The Natural History of the Inherited Methylmalonic Acidemias

Abstract

Six biochemical and genetic forms of methylmalonic acidemia have been defined previously: two (mut degrees and mut-) resulting from defects in the mutase apoenzyme, and four (cbl A, cbl B, cbl C, and cbl D) resulting from deficient adenosylcobalamin synthesis. We retrospectively surveyed the clinical presentation, response to cobalamin supplementation, and long-term outcome in the four most prevalent mutant classes by collecting detailed information on 45 patients (15 mut degrees, 5 mut-, 14 cbl A, and 11 cbl B). Most patients presented acutely with a common set of clinical and laboratory findings; however, there were significant differences between mutant classes: mut degrees patients presented earlier in infancy than did cbl A and cbl B patients; in response to cobalamin supplements, marked decreases in the concentration of methylmalonic acid in blood or urine were reported in most cbl A patients and in nearly half the cbl B patients, but not in mut degrees or mut- patients; and finally, most cbl A, cbl B, and mut- patients were still living, whereas most mut degrees patients died during the first few months of life. Our data indicate that genotypic classification of the methylmalonic acidemias has prognostic and therapeutic use as well as diagnostic value.

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

“…Patients deficient in methylmalonylCoA mutase (MUT) or adenosylcobalamin, the enzymatic cofactor, accumulate methylmalonic acid in their tissues and body fluids, and display secondary metabolic perturbations such as hyperglycinemia, hyperammonemia and intermittent hypoglycemia [1]. Despite meticulous dietary control, affected individuals exhibit extreme metabolic instability and suffer from severe complications, such as developmental delay, renal disease, pancreatitis and metabolic infarction of the basal ganglia [2][3][4][5]. The pathophysiology of these processes and disease complications remain poorly defined.…”

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

“…Progression to coma is not uncommon. If the patient does not succumb to the initial metabolic decompensation, failure to thrive, developmental retardation, renal failure and metabolic strokes follow [1,[3][4][5][6][7][8][9][10][11][12][13][14].…”

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

“…cobalamin | chronic renal failure | megamitochondria | organic acidemia R enal tubular dysfunction with progression into chronic tubulointerstitial nephritis (CTIN) and end stage renal disease (ESRD) is a cardinal manifestation of methylmalonic acidemia (MMA), a common and severe organic acidemia characterized by metabolic instability, multisystemic complications, and high mortality (1,2). Isolated MMA is primarily caused by mutations in the vitamin B 12 -dependent, mitochondrial matrix-localized methylmalonyl-CoA mutase (MUT), an enzyme that mediates the entry of carbon skeletons derived from branched-chain amino acid, odd-chained fatty acid, and cholesterol oxidation into the Krebs cycle (3).…”