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



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.

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  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.

    Article  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.

    CAS  Article  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.

    Article  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  7. 7.

    Russman BS. Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol. 2007;22(8):946–51.

    Article  Google Scholar 

  8. 8.

    Arnold WD, Burghes AHM. Spinal muscular atrophy: development and implementation of potential treatments. Ann Neurol. 2013;74(3):348–62.

    CAS  Article  Google Scholar 

  9. 9.

    Lefebvre S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  14. 14.

    Corey DR. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat Neurosci. 2017;20(4):497.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  17. 17.

    Balfour JA, Bryson HM. Valproic acid. CNS Drugs. 1994;2(2):144–73.

    Article  Google Scholar 

  18. 18.

    Löscher W. Basic pharmacology of valproate. CNS Drugs. 2002;16(10):669–94.

    Article  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.

    CAS  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  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.

    Article  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.

    Article  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.

    CAS  Article  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.

    Article  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.

    Article  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.

    Article  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  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.

    Article  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.

    Article  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.

    CAS  Article  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.

    Article  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.

    Article  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.

    CAS  Article  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.

    Article  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.

    CAS  Article  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.

    Article  Google Scholar 

  45. 45.

    Bezkorovainy A. Carnosine, carnitine, and Vladimir Gulevich. J Chem Educ. 1974;51:652–4.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  47. 47.

    Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47:101–11.

    CAS  Article  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.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  50. 50.

    Crawford TO, et al. Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol. 1999;45(3):337–43.

    CAS  Article  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.

    CAS  Article  Google Scholar 

  52. 52.

    Coulter D. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet. 1984;323(8378):689.

    Article  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.

    CAS  Article  Google Scholar 

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

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Correspondence to Nguyen Tien Huy.

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

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Elshafay, A., Hieu, T.H., Doheim, M.F. et al. Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis. CNS Drugs 33, 239–250 (2019). https://doi.org/10.1007/s40263-019-00606-6

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