Vitamin methylmalonic aciduria

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. 

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. 

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... 

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. 

As discussed in Section 10.8.2, moderate vitamin B12 deficiency results in increased accumulation of methylmalonyl CoA, and methylmalonic aciduria and methylmalonic acidemia. This can be exploited as both a means of detecting subclinical deficiency and monitoring vitamin B12 status in patients with pernicious anemia who have been treated with parenteral vitamin. As they become depleted, the excretion of methylmalonic acid, especially after a loading dose of valine, will provide a sensitive index of depletion of vitamin Bi2 reserves. 

Methylmalonyl CoA mutase is especially sensitive to vitamin B12 depletion, so methylmalonic aciduria is the most sensitive index of vitamin B12 status. Folate deficiency does not cause methylmalonic aciduria. However, up to 25% of patients with confirmed pernicious anemia excrete normal amounts of methylmalonic acid, even after a loading dose of valine (Chanarin et al., 1973). 

Higginbottom, M, C Sweetman, L., and Nyhan, W. L. (1978). A syndrome of methylmalonic aciduria, homocysteinuria, megaloblastic anemia, and tieurological abnormalities in a vitamin Bjj-deficient breast-fed infant of a strict vegetarian. W. f.ngl ]. Med. 299, 317-323. 

Methylmalonic aciduria Methylmalonyl-CoA isomerase or vitamin Bu coensyme Methylmalonic acid (4 glydne) Methylmalonic acid Metbylmalmiic add increased in CSF, keto-nuria, protdn intolerance Coma, extensOT spasna. retarded devdopment, metabolic addosis (vitamin Bu treats ment) Chromatography Aeetest sticks (01, R9. Rll, R12. S41. S53)... 

Inborn errors in the synthesis of adenosylcobalamin or of both adenosyl- and methylcobalamins have been described. They cause, respectively, methylmalonic aciduria alone or combined with homocystinuria (Table 38-1). These disorders respond to treatment with pharmacological doses of vitamin B12. Methylmalonic aciduria that does not respond to vitamin B12 is probably due to an abnormal methylmalonyl-CoA mutase. 

Not all patients who present the same clinical picture respond to vitamin therapy. Thus, if the structural gene for an apoenzyme or transport molecule is completely absent because of a gene deletion, no amount of vitamin or cofactor will correct the defect. If the mutation affects substrate rather than cofactor binding, the pathway is blocked just as effectively and cannot be relieved by increased concentration of cofactor. Thus, six mutations have been identified that cause methylmalonic aciduria. 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Defects in intracellular metabolism of vitamin Bj have been reported in children with methylmalonic aciduria and homocystinuria. Potential mechanisms include an inability of cells to transport vitamin Bj or accumulate the vitamin because of a failure to synthesize an intracellular acceptor, a defect in the formation of deoxyadenosylcobalamin, or a congenital lack of methyl-malonyl CoA isomerase. 

Gutierrez-Aguilar, G., Abenia-Us6n, P., Garcfa-Cazorla, A., Waseca, M.A., and Campistol, J. 2005. Encephalopathy with methylmalonic aciduria and homocystinuria secondary to a deficient exogenous supply of vitamin B12. Rev. Neurol. 40 605-608. 

Methylmalonyl-CoA mutase (EC 5.4.99.2). Failure to convert (/ )-methylmalonyl-CoA into succinyl-CoA. Large quantities of methylmalonic acid appear in plasma and urine. Affected children fail to thrive and show pronounced ketoacidosis. Often fatal in early life. Hyperammonemia and intermittent hyperglycinemia are also typical. Restricted protein intake and synthetic diets are helpful, in particular low intakes of leucine, isoleucine, valine, threonine and methionine. A similar condition may arise from a congenital deficiency of methylmalonyl-CoA epimerase (EC 5.1.99.1). Both conditions unresponsive to vitamin Bj2. Another type of methylmalonyl aciduria is thought to result from an hereditary deficiency of deoxyadenosyl transferase (transfers the 5 -deoxyade-nosyl group in cobalamin synthesis), which provides the coenzyme of methylmalonyl-CoA mutase. This condition responds to injection of B,2. Dietary B12 deficiency also results in methylmalonic aciduria. 

As was already pointed out, methylmalonic aciduria occurs in children as a hereditary disease. Some patients are responsive to large doses of vitamin Bi2-The biochemical pathogenesis of the disease has been clarified at least in part. Cultures of fibroblasts obtained from such patients oxidize propionate and methylmalonic acid to CO2 much more slowly than do fibroblasts obtained from normal cells. But if large amounts of hydroxycobalamin are added to the culture medium, methylmalonate and propionic acid oxidation is restored to normal, thus excluding a defect in the methylmalonate mutase levels. Assays for deoxyadenosylcobalamin in fibroblasts obtained from methylmalonic aciduria patients and normal individuals revealed that the concentration of coenzyme is in the mutant only 10% of that in the normal fibroblast. Inasmuch as the mechanism of vitamin B12 conversion to the deoxyadenosylcobalamin coenzyme is not known, except for the fact that several enzymic steps are involved, the exact nature of the defect in methylmalonic aciduria cannot be ascertained. 

Inasmuch as the levels of deoxyadenosine B12 are low in fibroblast, the defect in methylmalonic aciduria appears to result from an inability to convert the vitamin to the coenzyme. 

Vitamin B12 must be converted into its coenzyme forms, adenosylcobalamin and methylcobalamin, in the cell. These coenzymes function as cofactors of methylmalonyl-CoA mutase and methionine synthase, respectively. Chronic kidney disease (CKD) may affect the conversion from vitamin B12 to the coenzyme forms. This section describes the intracellular metabolism of cyanocobalamin, which is included in many dietary supplements, in particular, referring to a recently discovered trafficking chaperone called methylmalonic aciduria cdlC type with homocystinuria (MMACHC). Cyanocobalamin is first converted to cob(II)alamin, which has no cyanogen group on the ligand occupying the upper axial position of the cobalamin structure. Cob(II)alamin is further reduced to cob(I)alamin, which can function as a coenzyme in the body. 

Treatment of CBS deficiency includes a low-methionine diet, vitamin Bs, folic acid, and betaine (N-trimethylglycine) [1]. Betaine works by (re)methy-lating homocysteine to methionine, and it is used in conjunction with folic acid in the treatment of MTHFR deficiency [3]. Hydroxycobalamin should be given to patients with methylmalonic aciduria protein restriction, folic acid, vitamin Bg, betaine and other measures may also be appropriate, depending on which mutant class (cblA through cblG) a patient is assigned to by complementation analysis [3, 6]. 

A serum concentration of vitamin B below llOpmol/L is associated with megaloblastic bone marrow, incipient anaemia and myelin damage. Below 150pmol/L there are early bone marrow changes, abnormalities of the dUMP suppression test (section 11.11.6.2) and methylmalonic aciduria after a valine load (section 11.10.2). 

A compound which can be found in the urine of patients witl vitamin B,2 deficiency and in the very rare inborn error o metabolism, methylmalonic aciduria. It is an intermediate in th< metabolism of propionic acid (itself a metabolite of certaii amino acids, particularly valine and isoleucine). Vitamin B 2 is i cofactor in the enzymic step by which methylmalonyl coenzym A is converted to succinyl coenzyme A. In vitamin B,2 deficienc methylmalonate accumulates and passes out into the urine. It measurement in urine can therefore be used to diagnose deficier cy of this vitamin. It can be estimated colorimetrically by il reaction with diazotized p-nitroaniline to form a green con pound. 

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