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End stage kidney disease is a well-known complication of methylmalonic acidemia (MMA), and can be treated by dialysis, kidney transplant, or combined kidney-liver transplant. While liver and/or kidney transplantation in MMA may reduce the risk of metabolic crisis and end-organ disease, it does not fully prevent disease-related complications. We performed detailed metabolite and kinetic analyses in a 28-year-old patient with mut (0) MMA who underwent hemodialysis for 6 months prior to receiving a combined liver/kidney transplant. A single hemodialysis session led to a 54 % reduction in plasma methylmalonic acid and yielded a plasma clearance of 103 ml/min and VD0.48 L/kg, which approximates the total body free water space. This was followed by rapid reaccumulation of methylmalonic acid over 24 h to the predialysis concentration in the plasma. Following combined liver/kidney transplantation, the plasma methylmalonic acid was reduced to 3 % of pre-dialysis levels (6,965 ± 1,638 (SD) μmol/L and 234 ± 100 (SD) μmol/L) but remained >850× higher than the upper limit of normal (0.27 ± 0.08 (SD) μmol/L). Despite substantial post-operative metabolic improvement, the patient developed significant neurologic complications including acute worsening of vision in the setting of pre-existing bilateral optic neuropathy, generalized seizures, and a transient, focal leukoencephalopathy. Plasma methylmalonic acid was stable throughout the post-operative course. The biochemical parameters exhibited by this patient further define the whole body metabolism of methylmalonic acid in the setting of dialysis and subsequent combined liver/kidney transplant.

Methylmalonic acidemia is a lethal inborn error of metabolism that causes mitochondrial impairment, multi-organ dysfunction and a shortened lifespan. Previous transmission electron microscope studies of thin sections from normal (Mut(+/+)) and diseased (Mut(-/-)) tissue found that the mitochondria appear to occupy a progressively larger volume of mutant cells with age, becoming megamitochondria. To assess changes in shape and volume of mitochondria resulting from the mutation, we carried out ion-abrasion scanning electron microscopy (IA-SEM), a method for 3D imaging that involves the iterative use of a focused gallium ion beam to abrade the surface of the specimen, and a scanning electron beam to image the newly exposed surface. Using IA-SEM, we show that mitochondria are more convoluted and have a broader distribution of sizes in the mutant tissue. Compared to normal cells, mitochondria from mutant cells have a larger surface-area-to-volume ratio, which can be attributed to their convoluted shape and not to their elongation or reduced volume. The 3D imaging approach and image analysis described here could therefore be useful as a diagnostic tool for the evaluation of disease progression in aberrant cells at resolutions higher than that currently achieved using confocal light microscopy., (Published by Elsevier Inc.)

Introduction and Objective: To characterize enamel defects in patients with methylmalonic acidemia (MMA) and cobalamin (cbl) metabolic disorders and to examine salivary methylmalonate levels in MMA., Subjects and Methods: Teeth from patients (n = 32) were evaluated for enamel defects and compared with age- and gender-matched controls (n = 55). Complementation class (mut, cblA, cblB and cblC) and serum methylmalonate levels were examined. Primary teeth from two patients were examined by light and scanning electron microscopy and salivary methylmalonate levels from two patients were analyzed., Results: Enamel defects were significantly more prevalent per tooth in the affected group than the control group, across complementation types (P < 0.0001). The mut MMA subgroup had a significantly higher prevalence per individual of severe enamel defects than controls (P = 0.021), and those with enamel defects exhibited higher serum methylmalonate levels than those without (P = 0.017). Salivary methylmalonate levels were extremely elevated and were significantly higher than controls (P = 0.002). Primary teeth were free of enamel defects except for two cblC patients who exhibited severe enamel hypoplasia. One primary tooth from a cblC patient manifested markedly altered crystal microstructure., Conclusion: Enamel anomalies represent a phenotypic manifestation of MMA and cbl metabolic disorders. These findings suggest an association between enamel developmental pathology and disordered metabolism.

Methylmalonic acidemia (MMA), an autosomal recessive metabolic disorder, is most often caused by mutations in methylmalonyl-CoA mutase (MUT). Severely affected patients typically present with metabolic crisis in the early neonatal period and can perish despite intervention. Survivors follow an unstable course and can require elective liver transplantation to prevent life-threatening metabolic decompensation. Therapeutic alternatives to liver transplantation such as hepatocyte-directed gene and cell therapies lack experimental validation. We have used a murine model of mut0 MMA to assess the efficacy of virus-mediated gene therapy to rescue the neonatal lethality seen in the Mut(-/-) mice. Affected pups and control littermates received either intramuscular or intrahepatic injections of adenovirus carrying the Mut gene expressed under the control of the cytomegalovirus promoter. All of the Mut(-/-) pups injected via the intramuscular route perished within the first 48 hr of birth. However, more than 50% of the Mut(-/-) pups that received intrahepatic injections survived beyond weaning (day 15). The treated mutants expressed methylmalonyl-CoA mutase mRNA and protein, and displayed decreased metabolite levels compared with uninjected Mut(-/-) mice. The results demonstrate that adenovirus-mediated, hepatic methylmalonyl-CoA mutase expression can rescue Mut(-/-) pups from neonatal mortality and provide proof-of-principle evidence for the efficacy of liver-directed gene delivery in methylmalonic acidemia.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinyl-CoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.