PRESENTATION AND DIAGNOSIS

Most patients begin to experience some of the previous symptoms during childhood. The diagnosis of Fabry disease should be suspected in the setting of a positive family history and progressive multisystem disease. Given the myriad nonspecific clinical symptoms, however, a variety of other conditions (often rheumatologic) are often first proposed instead, frequently delaying the correct diagnosis. Most males are diagnosed in childhood or puberty. Female carriers may be diagnosed later in life, depending on the severity of their clinical manifestations.

In males, the diagnosis can be confirmed by measuring α-Gal A enzyme activity within leukocytes. In female carriers, who retain a functional copy of α-Gal A, this test is less sensitive. Genetic sequencing can be performed to identify female carriers and screen families of affected individuals.

Before diagnosis, renal manifestations sometimes prompt renal biopsy. The classic findings using light microscopy include enlarged podocytes with abundant foamy cytoplasm due to the accumulation of lipid in lysosomes. Electron microscopy reveals enlarged lysosomes with a distinctive “zebra body” or “myelin figure” appearance secondary to the accumulation of Gb3. These abnormal lysosomes are seen in podocytes, endothelial cells, smooth muscle cells, and tubular epithelial cells. Zebra bodies, however, are not pathognomonic for Fabry disease because they are a relatively common feature in lysosomal storage disorders in general, as well as in other forms of phospholipidoses. In addition, they are seen in certain types of drug-related nephrotoxicity. Thus care must be taken to correlate clinical and pathologic findings.

TREATMENT

Recombinant human α-Gal A can be given by intravenous infusion to replace the missing enzyme. It appears to both slow the progression of renal disease and decrease neuropathic pain. Its ability to prevent or reverse cardiac and cerebrovascular manifestations, however, is not well established.

Males with Fabry disease have a decreased life expectancy. Because of the numerous renal, cardiac, and neurologic complications, few live past the age of 60. The effect of enzyme replacement on mortality is currently unknown.