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

doi:10.1016/S0022-3476(98)70496-2

The Journal of Pediatrics

Volume 132, Issue 1, January 1998, Pages 121-124

From the Human Genetics Program, Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana.

https://doi.org/10.1016/S0022-3476(98)70496-2 Get rights and content

Abstract

Objective: To compare the therapeutic effectiveness of hydroxocobalamin and cyanocobalamin in patients with combined methylmalonic acidemia and homocystinuria. Study design: Analysis of urine methylmalonic acid, plasma homocystine, and growth of two unrelated patients with cobalamin C disease who were initially receiving cyanocobalamin and were subsequently switched to hydroxocobalamin. Results: Each patient had a significant decrease in urine methylmalonic acid excretion while receiving cyanocobalamin, but levels remained at least 10 times normal. Cyanocobalamin treatment resulted in a decrease of plasma homocystine to near normal in one patient but had no effect on plasma homocystine in the second patient. Each patient was switched to hydroxocobalamin and urine methylmalonic acid levels decreased to the limit of detection. Plasma homocystine values while taking hydroxocobalamin remained < 5 nmol/ml in both patients. In patient 1, who continued to receive cyanocobalamin therapy for more than 1 year, growth rates (height, weight, and head circumference) were very poor. After initiation of hydroxocobalamin, growth parameters normalized with growth rates above normal. Conclusion: Intramuscular cyanocobalamin treatment is inadequate in the treatment of patients with cobalamin C disease. Appropriate management of cobalamin C disease should include only the hydroxocobalamin form of cobalamin. (J Pediatr 1998;132:121-4)

Section snippets

Clinical Studies

Patients were referred to the Tulane University Human Genetics Program for consultation. History and results of physical examinations were obtained by one of the clinical geneticists in the program during regular clinic follow-up appointments.

Biochemical Studies

Urine and blood were obtained during clinic visits and put on ice or sent by overnight mail on ice. Samples were prepared and analyzed for amino acid (free homocystine) and organic acid content as previously described.¹⁴ Organic acids from extracted urine

Patient 1

An 11-month-old boy was referred to the program because of poor growth and generalized hypotonia. Urine organic acid and plasma amino acid analysis demonstrated massive excretion of urine MMA and elevation of plasma homocystine (Fig. 1).

. Metabolic effects of treatment with cyanocobalamin (CNCbl) and hydroxocobalamin (OHCbl) in two patients with cobalamin C disease (cblC). Note continued elevations of MMA and homocystine in patients while taking CNCbl and decreases of both after OHCbl was

Discussion

Effective therapy for cblC has long been assumed to include a source of Cbl to bypass the unknown processing abnormality hypothesized to be the basic defect. Confusion has resulted from early case reports in which various forms of Cbl were used. An early study cited success with methylcobalamin,¹³ and a later report suggested effective treatment with OHCbl.¹⁵ A comparison of oral versus IM OHCbl showed greater benefit from IM OHCbl in combination with oral betaine.¹⁶ More recent reviews on cblC

Acknowledgements

We wish to thank Dr. David Rosenblatt for fibroblast complementation studies.

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There are more references available in the full text version of this article.

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Interestingly, and in contrast to the dealkylation activity of CblC, the Arg-161 mutants do not significantly affect the decyanation activity in the presence of NADPH and the flavoprotein, methionine synthase reductase (Fig. 5). These results suggest that unlike a number of cblC patients who do not respond well to CNCbl (or vitamin B12) therapy (41, 42), patients carrying the R161Q/G mutants might. Given their lower Tm values, however, the efficacy of CNCbl therapy would be predicated by the steady-state levels of the R161Q/G mutants.
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Conclusion: The R161Q/G mutations impair the dealkylation but not the decyanation activity of CblC.
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^☆: Reprint requests: Hans C. Andersson, MD, Human Genetics Program SL-31, Hayward Genetics Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112.

^☆☆: 9/21/82570

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

Abstract

Section snippets

Clinical Studies

Biochemical Studies

Patient 1

Discussion

Acknowledgements

Biochem Med

Crit Rev Oncol Hematol

Blood

Am J Ophthalmol

J Biol Chem

Biochem Biophys Acta

J Nutr

J Pediatr