Project #1 - MELAS-3243: Natural history, functional outcome measures, and predic

项目摘要 在1984年，我们描述了两个病人“线粒体肌病，脑病，乳酸酸中毒， 和中风样癫痫”。1我们提出了首字母缩略词MELAS为这个新描述的独特的 临床实体，并推测母亲非孟德尔遗传，和线粒体DNA （mtDNA）突变干扰嵌入呼吸链中的蛋白质的合成。六年后，后藤 2002年，J.K.和同事在MELAS患者的mtDNA中发现了一个点突变（m.3243A>G）。 占MELAS病例的80%（通常称为MELAS/3243）。二十年来，我们的团队 对MELAS/3243例患者进行了长期纵向研究，为以下方面奠定了坚实的基础： 自然史、结果测量和生物标志物。然而，由于没有明确的验证， 用于预测转换风险、前驱症状和轻度症状家族亲属的生物标志物 继续生活在转化为严重MELAS表型的不确定性中。这一现实强调 需要扩大我们对MELAS自然历史的初步观察， 大脑生物标志物。我们的策略是基于（具体目标#1）复制的需要，使用1H MRSI， 我们非常有希望的，初步观察到的异常水平的乳酸，NAA，tCr和tCho，在100 突变携带者和30名组匹配的健康对照受试者，首先在基线，然后在2年时再次 随访;（具体目标#2）需要使用31 P MRSI与1H MRSI同步测量大脑 水平（a）磷酸肌酸（PCr），以补充和证实tCr水平，通过1H MRSI测量，作为 细胞能量学标记物; B）ATP，以补充和证实NAA的1H MRSI测量， 乳酸盐作为线粒体功能障碍的指标; c）磷酸单酯（PME）和磷酸二酯（PDE）， 补充和证实tCho水平，通过1H MRSI测量，作为膜生物合成的指标 和周转，和（d）无机磷酸盐（Pi）作为细胞内pH的指标;和（具体目标#3） 需要测量血浆和尿液中代谢物生物标志物的时间一致水平 从所有130名参与者中收集样本。这三个目标将加强我们先前的调查结果， 预测性神经成像生物标志物，告知我们代谢和临床的大脑机制 干扰，并提供补充血浆和尿液代谢物，如果与大脑相关， 生物标志物，将作为更便宜和更容易获得的生物标志物，预测转化为 重度MELAS表型。

Project Summary In 1984, we described two patients with "Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes".1 We proposed the acronym MELAS for this newly described distinctive clinical entity, and speculated about maternal non-Mendelian inheritance, and a mitochondrial DNA (mtDNA) mutation disturbing synthesis of proteins embedded in the respiratory chain. Six years later, Goto and colleagues identified a point mutation in mtDNA (m.3243A>G) of MELAS patients.2 This mutation now accounts for 80% of MELAS cases (commonly referred to as MELAS/3243). For two decades, our team has conducted a long-term longitudinal study of MELAS/3243 patients, establishing a strong foundation in terms of natural history, outcome measures, and biomarkers. However, since there are no clearly validated biomarkers for predicting the risk of conversion, prodromal and mildly symptomatic family relatives continue to live with the uncertainty of converting to the severe MELAS phenotype. This reality emphasizes the need to expand our nascent observations about the natural history of MELAS and the predictive value of brain biomarkers. Our strategies are based on (Specific Aim #1) the need to replicate, using 1H MRSI, our highly promising, preliminary observations of abnormal levels of lactate, NAA, tCr and tCho, in 100 mutation carriers and 30 group-matched healthy control subjects, first at baseline and then again at 2-year follow-up; (Specific Aim #2) the need to measure, using 31P MRSI in synchrony with 1H MRSI, brain levels of (a) phosphocreatine (PCr) to complement and corroborate tCr levels, measured by 1H MRSI, as a marker of cell energetics; b) ATP, to complement and corroborate the 1H MRSI measures of NAA and lactate as indices of mitochondrial dysfunction; c) phosphomonoesters (PME) and phosphodiesters (PDE), to complement and corroborate tCho levels, measured by 1H MRSI, as indices of membrane biosynthesis and turnover, and (d) inorganic phosphate (Pi) as an index of intracellular pH; and (Specific Aim #3) the need to measure temporally concordant levels of metabolite biomarkers in the plasma and urine samples collected from all 130 participants. These three Aims will strengthen our earlier findings of predictive neuroimaging biomarkers, inform us of brain mechanisms underlying metabolic and clinical disturbances, and provide complementary plasma and urine metabolites that, if correlated with the brain biomarkers, will serve as less expensive and more accessible biomarkers predicting risk of conversion to the severe MELAS phenotype.