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Specific diagnostic marker for methylmalonic acidemia
A Biochemical Genetics Laboratory genetic counselor or consultant approval is required prior to specimen collection. The prenatal diagnosis is made on a dual, complementary approach involving direct chemical determination of methylmalonic acid (MMA) (at Mayo Medical Laboratories) in cell-free supernatant of amniotic fluid and molecular analysis for previously identified familial mutations or complementation studies (not currently offered at Mayo Medical Laboratories) in cultured amniocytes. Both tests are required for a definitive diagnosis. The amniocentesis must be performed between 16 and 19 weeks of gestational age. Previous knowledge of the complementation group (typically labeled as mut0, mut-, CblA, CblB, CblC, etc), associated homocystinuria, responsiveness to vitamin B12 of the affected child, and B12 intake of the mother during the pregnancy (if receiving treatment) are critical to secure an accurate prenatal diagnosis.
Methylmalonic acid (MMA) is a specific diagnostic marker for the group of disorders collectively called methylmalonic acidemia, which includes at least 7 different complementation groups. Two of them (mut0 and mut-) reflect deficiencies of the apoenzyme portion of the enzyme methylmalonyl-CoA mutase. Two other disorders (CblA and CblB) are associated with abnormalities in the adenosylcobalamin synthesis pathway. CblC, CblD, and CblF deficiencies lead to impaired synthesis of both adenosyl- and methylcobalamin.
Since the first reports of this disorder in 1967, many hundreds of cases have been diagnosed worldwide. Newborn screening identifies approximately 1 in 30,000 live births with a methylmalonic acidemia. The most frequent clinical manifestations are neonatal or infantile metabolic ketoacidosis, failure to thrive, and developmental delay. Excessive protein intake may cause life-threatening episodes of metabolic decompensation and remains a lifelong risk unless treatment is closely monitored, including serum and urine MMA levels.
Because the morbidity and mortality of methylmalonic acidemia are high, genetic counseling and prenatal diagnosis are frequently sought by families with 1 or more affected children. The prenatal diagnosis is made on a dual, complementary approach: enzymatic assays in cultured amniocytes or molecular analysis for previously identified familial mutations and direct chemical determination of MMA in cell-free supernatant of amniotic fluid from amniocentesis between 16 and 19 weeks of gestational age.
A significantly increased amniotic fluid methylmalonic acid concentration supports a diagnosis of methylmalonic acidemia.
If termination is under consideration, validation of an abnormal result should be done by molecular analysis for previously identified familial mutations or assay of (14)C-propionate fixation and cobalamin uptake in cultured amniocytes, and no medical action should be undertaken before the completion of all in vitro studies.
A prenatal diagnosis of methylmalonic acidemia is made only if there is a commitment to perform molecular analysis for previously identified familial mutations or have the amniocytes analyzed at an independent laboratory (not currently offered at Mayo Medical Laboratories with the exception of MHCZ / Methylmalonic Aciduria and Homocystinuria, cblC Type, Full Gene Analysis and MHDZ / Methylmalonic Aciduria and Homocystinuria, cblD Type, Full Gene Analysis).
Previous knowledge of the complementation group (typically labeled as mut0, mut-, CblA, CblB, CblC, etc), associated homocystinuria, responsiveness to vitamin B12 of the affected child, and B12 intake of the mother during the pregnancy are critical to secure an accurate prenatal diagnosis.
We have performed more than 60 prenatal diagnoses of methylmalonic acidemia and identified 13 affected fetuses. Currently, a finding of elevated methylmalonic acid is verified by measuring the concentrations of propionylcarnitine and homocysteine using mass spectrometry-tandem mass spectrometry methods.
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