今日の臨床サポート

ミトコンドリア病

著者: 大越教夫 つくば国際大学 医療保健学部

監修: 庄司進一 筑波大学

著者校正済:2022/01/19
現在監修レビュー中
参考ガイドライン:
  1. 日本ミトコンドリア学会:ミトコンドリア病診療マニュアル2017
患者向け説明資料

概要・推奨   

  1. ミトコンドリア病は、エネルギーをミトコンドリアからの産生に依存する臓器障害を生じ、進行性の筋力低下、中枢神経症状(脳卒中様発作、知的退行・けいれんなど)、発達停止・退行などの多彩な臨床症状を来す疾患である。主にミトコンドリア遺伝子異常あるいは核遺伝子の異常により起こるといわれている。
  1. ミトコンドリア病でみられる症状は多彩であり、中枢神経、骨格筋、心臓だけでなく、眼、肝臓、腎臓、膵臓、血液、内耳、消化管、内分泌腺といったあらゆる組織・臓器に障害を起こしうる。
  1. ミトコンドリア病の主な病型としてMELAS、MERRF、CPEO/KSS、Leigh脳症などがある。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には ご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大越教夫 : 特に申告事項無し[2021年]
監修:庄司進一 : 特に申告事項無し[2021年]

改訂のポイント:
  1. ミトコンドリア病の概要を追記した。
  1. 定期レビューを行い、タウリンが保険適用となったため追記するとともに、治験段階の薬剤や試薬に関しては削除した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ミトコンドリア病の病因としてはmtDNA異常と核DNAの遺伝子変異がある。
  1. mtDNA異常には質的異常と量的異常があり、質的異常としては欠失/重複、点変異があり、量的異常としては細胞内のコピー数の減少がある。このため電子伝達系酵素欠損を来し、病気を発症させる。
  1. 核DNAの遺伝子でも、mtDNAの複製・転写・翻訳に関わる遺伝子は、mtDNAの欠乏状態や多重欠失を惹起し、電子伝達系酵素欠損を起こし、病気を発症させる。
  1. mtDNAに変異をみる疾患には、ミトコンドリア脳筋症・乳酸アシドーシス・脳卒中様発作症候群(Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes、MELAS)、慢性進行性外眼筋麻痺症候群(CPEO)/ Kearns-Sayre症候群(KSS)、ragged-red fiberを伴うミオクローヌスてんかん(Myoclonus epilepsy associated with ragged-red fibers、MERRF)、Leigh脳症、Leber病(Leber遺伝性視神経萎縮症:Leber’s hereditary optic neuropathy、LHON)、NARRPなどがある。
  1. 核DNAに変異をみる疾患には、進行性外眼筋麻痺(PEO)、MNGIE、Alpers病などがある。
  1. ミトコンドリア病の有病率は不明だが、諸外国の研究では人口1万人あたり1.5人、あるいは出生4,300~5,000人に対して1人との報告もある。
  1. わが国の有病率は不明だが、ミトコンドリア病741例の調査から、MELAS 233例(31.4%)、KSS(CPEO)159例(21.5%)、Leigh脳症135例(18.2%)の順である。小児科(430例)ではLeigh脳症127例(31.1%)、MELAS 122例(29.9%)、KSS(CPEO) 30例(7.4%)の順で、神経内科(430例)ではKSS(CPEO) 120例(38.6%)、MELAS 108例(34.7%)、糖尿病(DM)/難聴(deafness) 23例(7.4%)の順であった。
  1. 成人(16<、>60/65歳)におけるミトコンドリア病の有病率は、英国の調査では9.18人/10万人といわれ、全体では推定で16.5人/10万人という調査がある。
  1. 英国の北東部の地域(人口約250万人)で、労働年齢人口1,535,800人に対し有病率はm.3243A>G 3.65(n=56)、m.8344A>G 0.39(n=6)、Single large-scale deletion 1.17(n=18)、m.11778G>A/m.3460G>A/m.14484T>C 3.13(n=48)、その他 0.85(n=13)で、合計9.18(n=141)となった。それから推定して全人口では、16.49人/10万人となった[1]
  1. ミトコンドリア病は、指定難病であり、中等症以上の場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(平成27年1月施行
  1. 難病法に基づく医療費助成制度
 
