Skip to main content
SpringerLink
Log in

Methylmalonic aciduria with homocystinuria: Biochemical studies, treatment, and clinical course of a Cbl-C patient

  • Metabolic Diseases
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

A patient with infantile onset methylmalonic aciduria and homocystinuria (Cbl-C mutant) is described. Therapy with hydroxycobalamin, folate and vitamin B6 improved his condition. As hypomethioninaemia and homocystinaemia persisted, he was treated with intramuscular methylcobalamin, but without success. Treatment with betaine started at 25 months of age, normalizèd plasma methionine and elicited disappearance of homocystinaemia. Results of biochemical studies in cultured fibroblasts paralleled those described for other Cbl-C patients except that methylmalonyl-coenzyme A mutase activity in disrupted fibroblasts was in the normal range.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Ado-Cbl:

adenosylcobalamin

Cbl:

cobalamin

CoA:

coenzyme A

Me-Cbl:

methylcobalamin

MEM:

minimal essential medium

MMA:

methylmalonic acid

OH−Cbl:

hydroxycobalamin

References

  1. Anthony M, McLeay AC (1976) A unique case of derangement of Vitamin B12 metabolism. Proc Aust Assoc Neurol 13:61–65

    PubMed  Google Scholar 

  2. Bartholomew DW, Batshaw ML, Allen RH, Roe CR, Rosenblatt D, Valle DL, Francomano CA (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39

    PubMed  Google Scholar 

  3. Baumgartner R (1983) Activity of the Cobalamin dependent-MMa-CoA Mutase. In: Hall CA (ed) The cobalamins; methods in hematology Vol. 10. Churchill Livingstone, Edinburgh New York, pp 181–195

    Google Scholar 

  4. Baumgartner R, Wick H, Maurer R, Egli N, Steinman B (1979) Congenital defect in intracellular cobalamin metabolism resulting in homo-cystinuria and methylmalonic aciduria. I. Case report and histopathology. Helv Peadiatr Acta 34:465–482

    Google Scholar 

  5. Baumgartner R, Giardini O, Cantani A, Sabetta G, Castro M (1982) Methylmalonic acidaemia due to mutase apoenzyme defect: responsive to vitamin B12 in infact fibroblasts but not in vivo. J Inherited Metab Dis 5:137–141

    Article  PubMed  Google Scholar 

  6. Carmel R, Goodman SI (1982) Abnormal deoxyuridine suppression test in congenital methylmalonic aciduria-homocystinuria without megaloblastic anemia: divergent biochemical and morphological bone marrow manifestations of disordered cobalamin metabolism in man. Blood 59:306–311

    PubMed  Google Scholar 

  7. Carmel R, Bedros AA, Mace JW, Goodman SI (1980) Congenital methylmalonic aciduria-homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570–579

    PubMed  Google Scholar 

  8. Cooper BA, Rosenblatt DS (1987) Inherited defects of vitamin B12 metabolism. Annu Rev Nutr 7:291–320

    PubMed  Google Scholar 

  9. Dillon MJ, England JM, Gompertz DM, Goodey PA, Grant DB, Hussein HA-A, Linell JC, Mathews DM, Mudd SH, Newns GH, Seakins JWT, Uhlendorf BW, Wise J (1974) Mental retardation, megaloblastic anaemia, methylmalonic aciduria and abnormal homocysteine metabolism due to an error in vitamin B12 metabolism. Clin Sci Mol Med 47:43–61

    PubMed  Google Scholar 

  10. Fenton WA, Rosenberg LE (1978) Genetic and biochemical analysis of human cobalamin mutants in cell culture. Annu Rev Genet 12:223–248

    Article  PubMed  Google Scholar 

  11. Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW (1970) Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med 4:500–515

    Article  PubMed  Google Scholar 

  12. Levy HL, Mudd SH, Schulman JD, Oreyfus PM, Abeles RH (1970) A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia and methylmalonic aciduria. Am J Med 48:890–897

    Article  Google Scholar 

  13. Linnell JC, Miranda B, Bhatt HR, Dowton SB, Levy HL (1983) Abnormal cobalamin metabolism in a megaloblastic child with homocystinuria, cystathioninuria and methylmalonic aciduria. J Inherited Metab Dis 6:137–139

    Article  PubMed  Google Scholar 

  14. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the phenol reagent. J Biol Chem 193:265–275

    PubMed  Google Scholar 

  15. Mahoney MJ, Bick D (1987) Recent advances in the inherited methylmalonic acidemias. Acta Paediatr Scand 76:689–696

    PubMed  Google Scholar 

  16. Mamlok RJ, Isenberg JN, Rassin DK (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia. Neuropediatrics 17:94–99

    PubMed  Google Scholar 

  17. Matthews DM, Linnell JC (1982) Cobalamin deficiency and related disorders in infancy and children. Eur J Pediatr 138:6–16

    Article  PubMed  Google Scholar 

  18. Mellman I, Willard HF, Rosenberg LE (1978) Cobalamin binding and cobalamin dependent enzyme activity in normal and mutant human fibroblasts. J Clin Invest 62:952–960

