title: Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency.
abstract: A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.
authors.affiliation: Department of Nephrology, University Hospital, Brest, France. Electronic address: emilie.cornec-legall@chu-brest.fr.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cornec-Le Gall
authors.affiliation: Department of Nephrology, University Hospital, Bordeaux, France.
authors.forename: Yahsou
authors.initials: Y
authors.lastname: Delmas
authors.affiliation: Department of Pediatrics, University Hospital, Brest, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: De Parscau
authors.affiliation: Department of Pathology, University Hospital, Brest, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Doucet
authors.affiliation: Department of Neurologic and Metabolic Diseases, Robert Debré Children Hospital, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier
authors.affiliation: Department of Biochemistry and Hormonology, Robert Debré Hospital, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: Department of Biologic Immunology, Assistance-Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.affiliation: Department of Nephrology, University Hospital, Brest, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Meur
mesh_terms: D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001622:Betaine / Q000008:administration & dosage; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D004351:Drug Resistance; D006710:Homocysteine / Q000652:urine; D006712:Homocystinuria / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006879:Hydroxocobalamin / Q000008:administration & dosage; D006974:Hypertension, Malignant / Q000209:etiology*; D007155:Immunologic Factors / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D002955:Leucovorin; D008082:Lipotropic Agents / Q000008:administration & dosage; D008297:Male; D008715:Methionine / Q000097:blood; D008764:Methylmalonic Acid / Q000652:urine; D009154:Mutation; D010088:Oxidoreductases; D012008:Recurrence; D006435:Renal Dialysis; D016896:Treatment Outcome; D014806:Vitamin B 12 Deficiency / Q000151:congenital; D014803:Vitamin B Complex / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002352:Carrier Proteins; D007155:Immunologic Factors; D008082:Lipotropic Agents; D006710:Homocysteine; D014803:Vitamin B Complex; D001622:Betaine; D008764:Methylmalonic Acid; C481642:eculizumab; D008715:Methionine; C508359:MMACHC protein, human; D010088:Oxidoreductases; D006879:Hydroxocobalamin; D002955:Leucovorin
keywords: Hemolytic uremic syndrome (HUS); MMACHC (methylmalonic aciduria and homocystinuria type C protein); chronic kidney failure; cobalamin; cobalamin C disease; eculizumab