Inborn errors of metabolism comprise a heterogeneous group of genetic disorders that occur with an overall incidence of about 1: 1500 in the US population. Many are associated with significant childhood morbidity and mortality as well as frequent hospitalizations. Modern screening methodologies are allowing for the diagnosis of presymptomatic, affected patients but little is being done to develop new treatments and therapies, in part because the natural histories of the disease states are not fully understood and animal models do not exist for many of the disorders. One relatively common inborn error of metabolism is methylmalonic acidemia (MMA), which usually is caused by a deficiency of methylmalonyI-CoA mutase. It is a devastating metabolic disease and one of the most common organic acidemias. No definitive treatment exists, although some patients have benefited from liver and kidney-liver transplantation. To study MMA, we will produce a series of murine models to replicate the human disease state and test the following hypotheses: (1) Mice lacking methylmalonyI-CoA mutase activity will have a severe metabolic phenotype characterized by fatal ketoacidosis and massive accumulation of methymalonic acid. (2) Liver specific expression of methylmalonyI-CoA mutase will restore metabolic homeostasis in deficient mice but will not fully correct their metabolic abnormalities. A small animal model of methylmalonic acidemia will be of great use to examine the natural history and pathophysiology of MMA and to assess the possibility of liver-directed gene expression as a treatment for MMA.
| Chandler, Randy J; Venditti, Charles P (2008) Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. Hum Gene Ther 19:53-60 |
