Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 435–442 | Cite as

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

  • Fei Wang
  • Lianshu Han
  • Yanling Yang
  • Xuefan Gu
  • Jun Ye
  • Wenjuan Qiu
  • Huiwen Zhang
  • Yafen Zhang
  • XiaoLan Gao
  • Yu Wang
Research Report

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

References

  1. Ben-Omran TI, Wong H, Blaser S et al (2007) Late-onset cobalamin-C disorder: a challenging diagnosis. Am J Med Genet A 143:979–984Google Scholar
  2. Carrillo-Carrasco N, Sloan J, Valle D et al (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32:728–731PubMedCrossRefGoogle Scholar
  3. Coelho D, Suormala T, Stucki M et al (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358:1454–1464PubMedCrossRefGoogle Scholar
  4. Cusmano-Ozog K, Lorey F, Levine S et al (2007) Cobalamin C disease identified and expanded newborn screening: the California experience. J Investig Med 55:S90Google Scholar
  5. den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12CrossRefGoogle Scholar
  6. Froese DS, Zhang J, Healy S et al (2009) Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab 98:338–43PubMedCrossRefGoogle Scholar
  7. Han LS, Gao XL, Ye J et al (2005) Application of tandem mass spectrometry in diagnosis of organic acidemias. Zhonghua Er Ke Za Zhi 43:325–330PubMedGoogle Scholar
  8. Han LS, Ye J, Qiu WJ et al (2007) Selective screening for inborn errors of metabolism on clinical patients using tandem mass spectrometry in China: a four-year report. J Inherit Metab Dis 30:507–514PubMedCrossRefGoogle Scholar
  9. Han LS, Ye J, Qiu WJ et al (2008) Diagnosis of inborn errors of metabolism using tandem mass spectrometry and gas chromatography mass spectrometry. Zhonghua Yi Xue Za Zhi 88:2122–2126PubMedGoogle Scholar
  10. Hannibal L, Kim J, Brasch NE et al (2009) Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Mol Genet Metab 97:260–266PubMedCrossRefGoogle Scholar
  11. Kerem E, Hirawat S, Armoni S et al (2008) Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 30(372):719–727CrossRefGoogle Scholar
  12. Kuhara T (2002) Diagnosis and monitoring of inborn errors of metabolism using urease-pretreatment of urine, isotope dilution, and gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 781:497–517PubMedCrossRefGoogle Scholar
  13. Kim J, Gherasim C, Banerjee R (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci USA 105:14551–14554PubMedCrossRefGoogle Scholar
  14. 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 30:1072–1081PubMedCrossRefGoogle Scholar
  15. Lerner-Ellis JP, Tirone JC, Pawelek PD et al (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100PubMedCrossRefGoogle Scholar
  16. Morel CF, Lerner-Ellis JP, Rosenblatt DS (2006) Combined methylmalonic aciduria and homocystinuria (cblC): phenotype–genotype correlations and ethnic-specific observations. Mol Genet Metab 88:315–321PubMedCrossRefGoogle Scholar
  17. 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 93:475–480PubMedCrossRefGoogle Scholar
  18. Rosenblatt DS, Aspler AL, Shevell MI et al (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538PubMedCrossRefGoogle Scholar
  19. Rossi A, Cerone R, Biancheri R et al (2001) Early-onset combined methylmalonic aciduria and homocystinuria: Neuroradiologic findings. AJNR Am J Neuroradiol 22:554–563PubMedGoogle Scholar
  20. Rutsch F, Gailus S, Miousse IR et al (2009) Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat Genet 41:234–239PubMedCrossRefGoogle Scholar
  21. Smith SE, Kinney HC, Swoboda KJ et al (2006) Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 88:138–145PubMedCrossRefGoogle Scholar
  22. Thiele J, Van Raamsdonk JM (2006) Gene discovery in methylmalonic aciduria and homocystinuria. Clin Genet 69:402–403PubMedCrossRefGoogle Scholar
  23. Wang F, Han LS, Hu YH et al (2009) Analysis of gene mutations in Chinese patients with methylmalonic acidemia and homocysteinemia. Zhonghua Er Ke Za Zhi 47:189–193PubMedGoogle Scholar
  24. Welch EM, Barton ER, Zhuo J et al (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87–91PubMedCrossRefGoogle Scholar
  25. Yuen YP, Lai CK, Chan YW et al (2007) DNA-based diagnosis of methylmalonic aciduria and homocystinuria, cblC type in a Chinese patient presenting with mild developmental delay. Clin Chim Acta 375:171–172PubMedCrossRefGoogle Scholar
  26. Zhang Y, Song JQ, Liu P et al (2007) Clinical studies on fifty-seven Chinese patients with combined methylmalonic aciduria and homocysteinemia. Zhonghua Er Ke Za Zhi 45:513–517PubMedGoogle Scholar
  27. Zytkovicz TH, Fitzgerald EF, Marsden D et al (2001) Tandem mass spectrometry analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 47:1945–1955PubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Fei Wang
    • 1
  • Lianshu Han
    • 1
  • Yanling Yang
    • 2
  • Xuefan Gu
    • 1
  • Jun Ye
    • 1
  • Wenjuan Qiu
    • 1
  • Huiwen Zhang
    • 1
  • Yafen Zhang
    • 1
  • XiaoLan Gao
    • 1
  • Yu Wang
    • 1
  1. 1.Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Department of PediatricThe first Hospital, Beijing UniversityBeijingChina

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