Cobalamin disorder Cbl‐C presenting with late‐onset thrombotic microangiopathy

Abstract

Two siblings, a boy age 12 and his sister age 4 years, presented with proteinuria and hematuria, hypertension, and chronic hemolytic anemia. At age 13 years, the boy developed an episode of severe hypertensive encephalopathy and transient renal failure. Both children are attending normal school, have no neurologic symptoms, and only minimal pigmentary retinal abnormalities. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Both patients had hyperhomocysteinemia and mild methylmalonic aciduria. Fibroblasts showed decreased cobalamin uptake, reduced methyl- and adenosyl-cobalamin formation, and deficient incorporation of formate and propionate, compatible with the Cbl-C complementation group, but milder than that found in cells from most patients. Both patients and their father carry a balanced reciprocal translocation. Parenteral hydroxycobalamin treatment reduced the homocysteine levels, and methylmalonic acid disappeared. Increasing the dosage of hydroxycobalamin from 1 to 2.5, then 5 mg daily together with betaine, further reduced homocysteine levels (boy from 118 to 23 microM and girl from 59 to 14 microM). With this treatment, hemolysis has stopped, hematuria has disappeared, proteinuria has almost normalized, and creatinine clearance has been stable. Investigations for chronic thrombotic microangiopathy should include testing for this unusual but treatable disorder, regardless of age of presentation.

Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder

“…1 The steps of cobalamin (Cbl) metabolism involve activation of methylcobalamin and adenosylcobalamin, mediated by Cbl cofactors, and the final remethylation process. 5-methyl-THF 5-methyltetrahydrofolate, Cbl cobalamin, MTHFR methylene tetrahydrofolate reductase MRI magnetic resonance imaging in two sisters at age 6 and 8 years [13,14]. The delayed presentation did not have hematological, neurological, or failure-to-thrive issues.…”

Cobalamin C deficiency complicated by an atypical glomerulopathy

“…Renal biopsy findings were those of TMA. The renal and hematological manifestations of those patients improved with intramuscular administration of hydroxycobalamin [32].…”

Atypical Hemolytic Uremic Syndrome

“…In common medical language, the names typical or post-diarrheal (D+) HUS describe the most frequent form of HUS in children, due to Shigatoxin (Stx) producing Escherichia coli (STEC), mostly E coli 0157:H7. By opposition, the name atypical HUS (aHUS) has been historically used to describe any HUS not due to STEC, thus including: i) "Secondary" aHUS, due to a variety of causes, including infectious agents different from STEC, mostly Streptococcus pneumoniae (S pneumoniae) (via neuraminidase of S pneumoniae and T antigen exposure), human immunodeficiency virus and H1N1 influenza A, malignancy, cancer chemotherapy and ionizing radiation, bone marrow or solid organ transplantation, calcineurin inhibitors, sirolimus or anti vascular endothelial growth factor (VEGF) agents, pregnancy, HELLP (Hemolytic anemia, elevated Liver enzymes, and Low Platelets) syndrome, malignant hypertension, glomerulopathies, systemic diseases (systemic lupus erythematous and antiphospholipid antibody syndrome, sclerodermia) or, in children, methyl malonic aciduria with homocystinuria, cblC type, a rare hereditary defect of cobalamine metabolism [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Of note, it is now acknowledged that using the aHUS terminology rather than an etiological-based denomination (e.g.…”