病歴・診察のポイント  
  1. 小児と成人では内容も異なるが、発育の停止と退行、筋力低下・易疲労性、中枢神経症状を示唆する症候がある場合にはミトコンドリア病を疑う。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Andrew M Schaefer, Robert McFarland, Emma L Blakely, Langping He, Roger G Whittaker, Robert W Taylor, Patrick F Chinnery, Douglass M Turnbull
雑誌名: Ann Neurol. 2008 Jan;63(1):35-9. doi: 10.1002/ana.21217.
Abstract/Text OBJECTIVE: Diverse and variable clinical features, a loose genotype-phenotype relationship, and presentation to different medical specialties have all hindered attempts to gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease. Nevertheless, a clear understanding of its prevalence remains an important goal, particularly about planning appropriate clinical services. Consequently, the aim of this study was to accurately define the prevalence of mtDNA disease (primary mutation occurs in mtDNA) in the working-age population of the North East of England.
METHODS: Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center for investigation from 1990 to 2004. Those with pathogenic mtDNA mutations were identified and pedigree analysis performed. For the midyear period of 2001, we calculated the minimum point prevalence of mtDNA disease for adults of working age (>16 and <60/65 years for female/male patients, respectively).
RESULTS: In this population, we found that 9.2 in 100,000 people have clinically manifest mtDNA disease, making this one of the commonest inherited neuromuscular disorders. In addition, a further 16.5 in 100,000 children and adults younger than retirement age are at risk for development of mtDNA disease.
INTERPRETATION: Through detailed pedigree analysis and active family tracing, we have been able to provide revised minimum prevalence figures for mtDNA disease. These estimates confirm that mtDNA disease is a common cause of chronic morbidity and is more prevalent than has been previously appreciated.

PMID 17886296  Ann Neurol. 2008 Jan;63(1):35-9. doi: 10.1002/ana.21217・・・
著者: Joyeeta Rahman, Shamima Rahman
雑誌名: Lancet. 2018 Jun 23;391(10139):2560-2574. doi: 10.1016/S0140-6736(18)30727-X. Epub 2018 Jun 18.
Abstract/Text Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. Mitochondrial diseases represent one of the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and absence of disease-modifying curative therapies. This Review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread use of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease. New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets for therapeutic intervention. As we enter this new era of mitochondrial medicine, underpinned by global unbiased approaches and multifaceted investigation of mitochondrial function, omics technologies will continue to shed light on unresolved mitochondrial questions, paving the way for improved outcomes for patients with mitochondrial diseases.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29903433  Lancet. 2018 Jun 23;391(10139):2560-2574. doi: 10.1016/・・・
著者: Yutaka Ohsawa, Hiroki Hagiwara, Shin-Ichiro Nishimatsu, Akihiro Hirakawa, Naomi Kamimura, Hideaki Ohtsubo, Yuta Fukai, Tatsufumi Murakami, Yasutoshi Koga, Yu-Ichi Goto, Shigeo Ohta, Yoshihide Sunada, KN01 Study Group
雑誌名: J Neurol Neurosurg Psychiatry. 2019 May;90(5):529-536. doi: 10.1136/jnnp-2018-317964. Epub 2018 Apr 17.
Abstract/Text 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.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 29666206  J Neurol Neurosurg Psychiatry. 2019 May;90(5):529-536. ・・・
著者: N Bresolin, C Doriguzzi, C Ponzetto, C Angelini, I Moroni, E Castelli, E Cossutta, A Binda, A Gallanti, S Gabellini
雑誌名: J Neurol Sci. 1990 Dec;100(1-2):70-8.
Abstract/Text Forty-four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for 6 months in an open multi-center trial. No side effects of the drug were observed. Sixteen patients showing at least 25% decrease of post-exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were treated for a further 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences were observed between the 2 groups. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dose of CoQ10 used in this study (2 mg/kg/day) the therapy requires a long administration time before a response is seen.

PMID 2089142  J Neurol Sci. 1990 Dec;100(1-2):70-8.
著者: R S Chen, C C Huang, N S Chu
雑誌名: Eur Neurol. 1997;37(4):212-8.
Abstract/Text We report a short-term double-blind, crossover study of CoQ10 in 8 patients with mitochondrial encephalomyopathies. Four patients had myoclonus epilepsy with ragged-red fibers syndrome, 3 had mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome, and 1 had chronic progressive external ophthalmoplegia with myopathy. A trend of effectiveness of CoQ10 in several parameters was noted. Fatigability of daily activities was alleviated. The endurance to muscle exercise was augmented. Global muscle strength scored by Medical Research Council scale was increased. The extent of elevation in serum lactate and pyruvate levels after exercise was decreased. However, only the global MRC index score had a statistical significance (p < 0.05). There were no side effects during therapy. The serum CoQ10 levels were significantly lower in patients than in normal controls before CoQ10 treatment and increased significantly after treatment.

