High incidence of autoantibodies in Fabry disease patients

Abstract

Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism that results from a deficiency of the lysosomal enzyme alpha-galactosidase A. This defect leads to the accumulation of its substrates, mainly globotriaosylceramide, in lysosomes of cells of different tissues. Different studies have shown the involvement of immunopathologies in different sphingolipidoses. The coexistence of FD and immune disorders such as systemic lupus erythematosus, rheumatoid arthritis and IgA nephropathy, has been described in the literature. The aim of this study was to evaluate the prevalence of a group of autoantibodies in a series of Argentine FD patients. Autoantibodies against extractable nuclear antigens (ENAs), double-stranded DNA, anticardiolipin and phosphatidylserine were assayed by ELISA. Lupus anticoagulants were also tested. Fifty-seven per cent of the samples showed reactivity with at least one autoantigen. Such reactivities were more frequent among males than among females. Antiphospholipid autoantibodies were detected in 45% of our patients. The high rate of thrombosis associated with FD could be related, at least in part, to the presence of antiphospholipid autoantibodies in Fabry patients. We found the presence of ENAs, which are a characteristic finding of rheumatological diseases, previous a frequent misdiagnosis of FD, in around 39% of the cases. The detection of a high level of autoantibodies must be correlated clinically to determine the existence of an underlying autoimmune disease. With the recent development of therapy, the life expectancy in FD will increase and autoimmune diseases might play an important role in the morbidity of FD.

Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry’s disease

“…Stroke, thrombophilia and the presence of autoantibodies, including ‘lupus-associated’ antibodies to dsDNA, ENA and phospholipids, 37 can be features of patients with FD. Since the prevalence of aPL in Fabry’s patients is up to 45% 37 compared to around 30% in lupus patients, 38 it is difficult to assess whether the presence of aPL in this patient resulted from the FD or the APS. However, it seems likely that high levels of aPL that developed between 2002 and 2009 may well have contributed to the MI suffered in 2009.…”

Is there a pathogenic association between Fabry’s disease and IgA nephropathy?

“…The reason for the concomitant occurrence of autoimmune disorders and Fabry’s disease remains unclear. It has been suggested that immunogenic GL3 accumulation in patients with Fabry’s disease acts as a long-term antigenic stimulus that induces an autoimmune reaction [9, 10]. In addition, since GL3 is involved with lymphocyte function, one could imagine that deranged metabolism from alpha-galactosidase deficiency in Fabry’s disease could cause a shift in the balance in IgA glycosylation and lead to IgA nephropathy.…”

Lysosome dysfunction in the pathogenesis of kidney diseases

“…An alternate hypothesis as to how lysosomal dysfunction in Fabry’s disease leads to kidney failure is that abnormal GSL metabolism triggers inflammation, which then results in a self-sustaining process of fibrosis and eventually results in renal failure [31, 32]. Hence, Fabry’s disease may be considered to be a specific type of glomerulonephritis in which GSL accumulation, and/or the increased production of autoantibodies in Fabry’s disease [33], triggers glomerular inflammation and fibrosis, resulting in proteinuria and chronic kidney disease. In further support of this hypothesis, there have been numerous reports of the co-occurrence of glomerulonephritis and Fabry’s disease [32, 34–36].…”