title: Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Pediatric Nephrology Unit, Instituto da Crianca, University of Sao Paulo, Sao Paulo, Brazil. vaisbich@terra.com.br.
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Vaisbich
authors.affiliation: Pediatric Nephrology Unit, Instituto da Crianca, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Braga
authors.affiliation: Pediatric Nephrology Unit, Instituto da Crianca, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria
authors.initials: M
authors.lastname: Gabrielle
authors.affiliation: Mendelis Analise Genomica, Sao Paulo, Brazil.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Mendelis Analise Genomica, Sao Paulo, Brazil.
authors.forename: Flávia
authors.initials: F
authors.lastname: Piazzon
authors.affiliation: Mendelis Analise Genomica, Sao Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000071120:ADAMTS13 Protein / Q000378:metabolism; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000749:Anemia, Megaloblastic / Q000473:pathology; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D065766:Atypical Hemolytic Uremic Syndrome / Q000175:diagnosis*; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D006801:Humans; D006879:Hydroxocobalamin / Q000627:therapeutic use; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy; D007223:Infant; D007668:Kidney / Q000473:pathology; D007805:Language Development Disorders / Q000175:diagnosis / Q000209:etiology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D012008:Recurrence; D057049:Thrombotic Microangiopathies / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D014805:Vitamin B 12 / Q000097:blood* / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use; D000073359:Exome Sequencing
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014803:Vitamin B Complex; C481642:eculizumab; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D014805:Vitamin B 12; D006879:Hydroxocobalamin
keywords: Acute renal failure; Cobalamin metabolism; Hemolytic uremic syndrome; Methionine synthase; Microangiopathic hemolytic anemia; Thrombocytopenia; Thrombotic microangiopathy