CONGENITAL METHYLMALONIC ACIDEMIA: ENZYMATIC EVIDENCE FOR TWO FORMS OF THE DISEASE^*

Abstract

Methylmalonic acidemia is an inherited metabolic disorder thus far found in children and characterized by the excessive excretion of methylmalonate in the urine. Typically these children exhibit vomiting, lethargy, ketoacidosis, and failure to grow. Many of the patients are mentally retarded and die early in life. Two variants of this disease are known. In one, the administration of vitamin B₁₂ will reverse or prevent these clinical findings, whereas in a second variant vitamin B₁₂ therapy is of no value.

This paper presents the first enzymatic evidence (obtained with cell-free liver extracts) that bears on two important aspects of the disease. It has been found that methylmalonylCoA carbonylmutase activity is essentially absent in the livers of patients suffering from one variant (vitamin B₁₂-unresponsive) of the disease. Secondly, it has been found that the livers of patients with the second variant (vitamin B₁₂-responsive) of the disease show normal enzymatic behavior in the presence of the coenzyme form of vitamin B₁₂, but are identical to the vitamin B₁₂-unresponsive variant in the absence of the added coenzyme. Thus the enzyme studies fully support the clinical observations that two types of this disease exist.