Ophthalmology – Fabry’s Disease

Fabry disease, also called Anderson–Fabry disease or α-galactosidase A deficiency, is a rare X-linked lysosomal storage disorder caused by mutation of the GLA gene, which encodes the enzyme α-galactosidase A. Deficiency of this enzyme leads to accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3 or Gb3), within lysosomes throughout the body. Progressive accumulation produces dysfunction of vascular endothelial and smooth-muscle cells and ultimately damages the kidneys, heart, nervous system, skin, and eyes.

Fabry disease is potentially life-threatening if untreated. Historically, life expectancy was substantially shortened, especially in males, because of renal failure, cardiomyopathy, arrhythmias, and premature cerebrovascular disease. Females can also develop significant disease despite the X-linked inheritance pattern because random X-chromosome inactivation can result in substantial expression of the abnormal gene.

Epidemiology and Genetics

The traditionally estimated incidence ranges from approximately 1 in 40,000 to 1 in 170,000, although newborn screening programs have identified pathogenic variants much more frequently. The disorder results from mutations in the GLA gene located on Xq22.1.

Affected males generally have markedly reduced enzyme activity and more severe classical disease. Heterozygous females may range from asymptomatic to severely affected. A positive family history is therefore an important risk factor.

Genetic counseling is recommended for affected families. Prenatal diagnosis can be performed when the familial mutation is known, and molecular testing can identify affected relatives and carriers.

Pathophysiology

α-Galactosidase A normally participates in degradation of glycosphingolipids within lysosomes. When the enzyme is deficient, GL-3 and related substances accumulate progressively within cells.

Accumulation is particularly prominent in vascular endothelial cells, pericytes, smooth-muscle cells, renal cells, cardiac myocytes, and neurons. This produces progressive vascular dysfunction, tissue ischemia, inflammation, fibrosis, and organ damage.

Ocular Manifestations

Ocular findings often develop early in life and may provide an important clue to the diagnosis. The most characteristic finding is cornea verticillata, also called vortex keratopathy. This appears as fine, whorl-like deposits in the corneal epithelium, usually beginning inferiorly and forming a vortex pattern across the cornea.

Cornea verticillata is extremely common in Fabry disease and may occur in both males and females. Despite its striking appearance, it usually causes little or no visual impairment.

A second characteristic ocular manifestation is the Fabry cataract. Posterior lens opacities may have a distinctive spoke-like appearance, while wedge-shaped anterior lens opacities can also occur.

The conjunctival and retinal vessels may demonstrate increased tortuosity and aneurysmal dilation. These vascular changes usually do not significantly reduce vision but are useful diagnostic signs.

Systemic Manifestations

A characteristic dermatologic feature is the presence of angiokeratomas, which are small, nonblanching, dark-red to blue-black vascular lesions. They are typically concentrated between the umbilicus and knees, producing the classic “bathing-trunk” distribution.

Patients commonly develop hypohidrosis or anhidrosis, meaning decreased or absent sweating. This can result in heat intolerance and difficulty exercising.

Neurologic manifestations include acroparesthesias, consisting of recurrent burning or severe pain in the hands and feet. These pain crises frequently begin in childhood or adolescence and may be triggered by fever, exercise, emotional stress, or temperature changes.

Cerebrovascular disease can lead to transient ischemic attacks and strokes at relatively young ages. Hearing loss may also occur.

Renal disease usually begins with proteinuria or albuminuria and may progress to chronic kidney disease and eventually end-stage renal failure.

Cardiac manifestations include left ventricular hypertrophy, cardiomyopathy, valvular abnormalities, conduction disturbances, arrhythmias, and myocardial ischemic disease.

Diagnosis

Classical Fabry disease often begins in childhood or adolescence with a combination of pain crises, angiokeratomas, abnormal sweating, gastrointestinal symptoms, and ocular abnormalities. Renal, cardiac, and cerebrovascular complications become increasingly prominent with age.

Late-onset forms may present initially with otherwise unexplained cardiomyopathy, left ventricular hypertrophy, renal dysfunction, or stroke.

