Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia

Meer, Skadi van der; Poggi, F; Spada, Marco; Bonnefont, Jean‐Paul; Ogier, H.; Hubert, Philippe; Depondt, Eliane; Rapoport, D.; Rabier, Daniel; Charpentier, C.; Parvy, P; Bardet, Jean-Marc; Kamoun, P.; Saudubray, Jean Marie

doi:10.1016/s0022-3476(05)82005-0

Cited by 118 publications

(71 citation statements)

References 17 publications

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“…Progression to coma is not uncommon. If the patient does not succumb to the initial metabolic decompensation, failure to thrive, developmental retardation, renal failure and metabolic strokes follow [1,[3][4][5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Guire

Lim-Melia

Diaz

et al. 2008

Molecular Genetics and Metabolism

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Over 27 cases of liver transplant, kidney transplant and combined liver-kidney transplant have been reported for the treatment of methylmalonic aciduria. We describe a case of a 5-year-old boy who underwent combined liver-kidney transplant (CLKT) for phenotypic mut0 disease. His history was notable for more than 30 hospitalizations for severe acidosis, metabolic strokes, liver disease, pancreatic disease, chronic renal insufficiency with interstitial nephritis, and decreased quality of life. Post-CLKT, there was a marked reduction in serum (80%) and urine MMA levels (90%) as well as a cessation of metabolic decompensations. Neurologic deterioration continued post-CKLT manifested as a cerebellar stroke. The clinical details and therapeutic implications of solid organ transplant for methylmalonic aciduria are discussed.

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Section: Introductionmentioning

confidence: 99%

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Guire

Lim-Melia

Diaz

et al. 2008

Molecular Genetics and Metabolism

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“…Patients deficient in methylmalonylCoA mutase (MUT) or adenosylcobalamin, the enzymatic cofactor, accumulate methylmalonic acid in their tissues and body fluids, and display secondary metabolic perturbations such as hyperglycinemia, hyperammonemia and intermittent hypoglycemia [1]. Despite meticulous dietary control, affected individuals exhibit extreme metabolic instability and suffer from severe complications, such as developmental delay, renal disease, pancreatitis and metabolic infarction of the basal ganglia [2][3][4][5]. The pathophysiology of these processes and disease complications remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Chandler¹,

Aswani²,

Tsai³

et al. 2006

Molecular Genetics and Metabolism

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We have utilized Caenorhabditis elegans to study human methylmalonic acidemia. Using bioinformatics, a full complement of mammalian homologues for the conversion of propionyl-CoA to succinyl-CoA in the genome of C. elegans, including propionyl-CoA carboxylase subunits A and B (pcca-1, pccb-1), methylmalonic acidemia cobalamin A complementation group (mmaa-1), co(I) balamin adenosyltransferase (mmab-1), MMACHC (cblc-1), methylmalonyl-CoA epimerase (mce-1) and methylmalonyl-CoA mutase (mmcm-1) were identified. To verify predictions that the entire intracellular adenosylcobalamin metabolic pathway existed and was functional, the kinetic properties of the C. elegans mmcm-1 were examined. RNA interference against mmcm-1, mmab-1, mmaa-1 in the presence of propionic acid revealed a chemical phenotype of increased methylmalonic acid; deletion mutants of mmcm-1, mmab-1 and mce-1 displayed reduced 1-[ 14 C]-propionate incorporation into macromolecules. The mutants produced increased amounts of methylmalonic acid in the culture medium, proving that a functional block in the pathway caused metabolite accumulation. Lentiviral delivery of the C. elegans mmcm-1 into fibroblasts derived from a patient with mut o class methylmalonic acidemia could partially restore propionate flux. The C. elegans mce-1 deletion mutant demonstrates for the first time that a lesion at the racemase step of methylmalonyl-CoA metabolism can functionally impair flux through the methylmalonyl-CoA mutase pathway and suggests that malfunction of MCEE may cause methylmalonic acidemia in humans. The C. elegans system we describe represents the first lower metazoan model organism of mammalian propionate spectrum disorders and demonstrates that mass spectrometry can be employed to study a small molecule chemical phenotype in C. elegans RNAi and deletion mutants.

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“…Despite the improvement of therapy during the last 20 years, the overall outcome of these patients remains disappointing, e.g. there is growing evidence for the development of long-term neurological deficits (5). Neuroimaging has revealed a symmetric degeneration of the basal ganglia, in particular in globus pallidus (6).…”

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confidence: 99%

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Okun¹,

Hörster²,

Farkas³

et al. 2002

Journal of Biological Chemistry

160

151

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Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.

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Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia

Cited by 118 publications

References 17 publications

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

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