PMID 9208260  Eur Neurol. 1997;37(4):212-8.
著者: Elisa I Glover, Joan Martin, Amy Maher, Rebecca E Thornhill, Gerald R Moran, Mark A Tarnopolsky
雑誌名: Muscle Nerve. 2010 Nov;42(5):739-48. doi: 10.1002/mus.21758.
Abstract/Text Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.

PMID 20886510  Muscle Nerve. 2010 Nov;42(5):739-48. doi: 10.1002/mus.2・・・
著者: Peter W Stacpoole, Ton J deGrauw, Annette S Feigenbaum, Charles Hoppel, Douglas S Kerr, Shawn E McCandless, Michael V Miles, Brian H Robinson, Peter H Tang
雑誌名: Mitochondrion. 2012 Nov;12(6):623-9. doi: 10.1016/j.mito.2012.09.005. Epub 2012 Sep 25.
Abstract/Text We report the design and implementation of the first phase 3 trial of CoenzymeQ₁₀ (CoQ₁₀) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ₁₀ by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation--and ultimate approval--of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.

Copyright © 2012 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
PMID 23022402  Mitochondrion. 2012 Nov;12(6):623-9. doi: 10.1016/j.mit・・・
著者: P Kaufmann, K Engelstad, Y Wei, S Jhung, M C Sano, D C Shungu, W S Millar, X Hong, C L Gooch, X Mao, J M Pascual, M Hirano, P W Stacpoole, S DiMauro, D C De Vivo
雑誌名: Neurology. 2006 Feb 14;66(3):324-30. doi: 10.1212/01.wnl.0000196641.05913.27.
Abstract/Text OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.
METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.
RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.
CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

PMID 16476929  Neurology. 2006 Feb 14;66(3):324-30. doi: 10.1212/01.wn・・・
著者: Diego Martinelli, Michela Catteruccia, Fiorella Piemonte, Anna Pastore, Giulia Tozzi, Carlo Dionisi-Vici, Giuseppe Pontrelli, Tiziana Corsetti, Susanna Livadiotti, Viktoria Kheifets, Andrew Hinman, William D Shrader, Martin Thoolen, Matthew B Klein, Enrico Bertini, Guy Miller
雑誌名: Mol Genet Metab. 2012 Nov;107(3):383-8. doi: 10.1016/j.ymgme.2012.09.007. Epub 2012 Sep 10.
Abstract/Text BACKGROUND: Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases. In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. To confirm these initial findings, a phase 2A open label trial of EPI-743 for children with genetically-confirmed Leigh syndrome was conducted and herein we report the results.
METHODS: A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6 months with EPI-743 three times daily and all were eligible for a treatment extension phase. The primary objective of the trial was to arrest disease progression as assessed by neuromuscular and quality of life metrics. Results were compared to the reported natural history of the disease.
RESULTS: Ten consecutive children, ages 1-13 years, were enrolled; they possessed seven different genetic defects. All children exhibited reversal of disease progression regardless of genetic determinant or disease severity. The primary endpoints--Newcastle Pediatric Mitochondrial Disease Scale, the Gross Motor Function Measure, and PedsQL Neuromuscular Module--demonstrated statistically significant improvement (p<0.05). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale. No significant drug-related adverse events were recorded.
CONCLUSIONS: In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 23010433  Mol Genet Metab. 2012 Nov;107(3):383-8. doi: 10.1016/j.・・・
著者: Gregory M Enns, Stephen L Kinsman, Susan L Perlman, Kenneth M Spicer, Jose E Abdenur, Bruce H Cohen, Akiko Amagata, Adam Barnes, Viktoria Kheifets, William D Shrader, Martin Thoolen, Francis Blankenberg, Guy Miller
雑誌名: Mol Genet Metab. 2012 Jan;105(1):91-102. doi: 10.1016/j.ymgme.2011.10.009. Epub 2011 Oct 21.
Abstract/Text Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 22115768  Mol Genet Metab. 2012 Jan;105(1):91-102. doi: 10.1016/j・・・
著者: Alfredo A Sadun, Carlos Filipe Chicani, Fred N Ross-Cisneros, Piero Barboni, Martin Thoolen, William D Shrader, Kenneth Kubis, Valerio Carelli, Guy Miller
雑誌名: Arch Neurol. 2012 Mar;69(3):331-8. doi: 10.1001/archneurol.2011.2972.
Abstract/Text OBJECTIVE: To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures.
DESIGN: Open-label clinical trial.
SETTING: University medical center. Patients  Five patients with genetically confirmed LHON with acute loss of vision were consecutively enrolled and treated with the experimental therapeutic agent EPI-743 within 90 days of conversion. Intervention  During the course of the study, 5 consecutive patients received EPI-743, by mouth, 3 times daily (100-400 mg per dose).
MAIN OUTCOME MEASURES: Treatment effect was assessed by serial measurements of anatomic and functional visual indices over 6 to 18 months, including Snellen visual acuity, retinal nerve fiber layer thickness measured by optical coherence tomography, Humphrey visual fields (mean decibels and area with 1-log unit depression), and color vision. Treatment effect in this clinical proof of principle study was assessed by comparison of the prospective open-label treatment group with historical controls.
RESULTS: Of 5 subjects treated with EPI-743, 4 demonstrated arrest of disease progression and reversal of visual loss. Two patients exhibited a total recovery of visual acuity. No drug-related adverse events were recorded.
CONCLUSIONS: In a small open-label trial, EPI-743 arrested disease progression and reversed vision loss in all but 1 of the 5 consecutively treated patients with LHON. Given the known natural history of acute and rapid progression of LHON resulting in chronic and persistent bilateral blindness, these data suggest that the previously described irreversible priming to retinal ganglion cell loss may be reversed.

