Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p

A new endoscopic staging system for angiofibromas

Objective: To develop a new staging system for juvenile nasopharyngeal angiofibroma that reflects changes in surgical approaches (endonasal), route of intracranial extension, and the extent of vascular supply from the internal carotid artery. Design: Retrospective review of case series. Setting: Academic medical center. Patients: Patients undergoing endoscopic endonasal surgery for juvenile nasopharyngeal angiofibroma at the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, from 1998 through 2008. Intervention: Patients were staged according to current systems and compared with a new staging system that also incorporated the route of skull base extension and tumor vascularity. Main Outcome Measures: Estimated blood loss, number of operations, and tumor recurrence. Results: Skull base erosion was observed in 74% of cases. Following embolization of external carotid artery tributaries, residual vascularity from the internal carotid artery was seen in 51% of patients. Residual vascularity, classified as UPMC stage IV and V, strongly correlated with blood loss, requirement for multiple procedures, and residual or recurrent tumor. Conclusions: Tumor size and extent of sinus disease are less important in predicting complete tumor removal with endonasal surgical techniques. The UPMC staging system for juvenile nasopharyngeal angiofibroma accounts for 2 important prognostic factors, route of cranial base extension, and vascularity and is applicable to endoscopic or open approaches. Compared with other staging systems, the UPMC staging system provides a better prediction of immediate morbidity (including blood loss and need for multiple operations) and tumor recurrence.Carl H. Snyderman, Harshita Pant, Ricardo L. Carrau and Paul Gardne