Nephropathy in Fabry disease and iatrogenic phospholipidosis mimicking Fabry disease

Fabry disease is a rare X-linked inborn error of the glycosphingolipid metabolism caused by deficient activity of lysosomal enzyme alpha-galactosidase A. It is characterized by progressive multisystemic involvement that leads to premature death due to major organ failure, particularly the kidneys and heart. It appears that the disease is underdiagnosed in patients with end-stage renal disease. Clinical presentation can be atypical and, particularly in women, subtle. Its signs and symptoms are easily neglected or attributed to other disorders and biopsy is not indicated. It can be overlooked even when biopsy is performed in early stage in women or very advanced sclerotic stage, especially by an inexperienced pathologist looking at conventional light microscopic slides of inadequate quality and when electron microscopy is not done on a regular basis. Enzyme replacement therapy, which appears to reduce the harmful storage of undegradated sphyngolipids in cells, as well as potentially preventing the development and/or stopping the progression of secondary chronic sclerosing changes, is a revolutionary innovation. Early clinical diagnosis, standardized histopathology scoring of baseline disease before therapy, as well as longitudinal assessment of responses to therapy, highlight the important role of biopsy in disease management. The electron microscopy appearance of intracellular undegradated sphyngolipid deposits in the form of myelin-like cytoplasmic inclusions, with a peculiar distribution pattern within nephron structures, has been assumed to be typical and diagnostic for Fabry nephropathy. However, strikingly similar cytoplasmic inclusion bodies and the same distribution pattern have been presented in the kidney biopsies of 4 case reports in the literature since 2003 ascribed to iatrogenic injury as a side effect of anti-rheumatic therapy with chloroquine. Few physicians are aware of the potentially harmful effect of this drug, widely introduced as a safe treatment of mild forms of some autoimmune connective tissue diseases. A pathologist assessing the kidney biopsy of such a patient independently of clinical information about therapy can make a wrong diagnosis of Fabry disease or overlook diagnostically relevant cytoplasmic inclusions when storage is limited and electron microscopy is not applied.