PMID 22410442  Arch Neurol. 2012 Mar;69(3):331-8. doi: 10.1001/archneu・・・
著者: Keiko Saito, Nobusuke Kimura, Nozomi Oda, Hideki Shimomura, Tomohiro Kumada, Tomoko Miyajima, Kei Murayama, Masashi Tanaka, Tatsuya Fujii
雑誌名: Biochim Biophys Acta. 2012 May;1820(5):632-6. doi: 10.1016/j.bbagen.2011.08.006. Epub 2011 Aug 11.
Abstract/Text BACKGROUND: Mitochondrial DNA depletion syndromes are a group of heterogeneous autosomal recessive disorders associated with a severe reduction in mitochondrial DNA in the affected tissues. Sodium pyruvate has been reported to have a therapeutic effect in mitochondrial diseases.
METHODS: We analyzed the effects of 0.5g/kg of sodium pyruvate administered through a nasogastric tube in a one-year-old patient with myopathic mitochondrial DNA depletion syndrome. To evaluate the improvement, we used the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) and manual muscle testing. As the improvement of motor functions in this severely disabled infant could not be comprehensively detected by NPMDS, we also observed the infant's ability to perform several tasks such as pouting, winking, and number of times she could tap a toy xylophone with a stick. Blood lactate and pyruvate levels were also monitored.
RESULTS: After one month's treatment, the NPMDS score in section IV, the domain for the quality of life, improved from 17 to13. The infant became capable of raising her forearm, lower leg and wrist against gravity. The maximum number of times she could repeat each task increased and the movements became brisker and stronger. No significant change of the blood lactate level or lactate-to-pyruvate ratio, both of which were mildly increased at the initiation of the therapy, was observed despite the clinical improvement.
CONCLUSION: Sodium pyruvate administered at 0.5g/kg improved the muscle strength and the NPMDS score of an infant with myopathic mitochondrial DNA depletion syndrome.
GENERAL SIGNIFICANCE: Sodium pyruvate may be effective for ameliorating the clinical manifestations of mitochondrial diseases. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID 21855607  Biochim Biophys Acta. 2012 May;1820(5):632-6. doi: 10.1・・・
著者: Yasutoshi Koga, Nataliya Povalko, Koujyu Katayama, Noriko Kakimoto, Toyojiro Matsuishi, Etsuo Naito, Masashi Tanaka
雑誌名: Brain Dev. 2012 Feb;34(2):87-91. doi: 10.1016/j.braindev.2011.03.003. Epub 2011 Mar 31.
Abstract/Text Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h. The patient was diagnosed with LS due to a point mutation of an A-C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5 g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
PMID 21454027  Brain Dev. 2012 Feb;34(2):87-91. doi: 10.1016/j.brainde・・・
著者: Hirofumi Komaki, Yutaka Nishigaki, Noriyuki Fuku, Hiroko Hosoya, Kei Murayama, Akira Ohtake, Yu-Ichi Goto, Hiroyuki Wakamoto, Yasutoshi Koga, Masashi Tanaka
雑誌名: Biochim Biophys Acta. 2010 Mar;1800(3):313-5. doi: 10.1016/j.bbagen.2009.07.008. Epub 2009 Jul 17.
Abstract/Text BACKGROUND: Recently we proposed the therapeutic potential of pyruvate therapy for mitochondrial diseases. Leigh syndrome is a progressive neurodegenerative disorder ascribed to either mitochondrial or nuclear DNA mutations.
METHODS: In an attempt to circumvent the mitochondrial dysfunction, we orally applied sodium pyruvate and analyzed its effect on an 11-year-old female with Leigh syndrome due to cytochrome c oxidase deficiency accompanied by cardiomyopathy. The patient was administered sodium pyruvate at a maintenance dose of 0.5 g/kg/day and followed up for 1 year.
RESULTS: The exercise intolerance was remarkably improved so that she became capable of running. Echocardiography indicated improvements both in the left ventricle ejection fraction and in the fractional shortening. Electrocardiography demonstrated amelioration of the inverted T waves. When the pyruvate administration was interrupted because of a gastrointestinal infection, the serum lactate level became elevated and the serum pyruvate level, decreased, suggesting that the pyruvate administration was effective in decreasing the lactate-to-pyruvate ratio.
CONCLUSIONS: These data indicate that pyruvate therapy was effective in improving exercise intolerance at least in a patient with cytochrome c oxidase deficiency.
GENERAL SIGNIFICANCE: Administration of sodium pyruvate may prove effective for other patients with cytochrome c oxidase deficiency due to mitochondrial or nuclear DNA mutations.

