FABRY DISEASE
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.
PATHOPHYSIOLOGY
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.
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 e zyme replacement on
mortality is currently unknown.
