2013;22(2):398–407.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculty of MedicineAl-Azhar UniversityCairoEgypt
  2. 2.Faculty of MedicineUniversity of Medicine of Pharmacy at Ho Chi Minh CityHo Chi Minh CityVietnam
  3. 3.Faculty of MedicineAlexandria UniversityAlexandriaEgypt
  4. 4.The Ohio State University Wexner Medical CenterColumbusUSA
  5. 5.Faculty of MedicineMansoura UniversityMansouraEgypt
  6. 6.University of North TexasDentonUSA
  7. 7.Faculty of MedicineMenofia UniversityMenofiaEgypt
  8. 8.Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan
  9. 9.Evidence Based Medicine Research GroupTon Duc Thang UniversityHo Chi Minh CityVietnam
  10. 10.Faculty of Applied SciencesTon Duc Thang UniversityHo Chi Minh CityVietnam
  11. 11.Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global HealthNagasaki UniversityNagasakiJapan

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