Copyright (c) 2009 Elsevier B.V. All rights reserved.
PMID 19616603  Biochim Biophys Acta. 2010 Mar;1800(3):313-5. doi: 10.1・・・
著者: Masashi Tanaka, Yutaka Nishigaki, Noriyuki Fuku, Tohru Ibi, Ko Sahashi, Yasutoshi Koga
雑誌名: Mitochondrion. 2007 Dec;7(6):399-401. doi: 10.1016/j.mito.2007.07.002. Epub 2007 Aug 9.
Abstract/Text
PMID 17881297  Mitochondrion. 2007 Dec;7(6):399-401. doi: 10.1016/j.mi・・・
著者: Thomas Klopstock, Patrick Yu-Wai-Man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip, Marcus Kernt, Diana Petraki, Christian Rummey, Mika Leinonen, Günther Metz, Philip G Griffiths, Thomas Meier, Patrick F Chinnery
雑誌名: Brain. 2011 Sep;134(Pt 9):2677-86. doi: 10.1093/brain/awr170. Epub 2011 Jul 25.
Abstract/Text Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

PMID 21788663  Brain. 2011 Sep;134(Pt 9):2677-86. doi: 10.1093/brain/a・・・
著者: Xiujuan Zhao, Yuxin Zhang, Lin Lu, Hui Yang
雑誌名: Curr Eye Res. 2020 Oct;45(10):1315-1323. doi: 10.1080/02713683.2020.1736307. Epub 2020 Mar 9.
Abstract/Text Purpose: To characterize the potential therapeutic effects of idebenone on Leber hereditary optic neuropathy (LHON) in terms of visual acuity (VA), visual field (VF) defects, visual evoked potential (VEP) and retinal nerve fibre layer (RNFL) thickness using optical coherence tomography (OCT) measurements. Methods: This was a retrospective case-controlled study of the effect of idebenone (900 mg/d) on 30 patients with LHON due to m.3460 G > A, m.11778 G > A and m.14484 T > C mutations. The primary end-point was the recovery in VA after 3 and 6 mon. The main secondary end-point was the change in VF, VEP and RNFL thickness. The other secondary end-point was the correlation between visual changes after 6 mon and the VF, VEP and RNFL thickness at baseline of the groups. Results: Idebenone was shown to be safe and well tolerated. The primary end-point reached statistical significance. The VA in the idebenone group improved in both the best eye and worst eye. The mean defect of VF decreased and amplitude of VEP increased. There was no significant difference in latency and RNFL thickness between the groups. The treatment, together with the VA and amplitude at baseline, had a significant effect on the improvement in VA at 6 mon. Conclusion: This case-controlled study of LHON provides evidence that idebenone treatment may be beneficial in cases of LHON and that the influential factors governing outcomes are the VA and amplitude of the VEP at baseline.

