Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites
Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites
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DOI：
10.1016/j.ymgme.2013.07.011
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发表时间：
2013-09-01
影响因子：
3.8
通讯作者：
Falk, Marni J.
中科院分区：
文献类型：
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作者：
Clarke, Colleen;Xiao, Rui;Falk, Marni J.
长期以来，初级线粒体呼吸链(RC)功能障碍的诊断一直依赖于侵入性组织活检，因为还没有基于血液的生物标记物被证明在无数的个人临床表现中具有足够高的敏感性和特异性。我们试图确定通常获得的血液分析的队列水平评估是否可以揭示一致的模式来区分一组异质性的原发线粒体RC疾病受试者和对照组以及丙酮酸脱氢酶缺乏症受试者。方法：在IRB批准后，回顾分析了反映临床实践的三组明确且故意不同的受试者的62种生化分析物的浓度或比率：[1]原发线粒体疾病(n=19)；[2]丙酮酸脱氢酶缺乏症(n=4)；和[3]对照组(n=27)。血液分析类别包括综合化学谱、肌酸激酶、脂蛋白谱、乳酸、丙酮酸和血浆氨基酸谱。非参数分析用于比较队列间各分析物水平的中位数。结果：疾病队列中甘油三酯、乳酸、丙酮酸和多种单独的血浆氨基酸水平存在显著差异。在队列水平上，丙酮酸脱氢酶缺乏症患者的丙酮酸和丙氨酸水平显著升高，支链氨基酸(BCAA)水平显著升高，单个BCAA/谷氨酸比值增加，从而在队列水平上显著区别于丙酮酸脱氢酶缺乏症。结论：血液代谢产物谱分析可以区分不同类型的原发线粒体疾病和对照组以及丙酮酸脱氢酶缺乏症。支链氨基酸水平升高，无论是绝对的，还是与谷氨酸水平相关的，都是原发线粒体RC疾病的常见代谢后遗症。需要进行前瞻性研究，以证实观察到的血浆代谢物改变在更大的队列和个体受试者水平上都是疾病的潜在生物标记物。(C)2013 Elsevier Inc.保留所有权利。
Diagnosing primary mitochondrial respiratory chain (RC) dysfunction has long relied on invasive tissue biopsies, since no blood-based biomarker has been shown to have sufficiently high sensitivity and specificity across the myriad of individual clinical presentations. We sought to determine whether cohort-level evaluation of commonly obtained blood analytes might reveal consistent patterns to discriminate a heterogenous group of primary mitochondrial RC disease subjects both from control individuals and from subjects with pyruvate dehydrogenase deficiency.Methods: Following IRB approval, 62 biochemical analyte concentrations or ratios were retrospectively analyzed in three well-defined and intentionally heterogeneous subject cohorts reflective of clinical practice: [1] Primary mitochondrial disease (n = 19); [2] pyruvate dehydrogenase deficiency (n = 4); and [3] controls (n = 27). Blood analyte categories included comprehensive chemistry profile, creatine kinase, lipoprotein profile, lactate, pyruvate, and plasma amino acid profile. Non-parametric analyses were used to compare the median of each analyte level between cohorts.Results: Disease cohorts differed significantly in their median levels of triglycerides, lactate, pyruvate, and multiple individual plasma amino acids. Primary mitochondrial disease was significantly discriminated at the cohort level from pyruvate dehydrogenase deficiency by greater pyruvate and alanine elevation in pyruvate dehydrogenase deficiency, as well as significantly increased branched chain amino acid (BCAA) levels and increased ratios of individual BCAAs to glutamate in mitochondrial disease. In addition, significant elevation of median blood triglyceride level was seen in the primary mitochondrial disease cohort.Conclusions: Blood metabolite profile analysis can discriminate a heterogeneous cohort of primary mitochondrial disease both from controls and from pyruvate dehydrogenase deficiency. Elevated BCAA levels, either absolutely or when considered relative to the level of glutamate, are common metabolic sequelae of primary mitochondrial RC disease. Prospective study is needed to validate observed plasma metabolite alterations as a potential biomarker of disease both in larger cohorts and at the individual subject level. (C) 2013 Elsevier Inc. All rights reserved.