Abstract
The most common inborn error of cobalamin (cbl) metabolism in China is the cblC type characterized by combined methylmalonic acidemia and hyperhomocysteinemia. The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis. More specific biochemical findings include high levels of propionylcarnitine (C3), free carnitine (C3/C0), and acetylcarnitine (C3/C2) measured by tandem mass spectrometry (MS/MS), elevation of methylmalonic acid (MMA) measured by gas chromatography–mass spectrometry (GC-MS), and increased total homocysteine with normal or decreased methionine. We report on 50 Chinese patients with combined methylmalonic acidemia and hyperhomocysteinemia. Forty-six belonged to the cblC complementation group. Mutation analysis of the MMACHC gene was performed to characterize the mutational spectrum of cblC deficiency, and 17 different mutations were found. Most were clustered in exons 3 and 4, accounting for 91.3% of all mutant alleles. Two mutations were novel, namely, c.315 C>G (p.Y105X) and c.470 G>C(p.W157S). In terms of genotype–phenotype correlation, the c.609 G>A mutation was associated with early-onset disease when homozygous. Unlike previous reports from other populations, c.609 G>A (p.W203X) was the most frequent cblC mutation detected in our study of Chinese patients, affecting 51 of 92 MMACHC alleles (55.4%). The high prevalence of this nonsense mutation could have potential therapeutic significance for Chinese cblC patients. Besides traditional approaches consisting of hydroxocobalamin injections, carnitine, betaine, and protein restriction, novel drugs that target premature termination codons may have a role in the future.
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Abbreviations
- AdoCbl:
-
adenosylcobalamin
- cblC:
-
cobalamin C
- C3:
-
propionylcarnitine
- C0:
-
free carnitine
- C2:
-
acetylcarnitine
- C24:
-
tetracosane
- GC-MS:
-
gas chromatography–mass spectrometry
- MeCbl:
-
methylcobalamin
- MGA:
-
margaric acid
- MMA:
-
methylmalonic acid
- MS/MS:
-
tandem mass spectrometry
- PCR:
-
polymerase chain reaction
- TA:
-
DL-tropic acid
- VitB12 :
-
vitamin B12 cyanocobalamin
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Acknowledgments
We are very grateful to the patients, their families, and the pediatricians from the Peking University First Hospital and Guangdong Children’s Hospital who sent patient data and DNA samples. This study was supported by Technology Pillar Program in the Eleventh Five-year Plan Period (2006AB105A05, 2006BA105A07); National High Technology Research and Development Program (2007AA02Z447); Key Subject of Shanghai Municipality (2008ZD001); Scientific Research Foundation Project of Shanghai Municipality (2006043).
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Communicated by: Matthias Baumgartner
Competing interests: None declared.
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Wang, F., Han, L., Yang, Y. et al. Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. J Inherit Metab Dis 33 (Suppl 3), 435–442 (2010). https://doi.org/10.1007/s10545-010-9217-0
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DOI: https://doi.org/10.1007/s10545-010-9217-0