Nephrotic syndrome

A 30-year-old woman presented with a history of nephrotic syndrome diagnosed when she was 4 years old. There was no family history of renal disease. An initial renal biopsy performed in her native country of Sri Lanka showed minimal-change disease. She was treated with steroids and was determined to be steroid-dependent. Subsequent trials of cyclosporin and cyclophosphamide failed to improve her condition and she was referred for additional evaluation. Renal ultrasound found bilaterally swollen kidneys. The concentrations of serum urea and creatinine were 27 mg/dL and 0.47 mg/dL, respectively, both within their respective reference ranges. The creatinine clearance was 137 mL/min. The urinary total protein excretion was 10.8 g/d and the serum albumin concentration was 15 g/L. Microscopic examination of the urine sediment was unremarkable. A left renal biopsy was performed and tissue was processed for light microscopy, immunofluorescence, and electron microscopy.

Light microscopic examination showed a patchy but striking vacuolar change in the renal tubular cells, with large nodular aggregates of foamy cells (Figure 1). There were also aggregates of foamy cells in the interstitium. The glomeruli were enlarged, partially due to segmental vacuolar changes in the visceral epithelial cells (podocytes) (Figure 2). The vacuolated cells in the tubules, glomeruli, and interstitium showed strong staining with the oil-red-O stain (Figure 3). Immunofluorescence was essentially negative.

Electron microscopy showed abundant whorled lamellated electron-dense myelin-like bodies bound by single membranes within the podocytes and tubular epithelial cells (Figure 4). These ranged from 0.7 µm to over 2.0 µm in diameter, with central clear zones. The glomerular basement membranes were of normal thickness and appearance.

What is your diagnosis?

Pathologic Diagnosis: Heterozygous Fabry Disease

Fabry disease, first described in 1898, is an X-linked recessive lysosomal storage disease with an incidence of approximately 1 in 40 000. The disease results from a deficiency of [alpha]-galactosidase A. This enzyme, a lysosomal hydrolase, is involved in the catabolism of neutral glycosphingolipids. Its deficiency leads to the intracellular accumulation of several glycosphingolipids, predominantly galabiosylceramide (also known as globotriaosyl ceramide and ceramide trihexoside) but also related compounds, such as digalactosyl ceramide. These compounds accumulate within the cells of many tissues such as the skin, renal glomerular and tubular epithelium, blood vessels, corneal epithelium, myocardium, and ganglion cells of the autonomic nervous system. The gene for [alpha]-galactosidase A is located on the long arm of the X chromosome (Xq22.1).

In hemizygous males, the gene is highly penetrant. Patients present in infancy or childhood with acroparesthesias and hypohidrosis and later with angiokeratomas of the skin, whorllike corneal opacities, renal dysfunction, cardiac dysfunction, and gastrointestinal disturbances. Heterozygous females were once thought to be asymptomatic or have only mild manifestations, such as corneal opacities or a few angiokeratomas. Case reports of women with heterozygous Fabry disease indicate that they may initially present with a single abnormality, such as proteinuria,1-3 hematuria,3 or angiokeratomas.4 However, a recent study of 60 female heterozygotes reported that multiple manifestations occur with a high frequency.5 Twenty of the 60 women had serious or debilitating complications, including cerebrovascular accidents, transient ischaemic attacks, and renal failure. In general, the age of presentation is later in women than in men, with many presenting in adulthood. The variation in the severity of the disease in heterozygous female patients can be explained by variable lyonization of the X chromosome. Patients with a higher proportion of cells with the normal X chromosome in the lyonized state will have greater expression of the Fabry disease phenotype, as these cells show greater [alpha]-galactosidase A deficiency.

In kidneys affected by Fabry disease, light microscopy reveals enlarged, foamy-appearing podocytes and tubular epithelial cells. Similar changes may also be seen in the endothelial and smooth muscle cells of arteries and arterioles. Immunofluorescence is negative in typical cases. Ultrastructurally, characteristic single membrane bound intracellular inclusions are present, described by a variety of names including myelin-like figures, myelin figures, and zebra bodies. These are round and lamellated, with concentric electron-dense layers, and range from 0.1 µm to 10 µm in diameter. Ultrastructural studies were not performed on the initial biopsy and likely resulted in the diagnosis being missed.

