Mitochondrial encephalomyopathies - Therapeutic approach
Mitochondrial encephalomyopathies - Therapeutic approach
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DOI：
10.1196/annals.1293.023
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Naini, A
中科院分区：
文献类型：
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作者：
DiMauro, S;Mancuso, M;Naini, A
线粒体疾病的治疗方法严重不足。然而，缺乏治愈并不等于缺乏治疗。在这篇综述中，我们依次考虑几种不同的治疗方法。姑息治疗由良好的医疗实践决定，包括抗惊厥药物、内分泌功能障碍的控制和外科手术。有害代谢物的清除主要集中在对抗乳酸酸中毒，但它也延伸到其他代谢物，如线粒体神经胃肠脑肌病综合征患者的胸苷。通过人工电子受体来绕过呼吸链阻断的尝试尚未成功，但这一概念可能适用于基因工程。代谢物和辅因子的给药是现实生活中治疗的支柱，包括呼吸链和其他天然化合物的组分。在原发性线粒体疾病和直接或间接与线粒体功能障碍相关的神经退行性疾病中，活性氧清除剂的给药越来越受到关注。有氧运动和物理治疗可预防或纠正因mtDNA突变引起的线粒体肌病患者的失调，并提高运动耐量。基因治疗是一个挑战，因为多质性和异质性，但有趣的实验方法正在进行，包括，例如，减少突变体与野生型线粒体基因组的比例（基因转移），将突变的mtDNA基因转化为正常的nDNA基因（同素异形表达），从其他物种导入同源基因，或纠正mtDNA突变与特定的限制性内切酶。生殖系治疗引起了伦理问题，但正在认真考虑防止mtDNA突变的母体传播。通过遗传咨询和产前诊断的预防性治疗对mtDNA相关疾病仍然有限，但对nDNA相关疾病变得越来越重要。
Therapy for mitochondrial diseases is woefully inadequate. However, lack of cure does not equate with lack of treatment. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but it extends to other metabolites, such as thymidine in patients with the mitochondrial neurogastrointestinal encephalomyopathy syndrome. Attempts to bypass blocks in the respiratory chain by administration of artificial electron acceptors have not been successful, but this concept may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and includes both components of the respiratory chain and other natural compounds. There is increasing interest in the administration of reactive oxygen species scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with mitochondrial myopathies due to mtDNA mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nDNA genes (allotropic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being seriously considered to prevent maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is still limited for mtDNA-related disorders but is becoming increasingly important for nDNA-related disorders.