Late-onset renal TMA and tubular injury in cobalamin C disease: a report of three cases and literature review

Abstract

Background: Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists.

Case presentation: Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered.

Conclusions: The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease.

Clinical trial number: Not applicable.

Keywords: MMACHC; Cobalamin C disease; Homocystinuria; Renal tubular injury; Thrombotic microangiopathy.

Fig. 1

Sanger electropherogram figure of MMACHC mutation in patient 1. A to C and D to F shows the mutated locus of patient 1, his father, and his mother on c.609 G > A (p.W203*) and c.658_660del (p.K220del), separately

Fig. 2

Kidney biopsy findings. (A) The glomerulus exhibited segmental endothelial cell proliferation with diffusely thickened glomerular basement membrane and the formation of ‘double contours’, and a granuloma consisted of mainly foam cells at beside interstitium (PAS ×400). (B) The loss of brush border with epithelial simplification of tubular epithelia was presented, along with focal infiltration of lymphocyte and mononuclear cells in renal interstitium (HE×400). (C) Electron microscopy showed widening of subendothelial area of glomerular basement membrane with narrowed cavity of capillary loops (original magnification ×5,000). (D) Proliferation of mesangial cells and endothelial cells with occlusion of glomerular capillary lumen was observed (original magnification×6,000)