    PubMed  Google Scholar 

  19. Mellman I, Willard HF, Youngdahl-Turner P, Rosenberg LE (1979) Cobalamin coenzymes synthesis in normal and mutant human fibroblasts. Evidence for a processin genzyme activity deficient in Cbl C cells. J Biol Chem 254:11847–11853

    PubMed  Google Scholar 

  20. Mitchell GA, Watkins D, Melancon SB, Rosenblatt DS, Geoffrey G, Orquin J, Barsoum Homsy M, Dallaire L (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415

    PubMed  Google Scholar 

  21. Ravindranath Y, Krieger Y (1984) Vitamin B12 (Cb) and folate interrelation ship in a case of homocystinuria-methylmalonic acid (HC-MMA)-uria due to genetic co-factor deficiency. Pediatr Res 18:247A

    Google Scholar 

  22. Ribes A, Vilaseca MA, Briones P, Maya A, Sabater J, Pascual P, Alvarez L, Ros J, Gonzalez-Pascual L (1984) Methylmalonic aciduria with homocystinuria. J Inherited Metab Dis 7:129–130

    Article  Google Scholar 

  23. Robb RM, Dowton SB, Fulton AB, Levy HL (1984) Retinal degeneration in Vitamin B12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormalities. Am J Ophtalmol 97:691–696

    Google Scholar 

  24. Rosenberg LE (1983) Disorders of propionate and methylmalonate metabolism. In Stanbury JB, Wyngaarden JB, Fredickson DS, Goldstein JC, Brown MS (eds) The metabolic basis of inherited disease, 5th edn. Mc Graw-Hill, New York, pp 474–497

    Google Scholar 

  25. Rosenblatt DS, Cooper BA, Pottier A, Lue-Shing H, Matiaszuk N, Graner K (1984) Altered vitamin B12 metabolism in fibroblasts from a patient with megaloblastic anemia and homocystinuria due to a new defect in methionine biosynthesis. J Clin Invest 74:2149–2156

    PubMed  Google Scholar 

  26. Rosenblatt DS, Thomas IT, Watkins D, Cooper BA, Erbe RW (1987) Vitamin B12 Responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency. Am J Med Genet 26:377–383

    Article  PubMed  Google Scholar 

  27. Rowe PB (1983) Inherited disorders of folate metabolism. In Stanbury JB, Wyngaarden JB, Fredickson DS, Golstein JL, Brown MS (eds) The metabolic basis of inherited disease, 5th edn. Mc Graw-Hill, New York, pp 498–521

    Google Scholar 

  28. Shinnar S, Singer HS (1984) Cobalamin C mutation (methyl malonic aciduria and homocystinuria) in adolescence. N Engl J Med 311:451–454

    PubMed  Google Scholar 

  29. Tanaka K, Hine DG (1982) Compilation of gas chromatographic retention indices of 163 metabolically important organic acids, and their use in detection of patients with organic acidurias. J Chromatogr 239:301–322

    Article  PubMed  Google Scholar 

  30. Watkins D, Rosenblatt DS (1988) Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, Cbl E and Cbl G. J Clin Invest 88:1690–1694

    Google Scholar 

  31. Wilcken DEL, Wilcken B, Dudman NPB, Tynell PA (1983) Homocystinuria. The effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 25:448–453

    Google Scholar 

  32. Willard HF, Rosenberg LE (1979) Inborn errors of cobalamin metabolism: effect of cobalamin supplementation in culture on methylmalonylCoA mutase activity in normal and mutant human fibroblasts. Biochem Genet 17:57–75

    Article  PubMed  Google Scholar 

  33. Willard HF, Ambani LM, Hart AC, Mahoney MJ, Rosenberg LE (1976) Rapid prenatal and postnatal detection of inborn errors of propionate, methylmalonate and cobalamin metabolism. A sensitive assay using cultured cells. Hum Genet 32:277–283

    Article  Google Scholar 

  34. Willard HF, Mellman IS, Rosenberg LE (1978) Genetic complementation among inherited deficience of methylmalonyl-CoA mutasa activity: evidence for a new class of human cobalamin mutant. Am J Hum Genet 30:1–3

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de Bioquímica Clínica de la Diputació de Barcelona, Apartat de Correus 137, E-08290, Cerdanyola (Barcelona), Spain

    A. Ribes, M. A. Vilaseca, M. Lluch, M. Rodes & A. Maya

  2. Departmento de Bioquímica Clínica, CSIC, Barcelona, Spain

    P. Briones

  3. Hospital San Juan de Dios, Barcelona, Spain

    J. Campistol & P. Pascual

  4. Universitäts-Kinderklinik, Basel, Switzerland

    T. Suormala & R. Baumgartner

Authors
  1. A. Ribes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Briones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. A. Vilaseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Lluch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Rodes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Maya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Campistol
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Pascual
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T. Suormala
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ribes, A., Briones, P., Vilaseca, M.A. et al. Methylmalonic aciduria with homocystinuria: Biochemical studies, treatment, and clinical course of a Cbl-C patient. Eur J Pediatr 149, 412–415 (1990). https://doi.org/10.1007/BF02009662

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02009662

Keywords

Search

Navigation