Sequelae of storage in Fabry disease--pathology and comparison with other lysosomal storage diseases.
OBJECTIVE
To evaluate the sequelae of the lysosomal storage of globotriaosylceramide (Gb3) in a series of patients with Fabry disease.


METHODS
Biopsy and post-mortem samples from 12 patients with Fabry disease were examined microscopically, including, in some cases, immunohistochemistry and electron microscopy. Where possible, comparisons were made with other lysosomal storage disorders.


RESULTS
Storage of Gb3 in cardiocytes leads commonly to progressive hypertrophy, which is a non-specific phenomenon also observed in other lysosomal storage disorders. Capillary endothelial storage was associated with a tendency for capillary basement membrane multiplication. In the single angiokeratoma studied, the basement membrane was rudimentary. Sinusoids in the adrenal cortex and liver displayed either a slight degree of storage or were unaffected. The glomeruli of the kidney exhibited focal hyalinization starting in the mesangial region. Proximal tubular cells were essentially free of lysosomal accumulation, including protein absorption droplets, despite the presence of proteinuria. In only one case, an autopsied Fabry heterozygote, were the proximal tubular cells loaded with protein absorption droplets. The arterial wall in large muscular arteries (coronary, renal and intrarenal) displayed arteriopathy with pronounced involvement of the smooth muscle cells in the media. Arteriopathy started with storage, followed by cell degeneration and breakdown, extracellular matrix deposition and, often, calcification (confined to the muscular layer). Smooth muscle cells occasionally exhibited shrinkage-type necrosis, with dispersion of the stored lipid into the dense cytoplasmic mass. Intimal and mitral valve fibroblasts exhibited variable storage, which was associated with cell loss and necrosis. Intensive storage was found in Leydig cells and in the epididymal epithelium.


CONCLUSIONS
These long-term sequelae of Gb3 storage are mostly irreversible. Some may interfere with enzyme replacement therapy. It is important, therefore, to consider starting enzyme replacement therapy as early as possible.
Institute of Inherited Metabolic Disorders, Charles University 1st Faculty of Medicine and University Hospital Prague, Prague, Czech Republic. melleder@cesnet.cz
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M
Elleder
D000293:Adolescent; D000328:Adult; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D000795:Fabry Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D016464:Lysosomal Storage Diseases / Q000473:pathology / Q000503:physiopathology; D008297:Male