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Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type

  • Paul Hoff Backe
  • Mari Ytre-Arne
  • Åsmund Kjendseth Røhr
  • Else Brodtkorb
  • Brian Fowler
  • Helge Rootwelt
  • Magnar Bjørås
  • Lars Mørkrid
Research Report
Part of the JIMD Reports book series (JIMD, volume 11)

Abstract

Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.

Keywords

Sodium Dithionite Methylmalonic Acid Patient Fibroblast Methylmalonic Acidemia Methylcitric Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from University of Oslo and the Norwegian Research Council of Norway and the South-East Health Authority of Norway. B.F. was supported by a grant from Swiss National Science Foundation (320000_122568 and 31003A_138521). P.H.B. also received grants from “Legatet til Henrik Homans Minde” and “Dr. Fürst medisinske laboratoriums fond til klinisk kjemisk og klinisk fysiologisk forskning”.

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Paul Hoff Backe
    • 1
    • 2
  • Mari Ytre-Arne
    • 1
    • 2
  • Åsmund Kjendseth Røhr
    • 3
  • Else Brodtkorb
    • 2
  • Brian Fowler
    • 4
  • Helge Rootwelt
    • 2
  • Magnar Bjørås
    • 1
    • 2
  • Lars Mørkrid
    • 2
  1. 1.Department of MicrobiologyOslo University Hospital and University of OsloOsloNorway
  2. 2.Department of Medical BiochemistryOslo University Hospital and University of OsloOsloNorway
  3. 3.Department of BiosciencesUniversity of OsloOsloNorway
  4. 4.Division of Metabolism, Children’s Research Center (CRC)University Children’s HospitalZürichSwitzerland

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