Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

Abstract

Combined methylmalonic acidemia and homocystinuria, cblC type, is an inborn error of intracellular cobalamin metabolism with a wide spectrum of clinical manifestations that is stated to be the most common inherited disorder of cobalamin metabolism. This metabolic disease is caused by mutations in the MMACHC gene and results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, cofactors for the methylmalonyl-CoA mutase and methionine synthase enzymes. Elevated methylmalonic acid and homocysteine with decreased methionine production are the biochemical hallmarks of this disorder. Awareness of the diverse clinical presentations associated with cblC disease is necessary to provide a timely diagnosis, to guide management of affected individuals and to establish a framework for the future treatment of individuals detected through expanded newborn screening. This article reviews the biochemistry, clinical presentations, genotype-phenotype correlations, diagnosis and management of cblC disease.

Fig. 1

Intracellular metabolism of cobalamin and intersecting pathways. The steps of the intracellular cobalamin metabolism, their complementation groups and corresponding genes are shown. The folate cycle, 1-carbon metabolism and the betaine-homocysteine methyltransferase reaction are shown for their importance in the pathophysiology and treatment of cblC disease. Abbreviations. AdoCbl: 5’-deoxyadenosylcobalamin; Cbl: Cobalamin; Cbl lII: Dietary cobalamin contains a cobalt in the 3+ state (oxidized) and it is reduced to Cbl II and Cbl I, for its use in coenzyme synthesis. CBS: Cystathionine beta synthase; Gly: Glycine; LMBRD1: Lysosomal cobalamin exporter, defective in methylmalonic acidemia and homocystinuria, cblF type; MeCbl: Methylcobalamin; MMAA: Gene responsible for methylmalonic acidemia, cblA type; MMAB: Gene responsible for methylmalonic acidemia, cblB type; MMACHC: Gene responsible for methylmalonic acidemia and homocystinuria, cblC type; MMADHC: Gene responsible for methylmalonic acidemia and/or homocystinuria, cblD type; MUT: methylmalonyl-CoA mutase; MTR: 5-methyltetrahydrofolate-homocysteine S-methyltransferase also known as methionine synthase; MTRR: Methionine synthase reductase; SAM: S-adenosylmethionine; Ser: Serine; THF: Tetrahydrofolate