Advertisement

Pediatric Nephrology

, Volume 22, Issue 12, pp 2097–2103 | Cite as

Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder

  • Ajay P. Sharma
  • Cheryl R. Greenberg
  • Asuri N. Prasad
  • Chitra Prasad
Original Article
First Online:

Abstract

Diarrhea-positive hemolytic uremic syndrome (HUS) is a common cause of acute renal failure in children. Diarrhea-negative (D−), or atypical HUS, is etiologically distinct. A Medline search identified seven previously reported D− cases of HUS secondary to cobalamin C (cblC) disease presenting in infancy. An infantile presentation is reported to be associated with a high mortality rate (6/7 cases). We describe the results of a 5-year longitudinal follow-up in a child diagnosed with D− HUS secondary to cblC disease in infancy. Mutation analysis in this patient identified homozygosity for the 271 dupA mutation (c.271 dupA) in the cblC MMACHC gene. We briefly review the published experience in cblC-associated HUS to highlight the clinical characteristics of this uncommon, but potentially treatable, condition.

Keywords

HUS Cobalamin C Acute renal failure Autosomal recessive 

Abbreviations

HUS

hemolytic uremic syndrome

D−

diarrhea negative

Cbl

cobalamin

cblC

cobalamin C

MMA

methylmalonic acid

AdoCbl

adenosylcobalamin

MeCbl

methylcobalamin

MMACHC gene

methylmalonic aciduria cblC type with homocystinuria gene

TMA

thrombotic microangiopathy

vWF-protease

von Willebrand factor-cleaving protease

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

We are grateful to the patient and her mother. Our sincere thanks to the staff of the Metabolic Program at the Children’s Hospital of Winnipeg (Dr. Mhanni, Tara Dzwiniel, Judy Saltel-Olson, Dr. Lorne Seargent). We thank Dr. Malcolm Ogborn (pediatric nephrologist), Dr. Charuta Joshi (pediatric neurologist), and Dr. Diane Moddemann (developmental specialist) for providing clinical care for the patient. We are grateful to Dr. David Rosenblatt and his lab (McGill Montreal) for performing the fibroblast and molecular studies.