A complete ophthalmic examination may demonstrate cornea verticillata, characteristic lens opacities, and tortuous conjunctival or retinal vessels.

Laboratory Testing

In males, measurement of α-galactosidase A activity in plasma or leukocytes is an important diagnostic test. Markedly decreased enzyme activity strongly supports Fabry disease.

Enzyme activity may be normal in heterozygous females because of variable X-chromosome inactivation. Therefore, molecular genetic testing of the GLA gene is particularly important in females and is also useful for confirming the diagnosis in males.

Urinalysis may demonstrate proteinuria, and progressive renal disease may lead to elevated creatinine and reduced glomerular filtration.

Additional evaluation should assess systemic involvement. Cardiac testing may include ECG and echocardiography, while MRI or other neurologic imaging may be indicated for cerebrovascular manifestations.

Differential Diagnosis

The major differential diagnosis for cornea verticillata is drug-induced vortex keratopathy. Similar corneal deposits may occur with long-term use of medications such as amiodarone, chloroquine or hydroxychloroquine, tamoxifen, indomethacin, and several other drugs.

Angiokeratomas may occur in other lysosomal storage disorders and can also resemble petechiae or other vascular skin lesions.

The neuropathic pain of Fabry disease may initially be mistaken for rheumatologic disease, erythromelalgia, Raynaud phenomenon, juvenile arthritis, or other neurologic conditions.

A combination of cornea verticillata, angiokeratomas, acroparesthesias, decreased sweating, and unexplained renal or cardiac disease should strongly suggest Fabry disease.

Treatment

Fabry disease requires multidisciplinary management. The main disease-specific treatment is enzyme replacement therapy (ERT) with recombinant α-galactosidase A. Treatment is most beneficial when started before irreversible renal, cardiac, or neurologic injury has occurred.

Depending on the underlying mutation and local treatment availability, selected patients may also be candidates for pharmacologic chaperone therapy.

Neuropathic pain can be treated with medications such as carbamazepine or gabapentin.

Renal disease should be managed aggressively, particularly hypertension and proteinuria. Medications that inhibit the renin–angiotensin system may be useful when clinically appropriate.

Cardiovascular risk factors should also be controlled. Antiplatelet, lipid-lowering, antihypertensive, and antiarrhythmic therapy may be prescribed depending on the individual patient’s vascular and cardiac manifestations.

Advanced renal failure may require hemodialysis or kidney transplantation.

Angiokeratomas may be treated with laser therapy if they are symptomatic or cosmetically troublesome.

The ocular findings generally require no specific treatment, because cornea verticillata and Fabry cataract usually have little effect on visual acuity.

Follow-up

Fabry disease requires lifelong multidisciplinary follow-up. Patients should undergo regular renal, cardiac, neurologic, ophthalmic, and hearing evaluations.

Renal monitoring should include assessment of proteinuria, serum creatinine, and kidney function. Cardiac surveillance commonly involves ECG and echocardiographic or other cardiac imaging. Neurologic follow-up is important because of the risk of early stroke and other cerebrovascular complications.

Ophthalmologic examinations can document characteristic ocular findings and monitor for unrelated causes of visual loss.

Because Fabry disease is inherited, appropriate family members should be offered genetic testing.

Patient Education

Patients should understand that Fabry disease is a lifelong systemic disorder requiring coordinated care involving specialists such as nephrologists, cardiologists, neurologists, geneticists, dermatologists, and ophthalmologists.

Lifestyle measures that reduce cardiovascular risk, including appropriate diet, exercise when tolerated, and control of blood pressure and lipid levels, are important components of long-term care.

Prognosis

Without appropriate treatment, Fabry disease can lead to progressive renal failure, cardiomyopathy, arrhythmias, stroke, and premature death.

With earlier diagnosis, disease-specific therapy, and modern renal and cardiovascular management, the prognosis has improved considerably. Treatment can slow organ damage and reduce the severity of several systemic manifestations.

A particularly important ophthalmic clue is the combination of cornea verticillata, spoke-like lens opacities, and tortuous conjunctival or retinal vessels. These findings usually do not threaten vision, but they may allow an ophthalmologist to recognize Fabry disease before serious systemic complications become apparent.