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

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Abstract

Background

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.

Objectives

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

Methods

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).

Results

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.

Conclusions

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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Acknowledgements

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

Author information

Author notes

  1. Abdelrahman Elshafay, Truong Hong Hieu and Mohamed Fahmy Doheim contributed equally to this study.

Authors and Affiliations

  1. Faculty of Medicine, Al-Azhar University, Cairo, 11884, Egypt

    Abdelrahman Elshafay

  2. Faculty of Medicine, University of Medicine of Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam

    Truong Hong Hieu

  3. Faculty of Medicine, Alexandria University, Alexandria, 21544, Egypt

    Mohamed Fahmy Doheim

  4. The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA

    Mahmoud Attia Mohamed Kassem

  5. Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt

    Mohammed Fathi ELdoadoa

  6. University of North Texas, Denton, TX, 76205, USA

    Sarah Keturah Holloway

  7. Faculty of Medicine, Menofia University, Menofia, 32512, Egypt

    Heba Abo-elghar

  8. Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Kenji Hirayama

  9. Evidence Based Medicine Research Group, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam

    Nguyen Tien Huy

  10. Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam

    Nguyen Tien Huy

  11. Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, 852-8523, Japan

    Nguyen Tien Huy

Authors
  1. Abdelrahman Elshafay
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  2. Truong Hong Hieu
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Correspondence to Nguyen Tien Huy.

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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.

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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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  • DOI: https://doi.org/10.1007/s40263-019-00606-6

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