Ultrastructural study of skin biopsies in two cases of Gaucher disease (GD) patients (types II and III) revealed hitherto unknown alteration of the blood capillary endothelial cells (ECs) featured by hypertrophy and numerous subplasmalemmal microvesicles underneath both the apical and basal membranes. There was also prominent apical membrane folding with formation of filiform and large cytoplasmic projections, with occasional transcapillary cytoplasmic bridges. Similar, though less frequently expressed, changes were manifested at the basal membrane by numerous cytoplasmic projections into the subendothelial space. Regressive changes with EC breakdown were rare. Lysosomal storage was always absent. Besides EC hypertrophy, there was also increased EC density in the capillary lumen, leading to pronounced changes in capillary architecture with loose or incomplete EC anchoring. There were also signs of EC sprouting. Some pericytes displayed an increase in size and number of cytoplasmic processes, which often extended into distant pericapillary regions. The spectrum of changes suggests that a significant positive growth effect on EC occurs in GD. The putative mechanisms triggered by GBA1 deficiency leading to EC involvement are discussed. The authors are well aware of the fact the results, based on a nontraditional type of bioptic samples, are preliminary, but they are worth following, as further ultrastructural and functional studies of blood endothelium in GD may open a novel field in molecular cell pathophysiology of the disorder: endothelial dysfunction.

• MeSH
• Biopsy methods   MeSH
• Endothelium, Vascular diagnostic imaging   pathology   MeSH
• Cytoplasm metabolism   MeSH
• Fibroblasts metabolism   MeSH
• Gaucher Disease diagnostic imaging   pathology   MeSH
• Capillaries diagnostic imaging   pathology   MeSH
• Infant MeSH
• Skin blood supply   diagnostic imaging   pathology   MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• Neovascularization, Pathologic MeSH
• Pericytes metabolism   MeSH
• Child, Preschool MeSH
• Ultrasonography MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

AIM: We used intravascular ultrasound (IVUS) to characterize coronary artery involvement in patients with Fabry disease (FD). METHODS: Nine FD patients (5 women) were matched to 10 control patients (5 women) chosen from our IVUS database. Standard volumetric IVUS analyses were performed along with assessment of plaque echodensity. RESULTS: Plaques in FD patients were diffuse and hypoechogenic compared with more focal and more echogenic lesions in control patients. Echogenicity of plaques was significantly lower in FD patients (median 30.7 +/- 12.9 vs 55.9 +/- 15.7, p = 0.0052, mean 37.2 +/- 15.6 vs 66.2 +/- 13.3, p = 0.0014). Diffusiveness was assessed as differences between mean and median plaque burden versus the plaque burden in each of the analysed cross-sections. These differences were lower in FD vs controls (5.8 +/- 4.8 vs 8.7 +/- 6.6, p < 0.001 for mean, and 5.8 +/- 4.9 vs 8.8 +/- 7.3, p < 0.001 for median) indicating a more diffuse involvement. The occurrence of lipid cores was significantly higher in FD patients than in controls (2.4 +/- 1.5 vs 1.0 +/- 0.94, p = 0.02). CONCLUSION: IVUS showed diffuse hypoechogenic plaques in patients with FD. The explanation may be higher lipid content in plaques and accumulation of glycosphingolipid in smooth-muscle and endothelial cells.

• MeSH
• Endothelium, Vascular pathology   MeSH
• Fabry Disease complications   diagnosis   diagnostic imaging   MeSH
• Fibroblasts metabolism   MeSH
• Coronary Angiography methods   MeSH
• Coronary Vessels diagnostic imaging   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Coronary Artery Disease complications   diagnosis   diagnostic imaging   MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Trihexosylceramides metabolism   MeSH
• Ultrasonography MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• globotriaosylceramide MeSH Browser
• Trihexosylceramides MeSH

The function and intracellular delivery of enzyme therapeutics for Fabry disease were studied in cultured fibroblasts and in the biopsied tissues of two male patients to show diversity of affected cells in response to treatment. In the mutant fibroblasts cultures, the final cellular level of endocytosed recombinant alpha-galactosidases A (agalsidases, Fabrazyme, and Replagal) exceeded, by several fold, the amount in control fibroblasts and led to efficient direct intra-lysosomal hydrolysis of ((3)H)Gb3Cer. In contrast, in the samples from the heart and some other tissues biopsied after several months of enzyme replacement therapy (ERT) with Fabrazyme, only the endothelial cells were free of storage. Persistent Gb3Cer storage was found in cardiocytes (accompanied by increase of lipopigment), smooth muscle cells, fibroblasts, sweat glands, and skeletal muscle. Immunohistochemistry of cardiocytes demonstrated, for the first time, the presence of a considerable amount of the active enzyme in intimate contact with the storage compartment. Factors responsible for the limited ERT effectiveness are discussed, namely post-mitotic status of storage cells preventing their replacement by enzyme supplied precursors, modification of the lysosomal system by longstanding storage, and possible relative lack of Sap B. These observations support the strategy of early treatment for prevention of lysosomal storage.

• MeSH
• alpha-Galactosidase metabolism   therapeutic use   MeSH
• Biopsy MeSH
• Fabry Disease therapy   MeSH
• Fibroblasts enzymology   MeSH
• Genetic Therapy methods   MeSH
• Microscopy, Confocal MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Myocardium enzymology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• alpha-Galactosidase MeSH