Fabry disease: an ultrastructural comparative study of skin in hemizygous and heterozygous patients

Abstract

Fabry disease is a rare X-linked lysosomal storage disorder due to alpha galactosidase A deficiency, better known after the advent of a promising treatment, a periodical enzyme replacement. As other hereditary X-linked disorders, females have historically been considered non-affected carriers, although they are, actually, clinically and pathologically affected to a variable degree. Some women are asymptomatic, but the majority present milder forms of the disease and later onset. This wide range of disease expression is supposed to be related to the levels of enzymatic activity, probably in accordance with a skewing of X inactivation. Lysosomal deposits of ceramide trihexoside have been repeatedly documented in a wide range of tissues, including those found in angiokeratoma, the characteristic cutaneous lesion which allowed the definition of Fabry disease. The aim of this study was to investigate whether there was any difference in the amount of dermal lysosomal storage in males and females, thus accounting for the difference in clinical severity of both groups. For that purpose, with electron microscopy and quantitative methods, we studied the extent of lysosomal deposits in dermal fibroblasts of normal-appearing skin in six females and nine men, enzymatically and genetically proven as to have Fabry disease, and results were compared. Our results indicate a statistically significant difference between the two groups regarding both the percentage of dermal fibroblasts bearing stored material, and the storage surface occupied in 100 fibroblasts per case. We suggest that periodical ultrastructural examination of normal-appearing skin could be an indicator of the efficacy of enzyme replacement therapy and could help to evaluate results.

Fabry disease

“…However, due to the invasive nature of the procedure and the availability of reliable biochemical or molecular methods, these procedures should be considered only in the rare instances where there is residual α -galactosidase A activity in males or doubts on the causality of a DNA sequence change in females. Skin biopsy observed by EM may be a useful additional diagnostic test when carefully interpreted by an expert pathologist [275]. However, acquired metabolic disorders, such as the one induced by chloroquine therapy, may result in storage of ultrastructurally similar inclusions in many of the same cells as FD, leading to erroneous interpretation [276].…”

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

“…Skin Gb3 deposits have been demonstrated by using complex techniques such as electron microscopy[13] but they can also be detected by more simple and rapid techniques such as light microscopy[14,15]. However, by using this latter technique skin Gb3 deposits were not found in all analysed patients[15,16], preventing the use of this approach for diagnostic purposes.…”

Doença de Fabry

“…5 Na microscopia eletrônica se evidenciará a presença de inclusões lisossômicas, com a configuração lamelar concêntrica típica (alternância de bandas claras e escuras a cada 4-6nm), chamados de corpos de inclusão zebra-simil. 5,60 Quando esses achados não são conclusivos, pode ser realizada imunoeletromicroscopia com anticorpos antiGL-3.…”