Methylmalonic 712 Tests

Management is essentially the same as for folate deficiency but the site of the lesion, that may necessitate further investigation and treatment, needs accurate definition by means of the Schilling test. Additional useful determinations are homocysteine and methylmalonic acid levels. 

When Rinaldo analyzed Ryan s blood serum, he found high concentrations of methylmalonic acid, a breakdown product of the branched-chain amino acids isoleucine and valine, which accumulates in MMA patients because the enzyme that should convert it to the next product in the metabolic pathway is defective. And particularly telling, he says, the child s blood and urine contained massive amounts of ketones, another metabolic consequence of the disease. Like Shoemaker, he did not find any ethylene glycol in a sample of the baby s bodily fluids. The bottle couldn t be tested, since it had mysteriously disappeared. Ri-naldo s analyses convinced him that Ryan had died from MMA, but how to account for the results from two labs, indicating that the boy had ethylene glycol in his blood Could they both be wrong ... 

Methylmalonyl-CoA mutase is a cobalamin-linked enzyme of mitochondria that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. A reduction of this enzyme due to vitamin B12 deficiency will result in a metabolic block with the urinary excretion of methylmalonic acid, and the measurement of this metabolite has been used to confirm a deficiency of vitamin B12. The test has also been useful in investigating rare abnormalities of this enzyme that result in the excretion of methylmalonic acid in the presence of adequate vitamin B12. Given an oral loading dose of valine or isoleucine will increase the urinary excretion of methylmalonic acid in patients with a vitamin B12 deficiency (G4). However, Chanarin and his colleagues (CIO) found that one-quarter of their patients with pernicious anemia excreted a normal concentration of methylmalonic acid even after a loading dose of valine. Normal subjects excrete up to 15 mg of methylmalonic acid in their urine over a 24-hour period (Cll). 

He was provided with a diet restricted in protein but was found to limit his own protein intake to 1.0 to 1.2 g/kg. Treatment with large doses of vitamin B12 for a period of 4 months made no difference to the concentration of methylmalonic acid excreted in his urine. He required frequent hospitalization for anorexia, vomiting, and dehydration. At 18 months of age he developed renal failure, and at 3 years he became oliguric. His physical development appeared normal for the first 12 months and then it deteriorated. He started to walk at 31 years, but at this time he also had hepatomegaly and persistent vomiting. On the basis of a developmental screening test he was found to be 12 to 18 months behind in all areas tested. 

Test for serum levels of methylmalonic add (functional test). 

Both direct and indirect (ftmctional) methods are available for assessing vitamin B status. The indirect tests include assays for urinary and serum concentrations of methylmalonic acid, plasma homocysteine, the deoxyuridine suppression test, and the vitamin B12 absorption test. Cyto-chemical staining of red blood cell (RBC) precursors and the test for IF blocking antibodies are also ancillary methods for assessing vitamin B12 status. 

Indirect tests assess the functional adequacy of vitamin Bi2. Serum methylmalonic acid concentration is increased when a lack of adenyl-Cbl causes a block in the conversion of methylmalonyl-CoA to succinyl-CoA. It is a sensitive test of status, being often the first analyte to be raised in sub-clinical vitamin B12 deficiency. It has a further advantage in that it is unaffected by folate deficiency. Early methods for methylmalonic acid lacked sensitivity and specificity, a situation that has been resolved by the adoption of gas chromatographic-mass spectrometric methods,though these require specialized handling. Plasma total homocysteine concentration is a sensitive indicator of vitamin B status, because methyl-Cbl is required for the remethylation of... 

Laboratory tests on the urine of a patient identified the presence of methylmalonate ( OOC-CH(CH3)-COO ). Methyl-malonate... 

Bea Twelvlow, a 75-year-old woman, went to see her physician because of a numbness and tingling in her arms. A diet history indicated a normal and healthy diet, but Bea was not taking any supplemental vitamin pills. Laboratory results indicated a slight elevation of methylmalonic acid, and this led the physician to suspect a vitamin B12 deficiency. Direct measurement of serum B12 levels did indicate a deficiency, but the results of a Schilling test were normal. 

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 test which can be used in the investigation of vitamin Bj2 deficiency. The metabolism of valine contains a step in which methylmalonyl coenzyme A is converted to succinyl coenzyme A, an enzymic reaction which requires vitamin B12 as a cofactor. In vitamin B deficient individuals, administration of an oral load of valine results in a greater than normal excretion of methylmalonate in the urine which can be estimated colorimetrically. 

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