Investigations of Methylmalonic Acidemia and Related Disorders

这项研究包括遗传性甲基丙二酸缺乏症（MMA）和钴胺素缺乏症。这些代谢紊乱是遗传异质性的，共同代表了有机酸代谢的一个重要子集。 我们研究遗传性甲基丙二酸和钴胺素缺乏症通过翻译的方法，其中包括受影响的患者的临床和代谢评估和使用动物模型在实验室中检查疾病。 我们已经开发了小鼠和蠕虫模型的甲基丙二酸血症，并继续在过去的一年中，这两个系统的特点。研究的总体目标是确定患者中观察到的并发症，在小鼠或其他生物体中复制研究结果，并使用综合信息指导新疗法的开发和测试，如基因和干细胞疗法。我们维持一个小鼠群体，使用细胞培养设施，用放射性同位素进行实验以研究细胞中的代谢，并在实验室中培养小蛔虫。 人类受试者研究的重点是评估美国甲基丙二酸血症的自然史，以进一步了解这组疾病的治疗，结局和并发症。 我们已经开发了一个用于结局研究的患者数据库，自该项目开始以来，我们的临床研究已经招募了50多名受影响的患者。我们研究了实体器官移植对MMA的影响，描述了患有疾病相关性卒中的患者的一种新的神经系统综合征，并描述了在一个患者子集中观察到的一系列眼部发现。这些患者通常作为住院患者进入NIH临床研究中心3至4天，并接受广泛的代谢测试。许多患者需要对中枢神经系统进行磁共振成像和磁共振波谱分析。我们使用高场强磁体（3 Telsa）进行这些研究。基因型-表型-酶相关性正在患者人群中进行研究。 模式生物和人类调查的结合方法，使部分缺陷的甲基丙二酸血症小鼠模型的发展，并提供了新的见解，在这种疾病中看到的生物能量缺陷。明年将继续研究这些实验进展的细节。 我们小组最近的一份报告钱德勒RJ，Tsai MS，Dorko K，Sloan J，Korson M，Freeman R，Strom S，Venditti CP（2007）腺病毒介导的鼠成纤维细胞和人肝细胞中甲基丙二酰辅酶A缺乏症的纠正。BMC Med Genet 8：24描述了在鼠胚胎成纤维细胞和原代人肝细胞中有效基因治疗的首次证明，说明这些方法是成功的，并且可以产生对患者治疗策略的新见解。在甲基丙二酸血症小鼠模型中开发和测试病毒基因传递的努力也将在今年继续进行。

This research study encompasses the hereditary methylmalonic acidemias (MMA) and cobalamin deficiency disorders. These metabolic disorders are genetically heterogeneous and collectively represent an important subset of the organic acidemias. We study the hereditary methylmalonic acidemias and cobalmin deficiency disorders via a translational approach that includes a clinical and metabolic evaluation of affected patients and the use animal models to examine the disorder in the laboratory. We have developed mouse and worm models of methylmalonic acidemia and have continued to characterized both systems in the past year. The general goal of the research is to define the complications seen in the patients, replicate the findings in mice or other organisms and use the combined information to guide the development and testing of new therapies, such as gene and stem cell therapy. We maintain a mouse colony, use cell culture facilities, perform experiments with radioactive isotopes to study metabolism in cells and grow small roundworms in the laboratory. The human subject research is focused on assessing the natural history of methylmalonic acidemia in the United States to further understand the treatment, outcome and complications in this group of disorders. We have developed a patient database for outcomes research and have enrolled more than 50 affected patients in our clinical research studies since beginning this project. We have studied the effects of solid organ transplantation on MMA, delineated a new neurologic syndrome in patients who have suffered from a disease-related stroke and described a range of eye findings seen in one subset of patients. The patients are usually admitted to the NIH Clinical Research Center as inpatients for 3 to 4 days and undergo extensive metabolic testing. Many patients need magnetic resonance imaging and magnetic resonance spectroscopy of the central nervous system. We use a high field strength magnet (3 Telsa) for these studies. Genotype-phenotype-enzymatic correlations are under investigation in the patients population. The combined approach of model organism and human investigations has allowed the development of a partial deficiency murine model of methylmalonic acidemia and provided new insights into the bioenergic defect seen in this disorder. The details of these experimental advances will continue to be studied in the next year. A recent report from our group Chandler RJ, Tsai MS, Dorko K, Sloan J, Korson M, Freeman R, Strom S, Venditti CP (2007) Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes. BMC Med Genet 8:24 describing the first demonstration of efficacious gene therapy in murine embryonic fibroblasts and primary human hepatocytes illustrates that these approaches are successful and can yield new insights into therapeutic strategies in patients. Efforts to develop and test viral gene delivery in the murine models of methylmalonic acidemia will also continue this year.