Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Mol Genet Metab. 2013 Sep-Oct;110(1-2):145-52. doi: 10.1016/j.ymgme.2013.07.011. Epub 2013 Jul 19.
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.
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.
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.
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.
长期以来，诊断原发性线粒体呼吸链（RC）功能障碍依赖于侵入性组织活检，因为没有一种血液生物标志物在众多个体临床表现中具有足够高的灵敏度和特异性。我们试图确定通常获得的血液分析物的队列水平评估是否可能揭示一致的模式，以区分原发性线粒体 RC 疾病患者的异质组，既与对照个体又与丙酮酸脱氢酶缺乏症患者区分开来。
在获得 IRB 批准后，回顾性分析了三个定义明确且有意异质的受试者队列中 62 种生化分析物浓度或比值，以反映临床实践：[1]原发性线粒体疾病（n=19）；[2]丙酮酸脱氢酶缺乏症（n=4）；和[3]对照组（n=27）。血液分析物类别包括全面化学谱、肌酸激酶、脂蛋白谱、乳酸、丙酮酸和血浆氨基酸谱。使用非参数分析比较队列之间每个分析物水平的中位数。
疾病队列在甘油三酯、乳酸、丙酮酸和多种个体血浆氨基酸的中位数水平上有显著差异。原发性线粒体疾病在队列水平上与丙酮酸脱氢酶缺乏症显著区分，其特征为丙酮酸脱氢酶缺乏症中丙酮酸和丙氨酸升高，以及原发性线粒体疾病中支链氨基酸（BCAA）水平显著升高和单个 BCAA 与谷氨酸的比值升高。此外，原发性线粒体疾病队列中中位血液甘油三酯水平显著升高。
血液代谢物谱分析可以区分原发性线粒体疾病的异质队列，既与对照组又与丙酮酸脱氢酶缺乏症区分开来。升高的 BCAA 水平，无论是绝对值还是相对于谷氨酸水平，都是原发性线粒体 RC 疾病的常见代谢后果。需要前瞻性研究来验证观察到的血浆代谢物改变作为疾病的潜在生物标志物，无论是在更大的队列中还是在个体受试者水平上。