PMID 32111141  Curr Eye Res. 2020 Oct;45(10):1315-1323. doi: 10.1080/0・・・
著者: T Klopstock, V Querner, F Schmidt, F Gekeler, M Walter, M Hartard, M Henning, T Gasser, D Pongratz, A Straube, M Dieterich, W Müller-Felber
雑誌名: Neurology. 2000 Dec 12;55(11):1748-51.
Abstract/Text To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed.

PMID 11113239  Neurology. 2000 Dec 12;55(11):1748-51.
著者: M A Tarnopolsky, B D Roy, J R MacDonald
雑誌名: Muscle Nerve. 1997 Dec;20(12):1502-9.
Abstract/Text Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. x 14 days --> 2 g PO b.i.d. x 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities.

PMID 9390662  Muscle Nerve. 1997 Dec;20(12):1502-9.
著者: C Kornblum, R Schröder, K Müller, M Vorgerd, J Eggers, M Bogdanow, A Papassotiropoulos, K Fabian, T Klockgether, J Zange
雑誌名: Eur J Neurol. 2005 Apr;12(4):300-9. doi: 10.1111/j.1468-1331.2004.00970.x.
Abstract/Text The purpose of our randomized, double-blind, placebo-controlled crossover study in 15 patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) because of single large-scale mitochondrial (mt) DNA deletions was to determine whether oral creatine (Cr) monohydrate can improve skeletal muscle energy metabolism in vivo. Each treatment phase with Cr in a dosage of 150 mg/kg body weight/day or placebo lasted 6 weeks. The effect of Cr was estimated by phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS), clinical and laboratory tests. (31)P-MRS analysis prior to treatment showed clear evidence of severe mitochondrial dysfunction. However, there were no relevant changes in (31)P-MRS parameters under Cr. In particular, phosphocreatine (PCr)/ATP at rest did not increase, and there was no facilitation of post-exercise PCr recovery. Clinical scores and laboratory tests did not alter significantly under Cr, which was tolerated without major side-effects in all patients. Cr supplementation did not improve skeletal muscle oxidative phosphorylation in our series of patients. However, one explanation for our negative findings may be the short study duration or the limited number of patients included.

PMID 15804248  Eur J Neurol. 2005 Apr;12(4):300-9. doi: 10.1111/j.1468・・・
著者: M Christine Rodriguez, Jay R MacDonald, Douglas J Mahoney, Gianni Parise, M Flint Beal, Mark A Tarnopolsky
雑誌名: Muscle Nerve. 2007 Feb;35(2):235-42. doi: 10.1002/mus.20688.
Abstract/Text Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

PMID 17080429  Muscle Nerve. 2007 Feb;35(2):235-42. doi: 10.1002/mus.2・・・
著者: Tina D Jeppesen, Marianne Schwartz, David B Olsen, Flemming Wibrand, Thomas Krag, Morten Dunø, Simon Hauerslev, John Vissing
雑誌名: Brain. 2006 Dec;129(Pt 12):3402-12. doi: 10.1093/brain/awl149. Epub 2006 Jun 30.
Abstract/Text Exercise intolerance is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still unsettled whether exercise training is safe and beneficial for patients with MM. To address this, we studied the effect of 12 weeks cycle training on exercise capacity, quality of life and underlying molecular and cellular events in five patients with single large-scale deletions, one with a microdeletion and 14 with point mutations of mitochondrial DNA (mtDNA), and 13 healthy subjects. Each training session lasted 30 min, and was performed at an intensity of 70% of VO2max (maximal oxygen uptake). Each subject performed 50 training sessions in 12 weeks. All subjects were evaluated before and after training, and 13 MM patients were studied after 8 weeks of deconditioning. Evaluation included VO2max and mutation load and mtDNA quantity, mitochondrial enzymatic activity, and number of centrally nucleated, apoptotic, ragged red and cytochrome oxidase (COX)-negative fibres in muscle biopsies from the quadriceps muscle. After 12 weeks of training, VO2max and muscle citrate synthase increased in MM (26 and 67%) and healthy (17 and 65%) subjects, while mtDNA quantity in muscle only increased in the MM patients (81%). In the MM patients, training did not change mtDNA mutation load in muscle, mitochondrial enzyme complex activities, muscle morphology and plasma creatine kinase. After deconditioning, VO2max and citrate synthase activity returned to values before training, while muscle mtDNA mutation load decreased. These findings show that aerobic training efficiently improves oxidative capacity in MM patients. Based on unchanged levels of mutant load in muscle, morphological findings on muscle biopsy and plasma creatine kinase levels during training, the treatment appears to be safe. Regular, supervised aerobic exercise is therefore recommended in MM patients with the studied mutations.

