Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease
Anna J. Esser,
Srijan Mukherjee,
Ilia A. Dereven’kov,
Sergei V. Makarov,
Donald W. Jacobsen,
Ute Spiekerkoetter,
Luciana Hannibal
Affiliations
Anna J. Esser
Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, 79106 Freiburg, Germany
Srijan Mukherjee
Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, 79106 Freiburg, Germany
Ilia A. Dereven’kov
Department of Food Chemistry, Ivanovo State University of Chemistry and Technology, 153000 Ivanovo, Russian Federation
Sergei V. Makarov
Department of Food Chemistry, Ivanovo State University of Chemistry and Technology, 153000 Ivanovo, Russian Federation
Donald W. Jacobsen
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland 44195, USA
Ute Spiekerkoetter
Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, 79106 Freiburg, Germany
Luciana Hannibal
Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Corresponding author
Summary: Nutritional deficiency and genetic errors that impair the transport, absorption, and utilization of vitamin B12 (B12) lead to hematological and neurological manifestations. The cblC disease (cobalamin complementation type C) is an autosomal recessive disorder caused by mutations and epi-mutations in the MMACHC gene and the most common inborn error of B12 metabolism. Pathogenic mutations in MMACHC disrupt enzymatic processing of B12, an indispensable step before micronutrient utilization by the two B12-dependent enzymes methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). As a result, patients with cblC disease exhibit plasma elevation of homocysteine (Hcy, substrate of MS) and methylmalonic acid (MMA, degradation product of methylmalonyl-CoA, substrate of MUT). The cblC disorder manifests early in childhood or in late adulthood with heterogeneous multi-organ involvement. This review covers current knowledge on the cblC disease, structure–function relationships of the MMACHC protein, the genotypic and phenotypic spectra in humans, experimental disease models, and promising therapies.