References

  1. 1.
    Zimmerhackl LB, Besbas N, Jungraithmayr T, van de Kar N, Karch H, Karpman D, Landau D, Loirat C, Proesmans W, Prüfer F, Rizzoni G, Taylor MC, European Study Group for Haemolytic Uraemic Syndromes and Related Disorders (2006) Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 32:113–120PubMedCrossRefGoogle Scholar
  2. 2.
    Fitzpatrick MM, Walters MD, Trompeter RS, Dillon MJ, Barratt TM (1993) Atypical (non-diarrhea-associated) hemolytic-uremic syndrome in childhood. J Pediatr 122:532–537PubMedCrossRefGoogle Scholar
  3. 3.
    Chenel C, Wood C, Gourrier E, Zittoun J, Casadevall I, Ogier H (1993) Neonatal hemolytic-uremic syndrome, methylmalonic aciduria and homocystinuria caused by intracellular vitamin B 12 deficiency. Value of etiological diagnosis. Arch Fr Pediatr 50:749–754PubMedGoogle Scholar
  4. 4.
    Geraghty MT, Perlman EJ, Martin LS, Hayflick SJ, Casella JF, Rosenblatt DS, Valle D (1992) Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 120:934–937PubMedCrossRefGoogle Scholar
  5. 5.
    Kind T, Levy J, Lee M, Kaicker S, Nicholson JF, Kane SA (2002) Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 24:327–329PubMedCrossRefGoogle Scholar
  6. 6.
    Russo P, Doyon J, Sonsino E, Ogier H, Saudubray JM (1992) A congenital anomaly of vitamin B12 metabolism: a study of three cases. Hum Pathol 23:504–512PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Labrune P, Zittoun J, Duvaltier I, Trioche P, Marquet J, Niaudet P, Odièvre M (1999) Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 158:734–739PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenblatt DS, Whitehead VM (1999) Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 36:19–34PubMedGoogle Scholar
  10. 10.
    Shinawi M (2007) Hyperhomocysteinemia and cobalamin disorders. Mol Genet Metab 90:113–121PubMedCrossRefGoogle Scholar
  11. 11.
    Banerjee R, Ragsdale SW (2003) The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes. Annu Rev Biochem 72:209–247PubMedCrossRefGoogle Scholar
  12. 12.
    Carmel R, Green R, Rosenblatt DS, Watkins D (2003) Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program:62–81Google Scholar
  13. 13.
    Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, Mougenot B, Rosenblatt DS, Deschênes G (2005) Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 45:588–595PubMedCrossRefGoogle Scholar
  14. 14.
    Van Hove JL, Van Damme-Lombaerts R, Grunewald S, Grünewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B (2002) Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 111:195–201PubMedCrossRefGoogle Scholar
  15. 15.
    Rutledge SL, Geraghty M, Mroczek E, Rosenblatt D, Kohout E (1993) Tubulointerstitial nephritis in methylmalonic acidemia. Pediatr Nephrol 7:81–82PubMedCrossRefGoogle Scholar
  16. 16.
    Wolff JA, Strom C, Griswold W, Sweetman F, Kulovich S, Prodanos C, Nyhan WL (1985) Proximal renal tubular acidosis in methylmalonic acidemia. J Neurogenet 2:31–39PubMedGoogle Scholar
  17. 17.
    Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cb1-C type). Am J Med Genet 36:167–171PubMedCrossRefGoogle Scholar
  18. 18.
    Brunelli SM, Meyers KE, Guttenberg M, Kaplan P, Kaplan BS (2002) Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 17:800–803PubMedCrossRefGoogle Scholar
  19. 19.
    Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J (1993) Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91:308–318PubMedGoogle Scholar
  20. 20.
    Hajjar KA (1993) Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:2873–2879PubMedCrossRefGoogle Scholar
  21. 21.
    Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:1909–1916PubMedGoogle Scholar
  22. 22.
    McCully KS (1993) Chemical pathology of homocysteine. I. Atherogenesis. Ann Clin Lab Sci 23:477–493PubMedGoogle Scholar
  23. 23.
    Harrison HE, Harrison HC (1954) Experimental production of renal glycosuria, phosphaturia, and aminoaciduria by injection of maleic acid. Science 120:606–608PubMedCrossRefGoogle Scholar
  24. 24.
    Whelan DT, Ryan E, Spate M, Morris M, Hurley RM, Hill R (1979) Methylmalonic acidemia: 6 years’ clinical experience with two variants unresponsive to vitamin B12 therapy. Can Med Assoc J 120:1230–1235PubMedGoogle Scholar
  25. 25.
    Moake JL (2002) Thrombotic microangiopathies. N Engl J Med 347:589–600PubMedCrossRefGoogle Scholar
  26. 26.
    Neuhaus TJ, Calonder S, Leumann EP (1997) Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child 76:518–521PubMedCrossRefGoogle Scholar
  27. 27.
    Andersson HC, Shapira E (1998) Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr 132:121–124PubMedCrossRefGoogle Scholar
  28. 28.
    Bartholomew DW, Batshaw ML, Allen RH, Roe CR, Rosenblatt D, Valle DL, Francomano CA (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39PubMedCrossRefGoogle Scholar
  29. 29.
    Huemer M, Simma B, Fowler B, Suormala T, Bodamer OA, Sass JO (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang YH, Bressler J, Beaudet AL (2004) Epigenetics and human disease. Annu Rev Genomics Hum Genet 5:479–510PubMedCrossRefGoogle Scholar
  31. 31.
    Andersson HC, Marble M, Shapira E (1999) Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med 1:146–150PubMedCrossRefGoogle Scholar
  32. 32.
    Enns GM, Barkovich AJ, Rosenblatt DS, Fredrick DR, Weisiger K, Ohnstad C, Packman S (1999) Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 22:599–607PubMedCrossRefGoogle Scholar
  33. 33.
    Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154PubMedCrossRefGoogle Scholar
  34. 34.
    Linnebank M, Lutz H, Jarre E, Vielhaber S, Noelker C, Struys E, Jakobs C, Klockgether T, Evert BO, Kunz WS, Wüllner U (2006) Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol Dis 23:725–730PubMedCrossRefGoogle Scholar
  35. 35.
    Cusmano- Ozog K LF, Levine S, Martin M, Nicholas E, Packman S, Rosenblatt DS, Cederbaum SD, Cowan TM, Enns GM (2007) Cobalamin C disease identified by expanded newborn screening: The California experience. Molecular genetics and metabolism. Elsevier, Nashville, pp 227–352Google Scholar
  36. 36.
    Lerner-Ellis JP, Tirone JC, Pawelek PD, Doré C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2007

Authors and Affiliations

  • Ajay P. Sharma
    • 1
    • 2
    • 6
  • Cheryl R. Greenberg
    • 3
  • Asuri N. Prasad
    • 1
    • 4
  • Chitra Prasad
    • 1
    • 5
  1. 1.Department of PediatricsUniversity of Western OntarioLondonCanada
  2. 2.Section of NephrologyUniversity of Western OntarioLondonCanada
  3. 3.Department of Pediatrics and Child HealthUniversity of ManitobaWinnipegCanada
  4. 4.NeurologyUniversity of Western OntarioLondonCanada
  5. 5.GeneticsUniversity of Western OntarioLondonCanada
  6. 6.Childrens Hospital of Western OntarioLondon Health Sciences CentreLondonCanada

Personalised recommendations

Cite article

Buy options