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 in the past and have focused on mouse models and gene therapy 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 and non-radioactive isotopes to study metabolism in cells, construct gene therapy vectors, administer gene therapy treatments to mice and use routine molecular biological and biochemical studies to analyze our experiments. The human subject research is focused on assessing the natural history of methylmalonic acidemia and cobalamin metabolic disorders in the United States to further understand the treatment, outcome and complications in this group of patients. We have developed a patient database for outcomes research and have enrolled more than 75 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 bioenergetic defect seen in this disorder. The details of these experimental advances that have used mouse and patient derived materials has resulted in a major publication that has expanded the understanding of the pathophysiology of methylmalonic acidemia. In the past year, we three major research papers have appeared describing our results and filed a US patent on a device and method used to track gene therapy using stable isotopes in mice. Efforts to develop and test viral gene delivery and cell therapy in the murine models of methylmalonic acidemia will also continue this year, with hope that extension to patients will follow. Novel mouse models of methylmalonic acidemia will also be generated and studied.
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