Fabry disease can also be detected by biochemical testing of the blood or urine. Both the serum and the leukocytes can be tested for the activity of [alpha]-galactosidase by an enzymatic assay.6 Female heterozygotes, however, may have enzymatic activity close to the normal range. Alternately, detection of the excretion of ceramide trihexoside in the urine may be useful and is especially important when the serum enzyme activity is normal or near-nor mal, as in female heterozygotes.6 In our case, thin layer chromatography of the patient's urine showed a band in the region associated with ceramide trihexoside, in keeping with Fabry disease. A monoclonal antibody to ceramide trihexoside is available and has been used to detect the intracellular accumulation of this substance by immunohistochemistry7 and immunofluorescence8 in patients with Fabry disease and may be useful diagnostically.

The genetic defects responsible for Fabry disease include partial gene arrangements, splice junction defects, and point mutations of the [alpha]-galactosidase A gene and these may be detected by gene analysis. Recombinant human [alpha]-galactosidase A replacement therapy has been shown by clinical trials to be safe and able to reverse the lysosomal storage of galabiosylceramide.9

The differential diagnoses of intracellular lipid accumulation in the kidney giving rise to foam cell change include other lysosomal storage diseases such as Gaucher disease, gangliosidoses, fucosidosis, and mucopolysaccharidoses. However, the intracellular distribution and the ultrastructural features of the inclusions are different from those seen in Fabry disease. It is noteworthy that the ultrastructural features of the inclusions are merely highly characteristic, as similar but not necessarily identical myelin-like figures may be seen in the kidneys of patients treated with chloroquine and aminoglycoside antibiotics.6 In the case of our patient, there was no history of ingestion of antimalarial medication. The various types of storage diseases can also be distinguished by assays of the respective enzymes involved.

In conclusion, Fabry disease is a rare cause of renal dysfunction characterized by proteinuria and systemic manifestations and often with a family history of the disease. Female heterozygotes, especially those with no apparent family history, may pose a greater diagnostic challenge. The highly characteristic ultrastructural changes on biopsy should lead one to the correct diagnosis. The diagnosis can be confirmed by biochemical testing. In addition, genetic testing may be carried out if this is available.

References

1. Rodriguez FH Jr, Hoffmann EO, Ordinario AT Jr, Baliga M. Fabry's disease in a heterozygous woman. Arch Pathol Lab Med. 1985;109:89-91.

2. Farge D, Nadler S, Wolfe LS, Barre P, Jothy S. Diagnostic value of kidney biopsy in heterozygous Fabry's disease. Arch Pathol Lab Med. 1985;109:85-88.

3. Chen HC, Tsai JH, Lai YH, Guh JY. Renal changes in heterozygous Fabry's disease-a family study. Ami Kidney Dis. 1990;15:180-183.

4. Handa Y, Yotsumoto S, Isobe E, et al. A case of symptomatic heterozygous female Fabry's disease without detectable mutation in the alpha-galactosidase gene. Dermatology. 2000;200:262-265.

5. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769-775.

6. Cohen AH, Adler SG. Nail-patella syndrome (osteo-onychodysplasia), lipodystrophy, Fabry disease (angiokeratoma corporis diffusum universale) and familial lecithin-cholesterol acyltransferase deficiency. In: Tisher CC, Brenner BM, eds. Renal Pathology: With Clinical and Functional Correlations. 2nd ed. Philadelphia, Pa: JB Lippincott; 1994:1267-1290.

7. Fukushima M, Tsuchiyama Y, Nakato T, et al. A female heterozygous patient with Fabry's disease with renal accumulation of trihexosylccramide detected with a monoclonal antibody. Am J Kid Ois. 1995;26:952-955.

8. Itoh K, Takenaka T, Nakao S, et al. Immunofluorescence analysis of trihexosylceramide accumulated in the hearts of variant hemizygotes and heterozygotes with Fabry disease. Am J Cardiol. 1996;78:116-117.

9. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management and enzyme replacement therapy. Ann Intern Med. 2003;133:338-346.

Thomas Pauiraj Thamboo, MB, ChB; Pary Sivaraman, MBBS, MRCP(UK), MMed Int Med(Singapore), FAMS(Singapore); Norman Hock-Ling Chan, MDCM, FRCP(C)

Accepted for publication January 9, 2004.

From the Department of Pathology, National University of Singapore, Singapore (Drs Thamboo and Chan); Department of Renal Pathology, Department of Medicine, National University Hospital, Singapore (Dr Sivaraman). Dr Chan is currently with the Department of Pathology, FHMS UAE University, Al Ain, Abu Dhabi, United Arab Emirates.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Thomas Paulraj Thamboo, MB, ChB, Department of Pathology, National University of Singapore, National University Hospital, Lower Kent Ridge Road, Singapore 119074 (e-mail: pattpt@nus.edu.sg).

Reprints not available from the authors.

Copyright College of American Pathologists May 2004
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