CLINICAL SYNDROMES ASSOCIATED WITH mt DNA POINT MUTATION

与 mt DNA 点突变相关的临床综合征

• 批准号: 6859043
• 负责人: DARRYL C DE VIVO
• 金额: $ 83.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859043
• 关键词: bioenergetics; biomarker; brain disorder diagnosis; brain imaging /visualization /scanning; brain morphology; central nervous system disorders; clinical trials; dichloroacetate; family genetics; functional magnetic resonance imaging; genetic disorder; human subject; human therapy evaluation; lactates; lactic acidosis; longitudinal human study; mental retardation; mitochondrial DNA; mitochondrial disease /disorder; nervous system disorder chemotherapy; neuropsychological tests; pathologic process; patient oriented research; point mutation; positron emission tomography; prognosis

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.

临床项目是Programproject的转化研究部门。我们已经构成了具有mtDNA突变的最大，完全表征的家族（51）。将近90％（44个家庭）带有A3243G突变，完全有症状的概率表现出Melas表型。首次评估时，家庭成员被分配给三个临床组（无症状，寡症和完全症状）。纵向和交叉 这些主题的分段研究提供了有关自然历史的宝贵信息。这项纵向研究已进入第10年，扩大了我们对临床表型和医疗并发症频率的理解。已经确定了关键的生物学变量，可以预测无症状/寡症状组的发病率和完全有症状组的死亡率的增加。脑室乳酸是脑细胞代谢最敏感的生物标志物。尿液沉积物DNA是mtDNA的最可靠度量 突变。神经心理学研究表明，视觉记忆是最脆弱的大脑领域。有症状的MELAS患者正在进行三年的随机DCA/安慰剂双盲研究，以确定慢性脑乳酸性酸中毒是否有助于脑损伤。我们提出了三个具体目标。特定目的＃1继续我们的自然史研究将基因型和表型相关联。该目的检验了以下假设：脑心室乳酸与斜表表型和预后相关。特定目标＃2继续我们的MELAS/DCA临床试验。这个目的检验了以下假设：慢性脑乳酸性酸中毒加剧了Melas表型。特定目标＃3是一项新的研究，提早评估 使用PET，fMRI和基于体素的形态分析的脑功能障碍的生物标志物。该目标检验了以下假设：脑室乳酸与脑细胞功能障碍相关。我们预计这些研究将使我们能够确定某些具有A3243G突变的受试者是否会在预期寿命（低风险组）的持续时间内无症状（低风险组），而其他人则表现出最小的早期早期证据的结构/功能性脑部障碍的证据将成为症状，并且应有早期预防治疗的应有的（高风险组）。 该临床项目的最终目标是找到与mtDNA点突变相关的临床综合征的方法。