Summary
Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 μmol/L; normal range <0.27 μmol/L), a 55% reduction of tHcy (112 to 50 μmol/L; normal range: 0–13 μmol/L) and a greater than twofold increase in methionine (17 to 36 μmol/L; normal range: 7–47 μmol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.
Similar content being viewed by others
Abbreviations
- cblC:
-
cobalamin C
- IM:
-
intramuscular
- MMA:
-
methylmalonic acid
- OHCbl:
-
hydroxocobalamin
- SQ:
-
subcutaneous
- tHcy:
-
total plasma homocysteine
References
Allen RH, Stabler SP, Lindenbaum J (1993) Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 42:1448–1460
Andersson HC, Marble M, Shapira E (1999) Long--term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med. 1:146–150
Bartholomew DW, Batshaw ML, Allen RH et al (1988) Therapeutic approaches to cobalamin--C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39
Enns GM, Barkovich AJ, Rosenblatt DS et al (1999) Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 22:599–607
Fearing MK, Levy HL (2003) Expanded newborn screening using tandem mass spectrometry. Adv Pediatr 50:81–111
Huemer M, Simma B, Fowler B, Sourmala T, Bodamer OA, Sass JO (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472
Lerner--Ellis JP, Tirone JC, Pawelek PD et al (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100
Lerner--Ellis JP, Anastasio N, Liu J et al (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype––phenotype correlations. Hum Mutat 30:1072–1081
Mellman I, Willard HF, Youngdahl--Turner P, Rosenberg LE (1979) Cobalamin coenzyme synthesis in normal and mutant human fibroblasts. Evidence for a processing enzyme activity deficient in cblC cells. J Biol Chem 254:11847–11853
Mitchell GA, Watkins D, Melancon SB et al (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415
Morel CF, Lerner--Ellis JP, Rosenblatt DS (2006) Combined methylmalonic aciduria and homocystinuria (cblC): phenotype––genotype correlations and ethnic--specific observations. Mol Genet Metab 88:315–321
Nogueira C, Aiello C, Cerone R et al (2008) Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab 93:475–480
Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Suppl 2): S77–83
Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154
Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538
Shepherd G, Velez LI (2008) Role of hydroxocobalamin in acute cyanide poisoning. Ann Pharmacother 42:661–669
Smith DL, Bodamer OA (2002) Practical management of combined methylmalonicaciduria and homocystinuria. J Child Neurol 17:353–356
Smith SE, Kinney HC, Swoboda KJ, Levy HL (2006) Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 88:138–145
Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413
Uhl W, Nolting A, Golor G, Rost KL, Kovar A (2006) Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo--controlled study. Clin Toxicol (Phila) 44(Suppl 1):17–28
Van Hove JL, Van Damme--Lombaerts R, Grunewald S et al (2002) Cobalamin disorder Cbl--C presenting with late--onset thrombotic microangiopathy. Am J Med Genet 111:195–201
Acknowledgements
This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Johan Van Hove
Competing interests: None declared
References to electronic databases: Methylmalonic aciduria and homocystinuria, cblC type: OMIM #277400. MMACHC gene: OMIM *609831. Methionine synthase: EC 1.16.1.8. Methylmalonyl-CoA mutase: EC 5.4.99.2.
Rights and permissions
About this article
Cite this article
Carrillo-Carrasco, N., Sloan, J., Valle, D. et al. Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32, 728–731 (2009). https://doi.org/10.1007/s10545-009-1257-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-009-1257-y