Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease

Abstract

BackgroundThe X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.MethodsAt our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.ResultsWe found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.ConclusionsImmunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.

Hot topics in Fabry disease

“…As such Gb3—the end product which accumulates in lysosomes and is routinely used to diagnose the disease on tissue biopsy—heart, kidney15 and most recently skin16—has so far failed to convince as a suitable plasma or urine marker. A study by Young17 performed on hemizygotes, heterozygotes and healthy controls failed to reliably detect increased Gb3 levels in plasma and urine in heterozygotes and hemizygotes with non-classical mutation.…”

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. The reason of the absence of Gb3 deposits in the skin samples of few FD patients is unknown, although a possible correlation with plasma lyso-GL-3 levels was suggested[ 15 ].…”

Detection of blood Gb3 deposits as a new tool for diagnosis and therapy monitoring in patients with classic Fabry disease

“…Heart and kidneys are the organs of choice as these are most frequently involved. We recently described Gb3 deposits in skin punch biopsies of FD patients as a potential additional diagnostic tool . However, even if the risk for adverse events is estimated low during such an organ biopsy, it is still an invasive method.…”

“…Thus, myocardial or renal biopsy is recommended in cases where test results are equivocal, to search for the presence and extent of cellular Gb3 deposits . We recently showed that using easily applicable microscopy techniques, Gb3 deposits can be visualized in skin samples . However, although considered to be of low risk , biopsies are invasive.…”