Fabry disease is a lysosomal storage disorder in which galactosidase A (α-Gal A), a lysosomal hydrolase, becomes mutated and dysfunctional. As a result its substrate, globotriaosylceramide (Gb3), accumulates within cells and causes disease involving multiple organ systems. The gene encoding α-Gal A is located on the X-chromosome, and thus mutations are inherited in an X-linked manner. The estimated incidence is 1 in 40,000 males. Disease may also occur in female carriers, especially if X-inactivation (also known as lyonization) is skewed so that the mutant allele is more heavily expressed.
Renal complications usually begin in early adulthood and affect approximately half of patients by their fourth decade. Virtually all patients who survive into their sixth decade develop end-stage renal disease.
In the kidney, Gb3 accumulation primarily affects podocytes (visceral epithelial cells), distal tubular cells, and vascular endothelium. The major symptoms that result are proteinuria, isosthenuria, and progressive renal insufﬁciency.
In the skin, Gb3 accumulation in dermal endothelial cells leads to dark red macules or papules known as angiokeratomas on the trunk, genitalia, thighs, and buttocks. In the eyes, Gb3 accumulation often causes clinically silent corneal opacities. In the nervous system, Gb3 accumulation can lead to painful paresthesia that is exacerbated by exercise and extreme temperatures.
In the cerebral vasculature, Gb3 accumulates in vascular smooth muscle and endothelial cells, where it is hypothesized to cause a local increase in leukocyte activation that can lead to thrombosis. Indeed, patients have an especially high risk of stroke, usually starting in their third decade.
In the heart, Gb3 accumulation causes left ventricular hypertrophy, arrhythmias, and valvular regurgitation. The mechanism underlying left ventricular hypertrophy is unclear, because the direct accumulation of Gb3 within cardiac myocytes appears to be responsible for only a small portion (approximately 1%) of the overall increase in cardiac mass. Meanwhile, arrhythmias and regurgitation reﬂect Gb3 deposition within the cardiac conduction system and valves, respectively.
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.
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 e zyme replacement on mortality is currently unknown.