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Open Access 01-05-2017 | Review

Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity

Authors: Bodo B. Beck, FrancJan van Spronsen, Arjan Diepstra, Rolf M. F. Berger, Martin Kömhoff

Published in: Pediatric Nephrology | Issue 5/2017

Abstract

Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B₁₂) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment.

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Eschenmoser A (2011) Etiology of potentially primordial biomolecular structures: from vitamin B12 to the nucleic acids and an inquiry into the chemistry of life’s origin: a retrospective. Angew Chem Int Ed Engl 50:12412–12472CrossRefPubMed

Roth JR, Lawrence JG, Bobik TA (1996) Cobalamin (coenzyme B12): synthesis and biological significance. Annu Rev Microbiol 50:137–181CrossRefPubMed

Froese DS, Gravel RA (2010) Genetic disorders of vitamin B(1)(2) metabolism: eight complementation groups—eight genes. Expert Rev Mol Med 12:e37CrossRefPubMedPubMedCentral

Carrillo-Carrasco N, Chandler RJ, Venditti CP (2012) Combined methylmalonic acidemia and homocystinuria, cblC type I. Clinical presentations, diagnosis and management. J Inherit Metab Dis 35:91–102CrossRefPubMed

Mudd SH, Levy HL, Abeles RH, Jennedy JP Jr (1969) A derangement in B 12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun 35:121–126CrossRefPubMed

Gravel RA, Mahoney MJ, Ruddle FH, Rosenberg LE (1975) Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism. Proc Natl Acad Sci U S A 72:3181–3185CrossRefPubMedPubMedCentral

Harding CO, Pillers DA, Steiner RD, Bottiglieri T, Rosenblatt DS, Debley J, Michael Gibson K (2003) Potential for misdiagnosis due to lack of metabolic derangement in combined methylmalonic aciduria/hyperhomocysteinemia (cblC) in the neonate. J Perinatol 23:384–386CrossRefPubMed

Carrillo-Carrasco N, Venditti CP (2012) Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes. J Inherit Metab Dis 35:103–114CrossRefPubMed

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 38:93–100CrossRefPubMed

10.

Banerjee R (2006) B12 trafficking in mammals: a for coenzyme escort service. ACS Chem Biol 1:149–159CrossRefPubMed

11.

Kim J, Gherasim C, Banerjee R (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci U S A 105:14551–14554CrossRefPubMedPubMedCentral

12.

Moreno-Garcia MA, Pupavac M, Rosenblatt DS, Tremblay ML, Jerome-Majewska LA (2014) The Mmachc gene is required for pre-implantation embryogenesis in the mouse. Mol Genet Metab 112:198–204CrossRefPubMed

13.

Weisfeld-Adams JD, Morrissey MA, Kirmse BM, Salveson BR, Wasserstein MP, McGuire PJ, Sunny S, Cohen-Pfeffer JL, Yu C, Caggana M, Diaz GA (2010) Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab 99:116–123CrossRefPubMed

14.

Sonsino E, Ogier H, Mercier JC, Devictor D, Ferkdadji L, Bocquet L (1985) Congenital anomaly of the metabolism of vitamin B 12. Histopathological study. Arch Anat Cytol Pathol 33:98–99PubMed

15.

Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype–phenotype correlations. Hum Mutat 30:1072–1081CrossRefPubMed

16.

Liu MY, Yang YL, Chang YC, Chiang SH, Lin SP, Han LS, Qi Y, Hsiao KJ, Liu TT (2010) Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. J Hum Genet 55:621–626CrossRefPubMed

17.

Watkins D, Rosenblatt DS (2011) Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C: Semin Med Genet 157C:33–44CrossRef

18.

Fischer S, Huemer M, Baumgartner M, Deodato F, Ballhausen D, Boneh A, Burlina AB, Cerone R, Garcia P, Gökçay G, Grünewald S, Häberle J, Jaeken J, Ketteridge D, Lindner M, Mandel H, Martinelli D, Martins EG, Schwab KO, Gruenert SC, Schwahn BC, Sztriha L, Tomaske M, Trefz F, Vilarinho L, Rosenblatt DS, Fowler B, Dionisi-Vici C (2014) Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 37:831–840CrossRefPubMed

19.

Baumgartner ER, Wick H, Maurer R, Egli N, Steinmann B (1979) Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology. Helv Paediatr Acta 34:465–482PubMed

20.

Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN (1997) Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients. Gastroenterology 113:430–433CrossRefPubMed

21.

Li QL, Song WQ, Peng XX, Liu XR, He LJ, Fu LB (2015) Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children. World J Pediatr 11:276–280CrossRefPubMed

22.

Koenig JC, Rutsch F, Bockmeyer C, Baumgartner M, Beck BB, Kranz B, Konrad M (2015) Nephrotic syndrome and thrombotic microangiopathy caused by cobalamin C deficiency. Pediatr Nephrol 30:1203–1206CrossRefPubMed

23.

Carmel R, Bedros AA, Mace JW, Goodman SI (1980) Congenital methylmalonic aciduria—homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570–579PubMed

24.

Jiménez Varo I, Bueno Delgado M, Dios Fuentes E, Delgado Pecellin C, González Meneses A, Soto Moreno A, Venegas Moreno E (2015) Combined methylmalonic acidemia and homocystinuria; a case report. Nutr Hosp 31:1885–1888PubMed

25.

