Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC)

Andersson, Hans; Shapira, Emmanuel

doi:10.1016/s0022-3476(98)70496-2

Cited by 74 publications

(49 citation statements)

References 13 publications

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“…5). These results suggest that unlike a number of cblC patients who do not respond well to CNCbl (or vitamin B 12 ) therapy (41,42), patients carrying the R161Q/G mutants might. Given their lower T m values, however, the efficacy of CNCbl therapy would be predicated by the steady-state levels of the R161Q/G mutants.…”

Section: Discussionmentioning

confidence: 91%

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Gherasim

Ruetz

et al. 2015

Journal of Biological Chemistry

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Background: CblC processes cobalamins entering a cell to a common intermediate. Results:Pathogenic mutations at Arg-161 weaken glutathione binding to CblC and stabilize cob(II)alamin. Conclusion: The R161Q/G mutations impair the dealkylation but not the decyanation activity of CblC. Significance: Increased redox cycling by the CblC mutants explains the observed cellular oxidative stress associated with this disorder.

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Section: Discussionmentioning

confidence: 91%

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Gherasim

Ruetz

et al. 2015

Journal of Biological Chemistry

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“…Our results explain the observation that fibroblasts from the cblC class of patients exhibit some metabolic correction when supplemented with aquocobalamin but not with CNCbl, and they exhibit normal internalization of cobalamin, but enhanced efflux of CNCbl compared with aquocobalamin (24). These observations with cultured primary cell lines are mirrored by the poorer clinical and biochemical responses in cblC patients receiving intramuscular CNCbl versus aquocobalamin injections (25,26). Together with the studies on patients and their fibroblasts (24)(25)(26), our results support the proposed model for cobalamin trafficking in which MMACHC accepts the cofactor from the lysosomal compartment and in partnership with a cytoplasmic reductase, catalyzes the reductive elimination of CNCbl to base-off cob(II)alamin, which is a metabolic prerequisite for the assimilation of this cobalamin precursor to its active cofactor forms (Fig.…”

Section: Discussionmentioning

confidence: 99%

Decyanation of vitamin B ₁₂ by a trafficking chaperone

Kim

Gherasim

Banerjee

2008

Proc. Natl. Acad. Sci. U.S.A.

194

168

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The mystery of how the cyanide group in vitamin B12 or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt-carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5 -deoxyadenosylcobalamin, and is bound in the ''base-off'' state that is needed by the two B12-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B12 metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B12 but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano-versus aquocobalamin.cobalamin ͉ flavin oxidoreductase ͉ methylmalonic aciduria ͉ homocystinuria ͉ cyanide V itamin B 12 (or cyanocobalamin, CNCbl) was discovered exactly 60 years ago in the laboratories of Folkers and Smith as the anti-pernicious anemia factor (1, 2), and its structure was revealed a few years later by the crystallographic studies in the Hodgkin laboratory (3). B 12 is one of the most complex cofactors in nature and belongs to the family of tetrapyrrolic-derived macrocyclic compounds. Five of the six ligands to the central cobalt atom in free B 12 are endogenous, being provided by the corin ring itself (Fig. 1A). In CNCbl, the sixth ligand, which occupies the upper axial position, is a cyano group. Although the biological origin of the cyano group in vitamin B 12 is unknown, it is the cofactor form commonly used in multivitamin formulations and one that individuals on vitamin supplementation are regularly exposed to. Decyanation of CNCbl is a prerequisite for its conversion to the active cofactor forms used by mammals in which the cyano ligand is replaced by a methyl group (in methylcobalamin) or a 5Ј-deoxyadenosyl group (in coenzyme B 12 or 5Ј-deoxyadenosylcobalamin) (Fig. 1B).Defects in B 12 metabolism are inherited as autosomal recessive disorders and are classified as belonging to one of eight genetic complementation groups, cblA-G and mut (4). Two loci, cblG and mut, encode B 12 -dependent enzymes: methionine synthase, which is cytoplasmic, and methylmalonyl-CoA mutase, which is mitochondrial. The remaining loci encode functions needed for intercompartmental trafficking and assimilation of the cofactor into its active forms. B 12 is present at relatively low concentrations in human tissues (5) and is reactive in all three of its biologically relevant oxidation states, factors that pose challenges for its unescorted delivery to target enzymes (6). The problem is further exacerbated by the use of the ''base-off/Hison'' conformation of the cofactor ...

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“…Adherence to a low-protein diet, as well as supplementation with pyridoxine, folate, and methionine are considered in some patients. 2,24,25 Hydroxocobalamin has been found to be superior to cyanocobalamin. 24 Response to treatment is variable and patients require individualized dose escalation or reduction.…”

Section: Discussionmentioning

confidence: 99%

“…2,24,25 Hydroxocobalamin has been found to be superior to cyanocobalamin. 24 Response to treatment is variable and patients require individualized dose escalation or reduction. One patient required up to 20 mg of hydroxocobalamin daily to achieve both clinical and biochemical response.…”

Section: Discussionmentioning

confidence: 99%

A Treatable Metabolic Cause of Encephalopathy: Cobalamin C Deficiency in an 8-Year-Old Male

Krueger¹,

Piantino

Smith

et al. 2015

Pediatrics

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Neurologic regression in a previously healthy child may be caused by metabolic or neurodegenerative disorders, many of which have no definitive treatment. We report a case of a previously healthy 8-year-old boy who presented with a month-long history of waxing and waning encephalopathy and acute regression, followed by seizures. Evaluation for a metabolic disorder revealed methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C type due to a single, presumed homozygous pathogenic c.394 C.T mutation in the MMACHC gene. With the appropriate diet restrictions and vitamin replacement, he improved significantly and returned to his premorbid level of behavior. This case illustrates an unusual presentation of a treatable metabolic disorder and highlights the need to consider cobalamin defects in the differential diagnosis of healthy children with neurologic regression.

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Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC)

Cited by 74 publications

References 13 publications

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Decyanation of vitamin B ₁₂ by a trafficking chaperone

A Treatable Metabolic Cause of Encephalopathy: Cobalamin C Deficiency in an 8-Year-Old Male

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Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC)

Cited by 74 publications

References 13 publications

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Decyanation of vitamin B 12 by a trafficking chaperone

A Treatable Metabolic Cause of Encephalopathy: Cobalamin C Deficiency in an 8-Year-Old Male

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Decyanation of vitamin B ₁₂ by a trafficking chaperone