Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review

Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.

[1]  B. Souweine,et al.  Cobalamin c deficiency associated with antifactor h antibody-associated hemolytic uremic syndrome in a young adult , 2020, BMC Nephrology.

[2]  T. Coşkun,et al.  Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency , 2019, Nephron.

[3]  E. Şevketoğlu,et al.  Hemolytic uremic syndrome with dual caution in an infant: cobalamin C defect and complement dysregulation successfully treated with eculizumab , 2018, Pediatric Nephrology.

[4]  J. Balcells,et al.  Cobalamin disorder CblC presenting with hemolytic uremic syndrome and pulmonary hypertension. , 2017, Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia.

[5]  M. Baumgartner,et al.  Cobalamin C defect‐hemolytic uremic syndrome caused by new mutation in MMACHC , 2016, Pediatrics international : official journal of the Japan Pediatric Society.

[6]  A. Diepstra,et al.  Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity , 2016, Pediatric Nephrology.

[7]  R. Coppo,et al.  An international consensus approach to the management of atypical hemolytic uremic syndrome in children , 2015, Pediatric Nephrology.

[8]  M. Baumgartner,et al.  Clinical presentation and outcome in a series of 88 patients with the cblC defect , 2014, Journal of Inherited Metabolic Disease.

[9]  L. Doucet,et al.  Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. , 2014, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[10]  C. Venditti,et al.  Disorders of Intracellular Cobalamin Metabolism , 2013 .

[11]  S. Testa,et al.  Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria , 2012, Pediatric Nephrology.

[12]  C. Venditti,et al.  Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes , 2012, Journal of Inherited Metabolic Disease.

[13]  R. Chandler,et al.  Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management , 2012, Journal of Inherited Metabolic Disease.

[14]  G. Salomons,et al.  CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency , 2010, Pediatric Nephrology.

[15]  M. Baumgartner,et al.  Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype–phenotype correlations , 2009, Human mutation.

[16]  C. Greenberg,et al.  Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder , 2007, Pediatric Nephrology.

[17]  C. Morel,et al.  Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. , 2006, Molecular genetics and metabolism.

[18]  E. Shoubridge,et al.  Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type , 2006, Nature Genetics.

[19]  R. Favier,et al.  Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[20]  G. Werstuck,et al.  Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease , 2004, Cell Death and Differentiation.

[21]  P. Francis,et al.  An infant with methylmalonic aciduria and homocystinuria (cblC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury , 2004, European Journal of Pediatrics.

[22]  M. Seashore,et al.  Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC) , 1997, Journal of Inherited Metabolic Disease.

[23]  M. Geraghty,et al.  Tubulointerstitial nephritis in methylmalonic acidemia , 1993, Pediatric Nephrology.

[24]  T. Kind,et al.  Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. , 2002, Journal of pediatric hematology/oncology.

[25]  G. Barbano,et al.  SYNDROME HEMOLYTIQUE ET UREMIQUE NEONATAL, ACIDURIE METHYLMALONIQUE ET HOMOCYSTINURIE PAR DEFICIT INTRACELLULAIRE DE LA VITAMINE B12 [1] , 1994 .

[26]  D. Valle,et al.  Cobalamin C defect associated with hemolytic-uremic syndrome. , 1992, The Journal of pediatrics.

[27]  J. Doyon,et al.  A congenital anomaly of vitamin B12 metabolism: a study of three cases. , 1992, Human pathology.

[28]  W. Nyhan,et al.  Proximal renal tubular acidosis in methylmalonic acidemia. , 1985, Journal of neurogenetics.

[29]  J. Graeber,et al.  Effect of Homocysteine and Homocystine on Platelet and Vascular Arachidonic Acid Metabolism , 1982, Pediatric Research.

[30]  R. Carmel,et al.  Congenital methylmalonic aciduria--homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. , 1980, Blood.

[31]  E. R. Baumgartner,et al.  Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology. , 1979, Helvetica paediatrica acta.