Fabry Nephropathy: An Important Phenotype of the Mutation p.R356W (c.1066C>T)

Introduction: Nephropathy is a serious manifestation of Fabry disease. Kidney biopsy (KB) is a valuable tool for diagnosing nephropathy. The aim of this study is to describe renal impairment in three generations of patients with the p.R356W mutation. Case Description: CASE 1- Male, aged 65, diabetes mellitus for 12 years. Enzyme activity (EA): 0.52 (VR >2.2 umol/L/h); Lyso-GB3: 1.8 (VR < 1.8 ng/mL); Creatinine (Cr) 1.6 mg/dL; proteinuria 2.2 g/24h. KB: Optical microscopy (OM): 4/9 glomeruli with global sclerosis, foamy podocytes, mild tubular atrophy, and interstitial fibrosis, moderate arteriolar hyalinosis, artery with moderate fibrointimal hyperplasia. Electron microscopy (EM): lamellar inclusions in podocytes, thickened capillary loops, podocyte foot process effacement. CASE 2 Female, aged 50. EA: 2.2 (VR1.68-13.3 umol/L/h); Lyso-GB3: 1.6 (VR < 2.0 ng/mL); Cr 0.6 mg/dL; proteinuria 0.2 g/24h; albuminuria 18.5 mg/L. KB OM: segmental sclerosis in 3/47 glomeruli, global sclerosis in 2/47 glomeruli, podocytes with large and vacuolated cytoplasm, interstitial fibrosis (<10%). EM: podocytes with disorganized cytoplasm, foot process effacement containing zebra bodies. CASE 3 Male, aged 31. Lyso-GB3: 2.1 (VR < 0.8 ng/mL); Cr 0.76 mg/dL; proteinuria 0.22 g/24h; urinary albumin/creatinine ratio (ACR) 9.15mg/g. KB: diffuse podocyte vacuolation, preserved tubulointerstitium, arteries with slightly thickened walls. EM: lamellar inclusions in podocytes, with foot process effacement. CASE 4 Female, aged 17. Cr 0.6 mg/dL; ACR 29 mg/g; Lyso-GB3: 0.8 (VR < 1.8 ng/mL). KB OM: Podocyte hypertrophy, artery with mild fibrointimal hyperplasia, tubulointerstitium with no particularities. EM: podocytes with voluminous cytoplasm containing inclusions with myelin figures and zebra bodies and foot process effacement. CASE 5 Male, aged 8. EA: 0.16 (VR 1.68-13.3 umol/L/h), Lyso-GB3: 6.5 (VR < 1.8 ng/mL); Cr 0.4 mg/dL; ACR 4.6 mg/g. KB OM: Discreet podocyte hyperplasia, tubulointerstitial and vascular compartment with no particularities; EM: focal lamellar inclusions in podocytes, endothelium, and tubules; preserved foot process. Discussion: This study demonstrates the importance of KB in an early diagnosis of Fabry nephropathy and for understanding the phenotypic presentation of the different mutations. This study has demonstrated the tropism of the p.R356W mutation for the kidney.