INVESTIGATION OF CLINICAL SYNDROMES ASSOCIATED WITH mt DNA POINT MUTATIONS

该临床项目是该项目的翻译研究分支。我们已经收集了最大的、具有完整特征的线粒体DNA突变家族队列(51个)。近90%(44个家系)携带A3243G突变，完全有症状的先证者表现为MELAS表型。当第一次评估时，这些家庭成员被分成三个临床组(无症状、少症状和完全有症状)。纵向和横向- 对这些科目的分门别类研究提供了有关自然历史的宝贵信息。这项纵向研究现在已经进行了10年，扩大了我们对临床表型和医学并发症频率的理解。已确定的关键生物学变量预测无症状/少症状组的发病率增加，而完全有症状组的死亡率增加。脑室乳酸是脑细胞代谢最敏感的生物标志物。尿沉渣DNA是检测mtDNA最可靠的方法 突变。神经心理学研究表明，视觉记忆是大脑中最脆弱的领域。有症状的MELAS患者正在进行一项为期三年的随机DCA/安慰剂双盲研究，以确定慢性脑乳酸酸中毒是否导致脑损伤。我们提出了三个具体目标。具体目标#1继续我们的自然历史研究，将基因和表型联系起来。这一目的验证了脑室乳酸与临床表型和预后相关的假设。特殊目标2继续我们的MELAS/DCA临床试验。这一目的验证了慢性脑乳酸酸中毒加剧MELAS表型的假说。具体目标3是一项新的研究，评估早期 用PET、fMRI和基于体素的形态计量学分析脑功能障碍的生物标志物。这一目标验证了脑室乳酸与脑细胞功能障碍相关的假说。我们预计，这些研究将使我们能够确定一些携带A3243G突变的受试者是否会在其预期寿命内保持无症状(低风险组)，而其他仅显示出结构/功能障碍的早期证据的受试者将出现症状，值得早期预防治疗(高危组)。 这个临床项目的最终目标是找到治疗与mtDNA点突变相关的临床综合征的方法。

The clinical project is the translational research arm of the ProgramProject. We have ssembled the largest, fully characterized cohort of families (51) harboring mtDNA mutations. Nearly 90% (44 families)carry a A3243G mutation and the fully symptomatic probands manifest the MELAS phenotype. The family members are assigned to three clinical groups (asymptomatic, oligosymptomatic and fully symptomatic) when first evaluated. Longitudinal and cross- sectional studies of these subjects have provided valuable information regarding natural history. The longitudinal study, now in its 10th year, expands our understanding of the clinical phenotypes and the frequency of medical complications. Key biological variables have been identified that predict increasing morbidity in the asymptomatic/oligosymptomatic group and mortality in the fully symptomatic group. Brain ventricular lactate is the most sensitive biomarker of brain cellular metabolism. Urine sediment DNA is the most reliable measure of mtDNA mutation. Neuropsychological studies show visual memory to be the most vulnerable brain domain. Symptomatic MELAS patients are midway through a three-year, randomized DCA/placebo double-blinded study to determine whether chronic cerebral lactic acidosis contributes to brain injury. We propose three Specific Aims. Specific Aim #1 continues our natural history study correlating genotype and phenotype. This aim tests the hypothesis that brain ventricular lactate correlates with clincal phenotype and prognosis. Specific Aim #2 continues our MELAS/DCA clinical trial. This aim tests the hypothesis that chronic cerebral lactic acidosis exacerbates the MELAS phenotype. Specific Aim #3 is a new study assessing early biomarkers of brain dysfunction using PET, fMRI and voxel-based morphometric analysis. This aim tests the hypothesis that brain ventricular lactate correlates with brain cellular dysfunction. We anticipate that these studies will allow us to determine whether some subjects with the A3243G mutation will remain asymptomatic for the duration of their expected life (low risk group) whereas others who reveal minimal early evidence of structural/functional brain disturbances will become symptomatic and are deserving of early prophylactic treatment (high risk group). The ultimate objective of this clinical project is to find a cure for clinical syndromes associated with mtDNA point mutations.