Early renal changes in hemizygous and heterozygous patients with Fabry's disease

Abstract

Renal biopsy specimens were obtained for light and electron microscopy in 12 patients with Fabry's disease (9 hemizygous males and 3 heterozygous females), ranging in age from 7 to 51 yr. Renal function and blood pressure were normal in all patients. In hemizygouspatients, diffuse glycolipid accumulation was observed early in life in every glomerular, vascular, and interstitial cell; tubules were involved irregularly, predominantly in distal convoluted tubules and Henle's loop. In heterozygous females, the glycolipid storage had the same morphological features but was found irregularly, being absent in one patient and present patchily in the 2 others: some cells were normal, others were involved massively. Associated degenerative renal changes were present in all patients but one (a heterozygous female) and were clearly age-related. They first affected vessels as round fibrinoid deposits resulting from necrosis of severely involved smooth muscle cells. In older patients, intimal thickening was superimposed, and degenerative glomerular and tubular changes were noted. They have been related partly to ischemic damage. In addition, mesangial cell necrosis could have contributed to the development of glomerular sclerosis. Our findings in heterozygotes are consistent with Lyon's hypothesis of X chromosome inactivation in each female cell. They suggest that renal glycolipid involvement and urine α-galactosidase activity are closely related. They provide theoretical evidence against the possible benefits of enzyme replacement therapy.