Abstract
Background
Inborn errors of cobalamin (Cbl) metabolism form a large group of rare diseases. One of these, Cbl deficiency type C (CblC), is a well-known cause of thrombotic microangiopathy (TMA), especially in infants. However, there has only been a single published case of TMA associated to Cbl deficiency type G (CblG), also known as methionine synthase deficiency (MSD).
Case diagnosis/treatment
A 21-month-old boy presented with pallor and oral ulcers during episodes of upper respiratory infection (URI). Further examination revealed signs of TMA, and the patient progressed to acute renal failure (ARF). Renal biopsy showed TMA. Evaluation for infection and autoantibodies were negative. The C3 and C4 complement fractions were normal. Analysis of the bone marrow aspirate suggested megaloblastic anemia and signs of hematopoiesis activation (secondary to peripheral hemolysis). Although the serum vitamin B12 level was normal, the patient was treated with cyanocobalamin, with no improvement. The ARF and hematologic parameters improved with conservative treatment. A severe relapse occurred during the follow-up, with normal ADAMTS13 activity. The presumed diagnosis was atypical hemolytic uremic syndrome, and the patient was started on eculizumab, but his response was poor, even when the dosage was increased. At this point it was also recognized that his developmental speech was delayed. Based on these findings, whole exome sequencing was performed, leading to the detection of two novel deleterious variants in the gene coding for methionine synthase, confirming the diagnosis of MSD. Subsequent treatment consisted of elevating the patient’s serum homocysteine level and starting him on hydroxicobalamin, with normalization of all hematologic parameters although the microalbuminuria remained.
Conclusions
Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.
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References
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 27:1401–1405
Bouts AH, Roofthooft MTR, Salomons GS, Davin JC (2010) CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency. Pediatr Nephrol 25:2547–2548
Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Anna Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NCAJ, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V, for HUS International (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31(1):15–39
Mele C, Remuzzi G, Noris M (2014) Hemolytic uremic syndrome. Semin Immunopathol 36(4):399–420
Cataland SR, Wu HM (2014) Diagnosis and management of complement mediated thrombotic microangiopathies. Blood Rev 28:67–74
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(1):119–123
Grangé S, Bekri S, Artaud-Macari E, Francois A, Girault C, Poitou AL, Benhamou Y, Vianey-Saban C, Benoist JF, Châtelet V, Tamion F, Guerrot D (2015) Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency. Lancet 386:1011–1012
Labrune P, Zittoun J, Duvaltier I, Trioche P, Marquet J, Niaudet P, Odie Ávre M (1999) Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 158:734–739
Schalk G, Kirschfink M, Wehling C, Gastoldi S, Bergmann C, Hoppe B, Weber LT (2015) A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab. Pediatr Nephrol 30(6):1039–1042
Antony AC (2009) Megaloblastic anemias. In: Hoffman R (ed) Hematology: basic principles and practice. Churchill Livingstone Elsevier, Philadelphia, pp 491–524
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(1):91–102
Watkins D, Ming Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Doré C, Hosack A, Wilson A, Gravel RA, Shane B, Hudson TJ, Rosenblatt DS (2002) Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet 71:143–153
Lentz SR (2005) Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost 3:1646–1654
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Vaisbich, M.H., Braga, A., Gabrielle, M. et al. Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls. Pediatr Nephrol 32, 1089–1092 (2017). https://doi.org/10.1007/s00467-017-3615-6
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DOI: https://doi.org/10.1007/s00467-017-3615-6