Inherited disorders of vitamin B₁₂ utilization

Abstract

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA-cblG) are reviewed here.

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

“…Patients were assigned to complementation groups (cblA-H, mut) based on the outcome of cell fusion experiments and the apparent biochemical defect involved [16][17][18]. The cblE complementation group was shown to result from defective reactivation of methionine synthase [19].…”

Disruption of a Regulatory System Involving Cobalamin Distribution and Function in a Methionine-dependent Human Glioma Cell Line

“…cblA and -B are mutants that affect MCM, but the CH 3 Cbl content and the activity of Met synthase are normal. cblG and -E mutants have a low Met synthase activity and cellular level of CH 3 Cbl, but the AdoCbl content is normal (5). Although some cases with cblG and -E disease have slightly decreased activity of MCM in intact cells, the levels are still much higher than those observed in cblA and -B, and patients with cblG and -E disease have no symptoms indicating dysfunction of MCM (32).…”

“…We have previously (3,13) shown that the Met-dependent variant of a human glioma cell line is related to a biochemical defect leading to low levels of both CH 3 Cbl and AdoCbl, thus resembling the inborn errors of Cbl metabolism belonging to the complementation classes C and D (5). In the present study, we investigated key processes operating at different levels along the Cbl pathway, from transport to metabolism to the catalytic function of the Cbl-dependent enzymes.…”

“…A common finding in the Met-dependent cells is a low rate of Hcy remethylation (1), which seems related to lack of CH 3 Cbl (3,4). Certain inborn errors in cobalamin (Cbl) metabolism (5), Cbl deficiency as well as N 2 O exposure, are associated with marked reduction in Hcy remethylation and may render the cells fully or partly dependent on an exogenous supply of Met. Thus, these clinical conditions may have biochemical characteristics similar to those observed in Met-dependent cancer cells.…”

Vitamin B12 (Cb1)-Responsive Disorders

“…In cells Cb1 is found bound to its target enzymes, and not as free Cb1. The inborn errors have a deficiency of either or both cobalamin cofactors, and they have been divided into different classes based on somatic cell complementation and designated Cb1A through cb1G [1][2][3].…”