Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 435–442

Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China

Authors

  • Fei Wang
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Yanling Yang
    • Department of PediatricThe first Hospital, Beijing University
  • Xuefan Gu
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Jun Ye
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Wenjuan Qiu
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Huiwen Zhang
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Yafen Zhang
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • XiaoLan Gao
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
  • Yu Wang
    • Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of Medicine
Research Report

DOI: 10.1007/s10545-010-9217-0

Cite this article as:
Wang, F., Han, L., Yang, Y. et al. J Inherit Metab Dis (2010) 33: 435. doi:10.1007/s10545-010-9217-0

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.

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

Copyright information

© SSIEM and Springer 2010