Cobalamin E deficiency complicated with thrombotic microangiopathy: a case report

Cobalamin E (cblE) defect, caused by pathogenic variants in MTRR encoding methionine synthase reductase, is a rare remethylation disorder typically documented in small case series. While common features include failure to thrive, cognitive impairment, and macrocytic anemia, renal thrombotic microangiopathy (TMA) is uncommon and remains under-recognized. An 8-year-old, previously healthy Thai boy presented with a 4-day history of fever and fatigue. Initial investigation revealed bicytopenia with megaloblastic anemia and renal dysfunction. Chronic TMA was diagnosed by renal pathology which demonstrated double contours of the glomerular basement membrane without mesangial or endocapillary hypercellularity. Given the combination of megaloblastic anemia, TMA, and renal impairment, an inborn error of cobalamin metabolism was suspected. A serum total homocysteine test revealed markedly elevated levels with undetectable urine methylmalonic acid, suggesting a remethylation defect. Singleton whole exome sequencing (WES) was carried out, followed by Sanger sequencing of the supposed variant. The result indicated a compound heterozygous MTRR mutation, c.309dup (p.Phe104Leufs*9) and c.1770-5T>G, confirming cblE defect. After parenteral hydroxocobalamin was given, the patient demonstrated gradual improvement in TMA and renal function, accompanied by a decline in homocysteine levels. This case underscores that cblE defects can present in late childhood with chronic TMA and megaloblastic anemia. Prompt recognition of remethylation disorders and early institution of hydroxocobalamin therapy can mitigate microangiopathic injury and prevent progression to kidney failure. Genetic confirmation remains essential to guide long-term management and family counseling.