PMID 16815877  Brain. 2006 Dec;129(Pt 12):3402-12. doi: 10.1093/brain/・・・
著者: Tanja Taivassalo, Julie L Gardner, Robert W Taylor, Andrew M Schaefer, Jane Newman, Martin J Barron, Ronald G Haller, Douglass M Turnbull
雑誌名: Brain. 2006 Dec;129(Pt 12):3391-401. doi: 10.1093/brain/awl282. Epub 2006 Nov 3.
Abstract/Text At present there are limited therapeutic interventions for patients with mitochondrial myopathies. Exercise training has been suggested as an approach to improve physical capacity and quality of life but it is uncertain whether it offers a safe and effective treatment for patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. The objectives of this study were to assess the effects of exercise training and detraining in eight patients with single, large-scale mtDNA deletions to determine: (i) the efficacy and safety of endurance training (14 weeks) in this patient population; (ii) to determine the effect of more prolonged (total of 28 weeks) exercise training upon muscle and cardiovascular function and (iii) to evaluate the effect of discontinued training (14 weeks) upon muscle and cardiovascular function. Our results show that: (i) 14 weeks of exercise training significantly improved tolerance of submaximal exercise and peak capacity for work, oxygen utilization and skeletal muscle oxygen extraction with no change in the level of deleted mtDNA; (ii) continued training for an additional 14 weeks maintained these beneficial adaptations; (iii) the cessation of training (detraining) resulted in loss of physiological adaptation to baseline capacity with no overall change in mutation load. Patients' self assessment of quality of life as measured by the SF-36 questionnaire improved with training and declined with detraining. Whilst our findings of beneficial effects of training on physiological outcome and quality of life without increases in the percentage of deleted mtDNA are encouraging, we did not observe changes in mtDNA copy number. Therefore there remains a need for longer term studies to confirm that endurance exercise is a safe and effective treatment for patients with mitochondrial myopathies. The effects of detraining clearly implicate physical inactivity as an important mechanism in reducing exercise capacity and quality of life in patients with mitochondrial myopathy.

PMID 17085458  Brain. 2006 Dec;129(Pt 12):3391-401. doi: 10.1093/brain・・・
著者: Y Koga, Y Akita, J Nishioka, S Yatsuga, N Povalko, Y Tanabe, S Fujimoto, Toyojiro Matsuishi
雑誌名: Neurology. 2005 Feb 22;64(4):710-2. doi: 10.1212/01.WNL.0000151976.60624.01.
Abstract/Text Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered L-arginine intravenously at the acute phase or orally at the interictal phase. L-arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.

PMID 15728297  Neurology. 2005 Feb 22;64(4):710-2. doi: 10.1212/01.WNL・・・
著者: I Tein, S DiMauro, Z W Xie, D C De Vivo
雑誌名: Pediatr Res. 1993 Sep;34(3):281-7. doi: 10.1203/00006450-199309000-00008.
Abstract/Text The mechanisms of valproate-associated carnitine deficiency are controversial. The urinary excretion of valproylcarnitine is insufficient to account for tissue carnitine depletion. To explore this mechanism, we studied the effects of valproic acid (VPA) on carnitine uptake in cultured human skin fibroblasts by the method of Tein et al. (Pediatr Res 28:247-255, 1990). Fibroblasts were preincubated with varying concentrations (0-2000 microM) of VPA for 1, 3, 5, 7, 10, 14, 21, and 28 d and then incubated with fixed carnitine concentrations of 50 microM (normal physiologic concentration), 20 microM (as seen in secondary carnitine deficiency disorders), or 5 microM (as seen in the plasma membrane carnitine transport defect). There was an exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations, and the relative inhibitory effect was the same for all three carnitine concentrations. The mean percentages +/- SD (n-1) of residual carnitine uptake for all combined preincubation periods (1-28 d) and combined carnitine concentrations (5, 20, and 50 mumol/L) with increasing concentrations of VPA varied from 83.4 +/- 2.6% (10 microM VPA) to 56.7 +/- 0.1% (500 microM) to 19.8 +/- 1.3% (2000 microM). The degree of inhibition was directly proportional to the time of VPA preincubation and parallel for all three carnitine concentrations; the longer the preincubation period, the lower the toxic dose of VPA (to a minimum of 450 microM), resulting in a 50% suppression of carnitine uptake (TD50).(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 8134167  Pediatr Res. 1993 Sep;34(3):281-7. doi: 10.1203/0000645・・・
著者: S Krähenbühl, S Brandner, S Kleinle, S Liechti, D Straumann
雑誌名: Liver. 2000 Jul;20(4):346-8.
Abstract/Text We report on 3 siblings (2 females and 1 male) with chronic progressive external ophthalmoplegia (CPEO), compatible with inherited mitochondrial cytopathy. The younger of the two sisters died at the age of 37 due to progressive respiratory failure. The older one presented with a status epilepticus at the age of 39 and was treated with valproate. Five months after the start of treatment, she developed fulminant liver failure and died. The brother has suffered from CPEO since early childhood but has had so far no other symptoms of a mitochondrial disease. A muscle biopsy from the younger sister revealed ragged-red fibers and decreased activities of complex I and IV of the respiratory chain but no pathogenic mutations in the mitochondrial tRNA genes or in several locations in the coding region of the mitochondrial genome. In the older sister's liver (obtained post-mortem), mitochondrial DNA was fragmented and could not be investigated. The clinical presentation and the biochemical findings suggest that all 3 siblings suffered from a mitochondrial cytopathy. Since mitochondrial cytopathies and valproate-induced fulminant liver failure are both rare events, an association between them is likely. Mitochondrial diseases should therefore be considered as a risk factor for valproate-induced liver failure and be excluded before treatment with valproate.

