Investigations of Methylmalonic Acidemia and Related Dis

本研究包括遗传性甲基丙二酸血症（MMA）和钴胺素缺乏症。这些代谢紊乱在遗传上是异质的，它们共同代表了有机酸中毒的一个重要子集。这些疾病在参考文献2至4中进行了综述。我们研究遗传性甲基丙二酸血症和钴胺缺乏症通过翻译的方法，包括临床和受影响的患者的代谢评估和使用动物模型来检查疾病在实验室。我们在参考文献1中回顾了我们的方法。在过去的一年里，我们已经开发了甲基丙二酸血症的小鼠和蠕虫模型，并对这两种系统进行了表征。这项研究的总体目标是确定在患者身上看到的并发症，在小鼠或其他生物体中复制这些发现，并利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，进行放射性同位素实验，研究细胞代谢，并在实验室中培养小蛔虫。

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. They disorders are reviewed in references 2 through 4. 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 review our approaches in reference 1. We have developed mouse and worm models of methylmalonic acidemia and have 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 40 participants in our clinical research studies since last year. We have studied the effects of solid organ transplantation on MMA, delineated a new neurologic syndrome in pateints who have suffered from a disease-related stroke and decribed 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 adults 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.