Objective The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately.
Methods After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial.
Results The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine.
Conclusions The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS.
Trial registration number UMIN000011908.
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Contributors YO, HH, AH, YK, YG and YS conceptualised and designed the study, recruited patients, contributed data, performed statistical analysis, interpreted the results, and drafted and edited the manuscript. SN, NK, HO, YF, TM and SO analysed mitochondrial genotype, heteroplasmy and taurine modification. KN01 Study Members collected data for this study. All authors approved the submission.
Funding This study was funded by Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (H24-Nanchitou(Nan)-Ippan-068) and by Japan Agency for Medical Research and Development (AMED) under grant numbers JP15ek0109093h0001, JP16ek0109093h0002 and JP17ek0109093h0003.
Disclaimer The sponsors played no role in the study design; the collection, analysis and the interpretation of data; the writing of the report; or the decision to submit the article for publication.
Competing interests YS reports the following research grants: Intramural Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry (26-8), Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (C-24591281, C-26461285) and by research project grants from Kawasaki Medical School (23-T1, 26-T1).
Patient consent Obtained.
Ethics approval Each institutional review board (IRB) of individual 10 clinical institutions participating in this trial approved all trial procedures.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators KN01 Study Group includes the following people: H Onoue, K Kaida (National Defense Medical College Hospital, Tokyo, Japan), K Sato, T Uchiyama (Seirei Hamamatsu General Hospital, Shizuoka, Japan), A Ueda, T Mutoh (Fujita Health University School Hospital, Aichi, Japan), M Nakamura (National Hospital Organization Kyoto Medical Center, Kyoto, Japan), K Nishida, I Funakawa (National Hospital Organization Hyogo-Chuo National Hospital, Hyogo, Japan), A Ogawa (Chikushi Hospital, Fukuoka University, Fukuoka, Japan), R Nakata, H Shiraishi, A Tsujino (Nagasaki University Hospital, Nagasaki, Japan), T Takahashi and M Matsumoto (Hiroshima University Hospital, Hiroshima, Japan).
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