PMID 10959815  Liver. 2000 Jul;20(4):346-8.
著者: Chih-Ming Lin, Peterus Thajeb
雑誌名: Metab Brain Dis. 2007 Mar;22(1):105-9. doi: 10.1007/s11011-006-9039-9. Epub 2007 Jan 17.
Abstract/Text Epilepsy is one of the most common presentations of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is typically caused by an A-to-G substitution at nucleotide position 3243 of mitochondrial DNA. Valproic acid, a common anticonvulsant, can actually increase the frequency of seizures in individuals with MELAS. Here, we report a single case-study of a 38-year-old man who presented with focal seizures and had MELAS Syndrome due to the A3243G mitochondrial DNA mutation. Manifestation of epilepsia partialis continua was aggravated by use of valproic acid. Convulsions abated after discontinuation of valproic acid. Our experience suggests that valproic acid should be avoided for the treatment of epilepsy in individuals with mitochondrial disease.

PMID 17226098  Metab Brain Dis. 2007 Mar;22(1):105-9. doi: 10.1007/s11・・・
著者: C W Lam, C H Lau, J C Williams, Y W Chan, L J Wong
雑誌名: Eur J Pediatr. 1997 Jul;156(7):562-4.
Abstract/Text UNLABELLED: We report in this study a patient who developed repeated convulsions as a result of valproate therapy. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) was subsequently diagnosed and a nucleotide 3243 A-->G mutation was detected in the mitochondrial DNA. This mutation predisposes the patient to the detrimental effects of valproate on oxidative phosphorylation.
CONCLUSION: We support the suggestion of Ponchaut et al. [14] that valproate should not be given to patients suspected of having mitochondrial diseases. In addition, for patients whose seizures worsen with valproate therapy, an inborn error of mitochondrial metabolism should be suspected. The underlying mitochondrial DNA defects should be sought for family screening and genetic counselling.

PMID 9243242  Eur J Pediatr. 1997 Jul;156(7):562-4.
著者: Nobuko Sasano, Yoshihito Fujita, Minhye So, Kazuya Sobue, Hiroshi Sasano, Hirotada Katsuya
雑誌名: J Anesth. 2007;21(1):72-5. doi: 10.1007/s00540-006-0449-y. Epub 2007 Jan 30.
Abstract/Text A 53-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) underwent a gastrectomy. We administered bicarbonated Ringer's solution, which has a physiological concentration of bicarbonate. The level of serum lactate did not increase significantly, and metabolic acidosis did not occur throughout surgery or for 3 h after surgery. Aggressive warming was needed to maintain normothermia, presumably because the mitochondrial respiratory chain, which is responsible for thermogenesis, is impaired in MELAS patients. It is important to maintain normothermia in MELAS patients in order to avoid further mitochondrial metabolic depression.

PMID 17285419  J Anesth. 2007;21(1):72-5. doi: 10.1007/s00540-006-0449・・・

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