Methylmalonic aciduria

Homocystinuria with methylmalonic aciduria (Methylmalonic aciduria Type II) Methylmalonic... 

Dionisi-Vici C, et al. Classical organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006 29(2-3) 383-9. 

Hydroxyisobutyric aciduria Methylmalonic acidemia Multiple carboxylase def. 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

Methylmalonic aciduria (Bi2-reslstant) Mucolipidosis II (I-cell disease) Nlemann-Plck disease Sandhoff disease... 

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

On rare occasions an organic aciduria occurs not because of an enzyme deficiency but from a failure to transport or activate a water-soluble vitamin that serves as a cofactor for the reaction in question. Thus, congenital deficiencies in the metabolism of vitamin B12 commonly give rise to methylmalonic aciduria (Fig. 40-1, Table 40-2). Similarly, deficiencies of biotin metabolism can cause a severe organic aciduria (Table 40-2). It is very important to be aware of the defects of vitamin metabolism because the administration of large doses of these cofactors may completely prevent brain damage. 

Patients typically present by 6-12 months with severe developmental retardation, convulsions, microcephaly and homocysteinemia (=50pmol/l) with hypomethioninemia (<20 pmol/1). A few individuals have had psychiatric disturbances. The blood concentration of vitamin B12 is normal, and, unlike individuals with defects of cobalamin metabolism, these patients manifest neither anemia nor methylmalonic aciduria. The blood folic acid level is usually low. 

In cobalamin-E (cblE) disease there is a failure of methyl-B12 to bind to methionine synthase. It is not known if this reflects a primary defect of methionine synthase or the absence of a separate enzyme activity. Patients manifest megaloblastic changes with a pancytopenia, homocystinuria and hypomethioninemia. There is no methylmalonic aciduria. Patients usually become clinically manifest during infancy with vomiting, developmental retardation and lethargy. They respond well to injections of hydroxocobalamin. 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

Methylmalonic aciduria Propionic aciduria Isovaleric aciduria... 

Methylmalonic acidurias Methylmalonyl-CoA mutase, other defects... 

Roe CR, Hoppel CL, Stacey , Chalmers RA, Tracey BM, Millington DS (1983) Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of pro-pionyl groups. Arch Dis Child 58 916-920... 

Carrozzo R, Dionisi-Vici C, Steuerwald U, et al. (2007) SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain 130(Pt 3) 862-74. 

Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (pro ducing acetyl CoA) until the last three carbons (propionyl CoA). This compound is con verted to methylmalonyl CoA (a reaction requiring biotin), which is then converted to succinyl CoA by methylmalonyl CoA mutase (requiring vitamin B )- A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. 

In this hereditary disease up to 1 - 2 g of methylmalonic acid per day (compared to a normal of <5 mg/day) is excreted in the urine, and a high level of the compound is present in blood. Two causes of the rare disease are known/ One is the lack of functional vitamin B12-containing coenzyme. This can be a result of a mutation in any one of several different genes involved in the synthesis and transport of the cobalamin coenzyme.6 Cultured fibroblasts from patients with this form of the disease contain a very low level of the vitamin B12 coenzyme (Chapter 16), and addition of excess vitamin B12 to the diet may restore coenzyme synthesis to normal. Among elderly patients a smaller increase in methylmalonic acid excretion is a good indicator of vitamin B12 deficiency. A second form of the disease, which does not respond to vitamin B12, arises from a defect in the methylmalonyl mutase protein. Methylmalonic aciduria is often a very severe disease, frequently resulting in death in infancy. Surprisingly, some children with the condition are healthy and develop normally.3 1... 

Both methylmalonic aciduria and propionyl-CoA decarboxylase deficiency are usually accompanied by severe ketosis, hypoglycemia, and hyperglycinemia. The cause of these conditions is not entirely clear. However, methylmalonyl-CoA, which accumulates in methylmalonic aciduria, is a known inhibitor of pyruvate carboxylase. Therefore, ketosis may develop because of impaired conversion of pyruvate to oxalo-acetate. 

Methylmalonic aciduria is rare and can be diagnosed incorrectly. In 1989 a woman in St. Louis, Missouri, was convicted and sentenced to life in prison for murdering her 5-month-old son by poisoning with ethylene glycol. While in prison she gave birth to another son who soon fell ill of methylmalonyl aciduria and was successfully treated. Reexamination of the evidence revealed that the first boy had died of the same disease and the mother was released.1... 

Whlean et al. (W7) described a follow-up, extending over several years, of two infants with methylmalonic aciduria unresponsive to treatment with vitamin B12. The first patient, a boy, was the child of two first cousins delivery followed an uneventful pregnancy. The child had convulsions 4 days after birth and was found to have a profound metabolic acidosis, and was excreting a large amount of methylmalonic acid in his urine. His serum vitamin B12 concentration was normal. Further studies confirmed a diagnosis of methylmalonic aciduria. 

Kll. Kang, E. S., Snodgrass, P. J., and Gerald, P. S., Methylmalonic-coenzyme A racemase defect Another cause of methylmalonic aciduria. Pediatr. Res. 6, 875-879 (1972). 

Figure 20.20 Pathways of branched-chain amino acid metabolism. A, B, C, D, E, and F indicate defects in valinemia, maple syrup urine disease, isovaleric acidemia, /3-hydroxyisovaleric aciduria, a-methyl-j3-hydroxybutyric aciduria, and methylmalonic aciduria, respectively.

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