Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity.
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 Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn.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.
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Bodo B
BB
Beck
Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
FrancJan
F
van Spronsen
Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
Arjan
A
Diepstra
Centre for Congenital Heart Diseases-Paediatric Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
Rolf M F
RM
Berger
Division of Paediatric Nephrology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. martin.komhoff@yahoo.com.|University Children's Hospital, Philipps University Marburg, Baldinger Str., 35043, Marburg, Germany. martin.komhoff@yahoo.com.
Martin
M
Kömhoff
D017668:Age of Onset; D002648:Child; D006397:Hematinics / Q000627:therapeutic use; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D006879:Hydroxocobalamin / Q000627:therapeutic use; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D057049:Thrombotic Microangiopathies / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy
D006397:Hematinics; D006879:Hydroxocobalamin
Atypical hemolytic uremic syndrome; Children; Cobalamin C defect; Pulmonary arterial hypertension