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Heterogeneous inborn error of metabolism affecting amino acid metabolism, leading to metabolic acidosis and accumulation of methylmalonic acid (MMA) and its by-products.

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Methylmalonic Aciduria, Methylmalonic-Coenzyme A Mutase Deficiency; MMA.

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First reported in 1967 by Oberholzer and Stokke.

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Approximately 1:25,000-50,000 (all types of MMA included). Consanguinity is a risk factor. No gender predilection has been reported.

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Autosomal recessive (for all types). The gene encoding the enzyme methylmalonyl-CoA mutase has been mapped to 6p12-21.1. Two forms of this mutase deficiency exist: the mut0 form with complete absence of mutase activity, and the mut- form with reduced mutase activity. The mutase defect accounts for approximately 50% of patients with MMA. The defect in adenosylcobalamin synthesis has been mapped to chromosome 4q31.1-2.

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Methylmalonic-coenzyme A mutase is a vitamin B12-dependent enzyme involved in the catabolism of leucine, isoleucine, and valine; its deficiency leads to increased amounts of MMA in plasma and urine. Because of secondary inhibition of propionyl-CoA carboxylase, propionic acid also accumulates, as do other organic acids. Accumulation of propionyl-CoA results in inhibitory effects on various pathways of intermediary mitochondrial metabolism and secondary carnitine deficiency, thus explaining hypoglycemia, hyperammonemia, and hyperlactacidemia and the synthesis of odd-numbered abnormal fatty acids. Moreover, gut bacteria produce approximately 25% of the propionate to be metabolized.

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Neonatal screening for inborn errors of metabolism should detect all genetic variants of MMA. Large amounts of MMA, methylcitrate, propionic acid, and 3-hydroxy propionic acid can be detected in the urine by gas chromatography-mass spectrometry. However, once other causes for neonatal or infantile ketoacidosis have been ruled out, simple colorimetric assays for urinary MMA for suspected MMA are also available. Enzyme analysis in fibroblasts is used to detect the specific enzyme abnormality and finalize the diagnosis. Cultured amniotic cells are used for prenatal diagnosis.

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The clinical picture has a high variability, and asymptomatic children with mutase apoenzyme deficiency have been identified through newborn screening. Although the signs in symptomatic children are basically similar to those of Propionic Acidemia, complications and prognosis are worse in MAA. In 80%, manifestation of mut0 patients occurs in the first week of life and the remainder by 6 months of life. In contrast, mut- and cobalamin disorder patients most often present after the first month of life. The most common signs and symptoms at onset after a period of normal feeding are lethargy or coma, poor feeding with failure to thrive, recurrent vomiting with dehydration, hepatosplenomegaly, respiratory distress, and muscular hypotonia. MMA caused by a cobalamin-related defect usually has onset later in childhood or adolescence, starting with decreased lower leg sensitivity, thrombosis secondary to persistent homocystinuria, and progressive myopathy leading to chronic gait disturbances, which may not be irreversible. The majority of patients present with metabolic acidosis with a blood pH less than 6.9 and bicarbonate concentrations as low as 5 mmol/l. Ketonemia and ketonuria, hyperammonemia, ...

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