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Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

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  • Published:
Journal of Inherited Metabolic Disease

Abstract

Combined methylmalonic acidemia and homocystinuria, cblC type, is an inborn error of intracellular cobalamin metabolism with a wide spectrum of clinical manifestations that is stated to be the most common inherited disorder of cobalamin metabolism. This metabolic disease is caused by mutations in the MMACHC gene and results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, cofactors for the methylmalonyl-CoA mutase and methionine synthase enzymes. Elevated methylmalonic acid and homocysteine with decreased methionine production are the biochemical hallmarks of this disorder. Awareness of the diverse clinical presentations associated with cblC disease is necessary to provide a timely diagnosis, to guide management of affected individuals and to establish a framework for the future treatment of individuals detected through expanded newborn screening. This article reviews the biochemistry, clinical presentations, genotype-phenotype correlations, diagnosis and management of cblC disease.

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Abbreviations

AdoCbl:

5’-deoxyadenosylcobalamin

C3:

Propionylcarnitine

cblC:

Cobalamin C disease

CNCbl:

Cyanocobalamin

IM:

Intramuscular

IUGR:

Intrauterine growth retardation

MeCbl:

Methylcobalamin

MMA:

Methylmalonic acid

MTHFR:

Methylenetetrahydrofolate reductase

OHCbl:

Hydroxocobalamin

SQ:

Subcutaneous

tHcy:

Total plasma homocysteine

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Acknowledgements

The Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, supported this research. We would like to thank Jennifer Sloan, Brian Brooks, Natalie Hauser and Irini Manoli for helpful discussions, and Maria Teresa Amador for the preparation of Fig. 1.

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Authors and Affiliations

  1. Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A18, Bethesda, MD, 20892, USA

    Nuria Carrillo-Carrasco, Randy J. Chandler & Charles P. Venditti

  2. Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA

    Randy J. Chandler

Authors
  1. Nuria Carrillo-Carrasco
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  2. Randy J. Chandler
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  3. Charles P. Venditti
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Corresponding author

Correspondence to Charles P. Venditti.

Additional information

Communicated by: Johan Lodewijk Karel Van Hove

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.

Competing interests: None declared.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Ophthalmologic complications in patients with cblC disease (DOCX 191 kb)

Supplementary Table 2

Outcome of patients with cblC disease and their therapeutic regimens (DOCX 159 kb)

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Carrillo-Carrasco, N., Chandler, R.J. & Venditti, C.P. Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis 35, 91–102 (2012). https://doi.org/10.1007/s10545-011-9364-y

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  • DOI: https://doi.org/10.1007/s10545-011-9364-y

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