Congenital Methylmalonic Acidemia: Enzymatic Evidence for Two Forms of the Disease

Abstract

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 BH2-responsive) of the disease show normal enzymatic behavior in the presence of the coenzyme form of vitamin B,2, but are identical to the vitamin B,2-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.Introduction.-Two variants of inherited methylmalonic acidemia have been described since the original report of this inborn error of metabolism by Oberholzer et al. ' The metabolic pathway involved is the conversion of propionate to succinate, one step of which requires the cobamide coenzyme form of vitamin

Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism.

“…A theoretical exception to this rule is the failure of a polarity mutant to complement a point mutation in a distal gene of an operon or gene cluster (12,13), but such phenomena are very rare and have been observed only in bacteria and fungi. Second, the prominent biochemical differences both between the mutase apoenzyme and the Cbl mutants (1,7), and among the Cbl mutants (4,5) (1975) 3185 that these two classes reflect mutations at the same locus and that the complementation observed between them is intragenic. For instance, one step in AdoCbh synthesis could be catalyzed by an enzyme composed of two identical subunits and bound to the mitochondrial membrane.…”

“…Some patients with methylmalonicacidemia respond to administration of pharmacologic doses of vitamin B12 with decreased accumulation of methylmalonic acid and clinical improvement (7,14). Such responsive patients appear to be restricted to those with defects of Cbl metabolism.…”

Proceedings of Seminar on the Use of Stable Isotopes in Clinical Pharmacology, Univ. Of Chicago, November 10--11, 1971.

“…C succinate respectively before they are completely oxidized to C0 2 (6,32,33). Thus, it should be possible to assess the relative effect of metabolism occurring within and without the TCA cycle upon the radiorespirometry pattern by a comparison of the results obtained in studies with each pair of compounds.…”

“…Methods that are available to you, or at least some of them, are presented in Table IV. NUCLEAR MAGNETIC RESONANCE -ODD NUCLEI 13 C, 15 N, and 33 S CAN "SEE" THE ENVIRONMENT OF THE ATOM IN A COMPLEX MOLECULE.…”

Methylmalonyl-CoA mutase activity of leukocytes in variants and heterozygotes of methylmalonic acidemia.

“…In 1969 Morrow et al (1969b) measured the methylmalonyl-CoA mutase activity using liver biopsy specimens from patients with vitamin B12 responsive or unresponsive type of methylmalonic acidemia, and reported that in the case with vitamin B12 responsive type the mutase activity was restored to the normal when DBCC was added to the assay media.…”