Case#2

Clinical History

A 17 year old boy with corneal dystrophy and increased in serum creatinine 1.1 mg/dL. Serologies are negative. Complements levels are within normal limits. Urinalysis is normal without microscopic hematuria. The patient had a family history of kidney and heart disease.

Pathologic Examination

H&E

Glomeruli

Podocyte cytoplasm appears expanded, foamy, pale, and lacy due to lipid deposits dissolved in processing

Mesangium can be expanded and mildly hypercellular

Endothelial cells appear normal in routine sections, although they also contain lipid

Trichrome

Tubules
- Distal tubules have abundant lipid deposits, which make them pale and vacuolated in routine sections

Toluidine Blue Survey Section (10X)

Toluidine Blue Survey Section (40X)

Lipid granules most conspicuous as dense granules filling podocytes and distal tubular epithelium

Electron Microscopy

Diagnostic feature of laminated, electron-dense lipid deposits in podocytes, endothelial cells, mesangial cells, smooth muscle cells, distal tubules, and interstitial fibroblasts

Immunofluorescence

Negative

Fabry Disease

Key Facts

Terminology

Lysosomal storage disease caused by genetic deficiency in α-galactosidase (αGal) A enzyme, leading to accumulation of globotriaosylceramide (GL3) in many cell types
Affects function of kidney, heart, sweat glands, nerves.

Etiology/Pathogenesis

X-linked recessive primarily affecting males
Symptoms and signs vary with mutation and consequent functional level of αGal

> 500 different mutations; 5% spontaneous

GL3 accumulates in endothelial and smooth muscle cells, podocytes, distal tubules, and many other cells

Clinical Issues

Presentation in childhood-adolescence with acroparesthesias, hypohidrosis, angiokeratomas
Renal dysfunction: 15-40 years of age
~ 0.3% of patients on dialysis
Females vary from asymptomatic to renal failure and/or cardiomyopathy
Treatment: Enzyme replacement, chaperone drug, transplantation

Differential Diagnosis

1- Chloroquine Toxicity

Lipids that accumulate with lysosomal inhibitor (chloroquine) therapy are indistinguishable from Fabry disease
History of chloroquine therapy may not be known, but this possibility should be raised
Diagnosis of Fabry disease requires ancillary studies (GL3 blood levels or genetic testing)

2- Focal Segmental Glomerulosclerosis

Fabry patients commonly develop FSGS due to either direct lipid effect on podocyte or decreased nephron mass
Lipid in podocytes are best clue but can be overlooked in light microscopy
- Electron micrograph is best method to detect lipid
  - Readily detected in podocytes

3- Subclinical Fabry Disease (in Patients with Other Renal Diseases)

Lipid deposits may be incidental finding in biopsies for other diseases (e.g., crescentic glomerulonephritis, IgA nephropathy, myeloma, membranous glomerulonephritis) or in carriers who are transplant donors

References

Diagnostic Pathology Textbook; Kidney Diseases, Third Edition
P Brennan, et al.: Case-finding in Fabry disease: experience from the North of England. J Inherit Metab Dis. 37 (1):103-107 2014 23828401
L Barisoni, et al.: Novel quantitative method to evaluate globotriaosylceramide inclusions in renal peritubular capillaries by virtual microscopy in patients with fabry disease. Arch Pathol Lab Med. 136 (7):816-824 2012 22742555
AB Fogo, et al.: Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN). Nephrol Dial Transplant. 25 (7):2168-2177 2010 19833663
U Ramaswami, et al.: Assessment of renal pathology and dysfunction in children with Fabry disease. Clin J Am Soc Nephrol. 5 (2):365-370 2010 20056758
ER Bracamonte, et al.: Iatrogenic phospholipidosis mimicking Fabry disease. Am J Kidney Dis. 48 (5):844-850 2006 17060007

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