Cornec-Le Gall E, Delmas Y, De Parscau L, Doucet L, Ogier H, Benoist JF, Fremeaux-Bacchi V, Le Meur Y (2014) Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. Am J Kidney Dis 63:119–123CrossRefPubMed

26.

Kömhoff M, Roofthooft MT, Westra D, Teertstra TK, Losito A, van de Kar NC, Berger RM (2013) Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics 132:e540–e544CrossRefPubMed

27.

Menni F, Testa S, Guez S, Chiarelli G, Alberti L, Esposito S (2012) Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria. Pediatr Nephrol 27:1401–1405CrossRefPubMed

28.

Bouts AH, Roofthooft MT, Salomons GS, Davin JC (2010) CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency. Pediatr Nephrol 25:2547–2548CrossRefPubMedPubMedCentral

29.

Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103CrossRefPubMed

30.

Guigonis V, Frémeaux-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 45:588–595CrossRefPubMed

31.

Van Hove JL, Van Damme-Lombaerts R, 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 111:195–201CrossRefPubMed

32.

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 24:327–329CrossRefPubMed

33.

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 50:749–754PubMed

34.

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 120:934–937CrossRefPubMed

35.

Huemer M, Scholl-Bürgi S, Hadaya K, Kern I, Beer R, Seppi K, Fowler B, Baumgartner MR, Karall D (2014) Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis 9:161CrossRefPubMedPubMedCentral

36.

Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B, MMACHC Working Group (2009) Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 30:1558–1566CrossRefPubMed

37.

Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L (2008) The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 79:725–728CrossRefPubMed

38.

Brunelli SM, Meyers KE, Guttenberg M, Kaplan P, Kaplan BS (2002) Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 17:800–803CrossRefPubMed

39.

Benz K, Amann K (2010) Thrombotic microangiopathy: new insights. Curr Opin Nephrol Hypertens 19:242–247CrossRefPubMed

40.

Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R (1955) Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85:905–909PubMed

41.

Renaud C, Niaudet P, Gagnadoux MF, Broyer M, Habib R (1995) Haemolytic uraemic syndrome: prognostic factors in children over 3 years of age. Pediatr Nephrol 9:24–29CrossRefPubMed

42.

Mangge H, Becker K, Fuchs D, Gostner JM (2014) Antioxidants, inflammation and cardiovascular disease. World J Cardiol 6:462–477CrossRefPubMedPubMedCentral

43.

Keller MD, Ganesh J, Heltzer M, Paessler M, Bergqvist AG, Baluarte HJ, Watkins D, Rosenblatt DS, Orange JS (2013) Severe combined immunodeficiency resulting from mutations in MTHFD1. Pediatrics 131:e629–e634CrossRefPubMed

44.

Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, Majewski J, Rosenblatt DS (2011) Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband. J Med Genet 48:590–592CrossRefPubMed

45.

Andrès E, Affenberger S, Zimmer J, Vinzio S, Grosu D, Pistol G, Maloisel F, Weitten T, Kaltenbach G, Blicklé JF (2006) Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haematol 28:50–56CrossRefPubMed

46.

Han L, Wu S, Ye J, Qiu W, Zhang H, Gao X, Wang Y, Gong Z, Jin J, Gu X (2015) Biochemical, molecular and outcome analysis of eight chinese asymptomatic individuals with methyl malonic acidemia detected through newborn screening. Am J Med Genet A 167A:2300–2305CrossRefPubMed

47.

Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschênes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562CrossRefPubMedPubMedCentral

48.

Geerdink LM, Westra D, van Wijk JA, Dorresteijn EM, Lilien MR, Davin JC, Kömhoff M, Van Hoeck K, van der Vlugt A, van den Heuvel LP, van de Kar NC (2012) Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatr Nephrol 27:1283–1291CrossRefPubMedPubMedCentral

49.

Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type). Am J Med Genet 36:167–171CrossRefPubMed

50.

Iodice FG, Di Chiara L, Boenzi S, Aiello C, Monti L, Cogo P, Dionisi-Vici C (2013) Cobalamin C defect presenting with isolated pulmonary hypertension. Pediatrics 132:e248–e251CrossRefPubMed

51.

Solomon LR (2007) Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev 21:113–130CrossRefPubMed

52.

Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32:728–731CrossRefPubMedPubMedCentral

53.

Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V, French Study Group for aHUS/C3G (2012) Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 8:643–657CrossRefPubMed

54.

MacLennan S, Barbara JA (2006) Risks and side effects of therapy with plasma and plasma fractions. Best Pract Res Clin Haematol 19:169–189CrossRefPubMed

55.

Abels J, Kroes AC, Ermens AA, van Kapel J, Schoester M, Spijkers LJ, Lindemans J (1990) Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide. Am J Hematol 34:128–131CrossRefPubMed

56.

Drummond JT, Matthews RG (1994) Nitrous oxide degradation by cobalamin-dependent methionine synthase: characterization of the reactants and products in the inactivation reaction. Biochemistry 33:3732–3741CrossRefPubMed

57.

Komhoff M, Roofthooft MT, Spronsen F (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371:1846–1847CrossRefPubMed

Title: Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity
Authors: Bodo B. Beck
FrancJan van Spronsen
Arjan Diepstra
Rolf M. F. Berger
Martin Kömhoff
Publication date: 01-05-2017
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 5/2017
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-016-3399-0

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Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity

Abstract

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