These images are from the kidney biopsy of a 70-year-old woman with a history of hypertension and valvular heart disease presenting with renal failure and serum creatinine of 4 mg/dl. The findings are suggestive of a mutation in which of the following genes:

A. Podocin

B. Glucocerebrosidase

C. a-galactosidase A

D. Nephrin

E. Phospholipase C

Answer: C

The images highlight podocytes loaded with numerous myelinosomes. There are only a few causes that can cause such accumulation, most notably Fabry disease. However, rare secondary causes to be considered include drugs such as chloroquine and chloroquine-like drugs (e.g., Plaquenil), amiodarone, aminoglycoside antibiotics, antidepressants and anti-cholesterol medications.

Fabry’s disease is an X-linked recessive, lysosomal storage disease caused by mutations in the gene a-galactosidase A (GLA) on the long arm of chromosome X (Xq22.1).  The mutations lead to a deficiency of the enzyme a-galactosidase A and accumulation of globotriaosylceramide (GL3) in different cells including myocytes, podocytes, endothelial and distal tubules. The lipid-containing myelinosomes can be appreciated in the toluidine blue sections because osmium fixation preserves the lipid. By electron microscopy laminated, electron-dense deposits can be seen, which have been classically described as “zebra bodies”. Females are heterozygous carriers and many (30%) are asymptomatic.