title: Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation.
abstract: OBJECTIVE
  Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment.
  
  
  METHODS
  We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them.
  
  
  METHODS
  The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency.
  
  
  CONCLUSIONS
  Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ruiz-Mercado
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Vargas
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: I Pérez
authors.initials: IP
authors.lastname: de Soto
authors.affiliation: b Clinical Laboratory Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: C Delgado
authors.initials: CD
authors.lastname: Pecellín
authors.affiliation: b Clinical Laboratory Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: M Conde
authors.initials: MC
authors.lastname: Sánchez
authors.affiliation: c Pediatrics Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: M A Bueno
authors.initials: MA
authors.lastname: Delgado
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: R Bernal
authors.initials: RB
authors.lastname: Ruiz
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Pérez-Simón
authors.affiliation: a Hematology Department , Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CISC , Seville , Spain.
authors.forename: A Herrera
authors.initials: AH
authors.lastname: Díaz-Aguado
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000748:Anemia, Macrocytic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D001622:Betaine / Q000008:administration & dosage*; D002648:Child; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000172:deficiency / Q000235:genetics; D006801:Humans; D006879:Hydroxocobalamin / Q000008:administration & dosage*; D020138:Hyperhomocysteinemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense
chemical_list: D001622:Betaine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D006879:Hydroxocobalamin
keywords: Cobalamine E deficiency; Hyperhomocysteinemia; Hypomethioninemia; Megaloblastic anemia; Methionine synthase reductase