• Also known as Anderson–Fabry disease and α-galactosidase A deficiency, Fabry disease is a rare, X-linked recessive lysosomal storage disorder that, when left untreated, is potentially fatal. Defect in the GLA gene coding for the enzyme α-galactosidase A (α-GAL), which leads to an accumulation of glycosphingolipids, in particular globotriaosylceramide (GL-3), throughout the body. Elevated GL-3 causes cellular dysfunction, most notably in the vasculature, with resulting damage to the renal, cardiac, and vascular systems. Life expectancy shortened by 20 years in males and 15 years in females, often from renal failure, cardiomyopathy, and early stroke.

• Systemic manifestations include angiokeratomas characteristically found between the umbilicus and knees, intermittent pain crises, and hypohidrosis/anhydrosis.

• Ocular manifestations appear early and include whorl-like corneal deposits (cornea verticillata), distinctive spoke-like posterior cataracts, and vascular tortuosity of the bulbar conjunctiva and retina. Rarely affects vision.



Estimated 1:40,000 to 1:170,000, though newborn screening has demonstrated 1:3,100 males.


1:80,000 to 117,000.


Family history, male sex, though heterozygous females can express the Fabry phenotype at various levels of severity due to random variations in X-chromosome inactivation.


• X-linked recessive, mutation of GLA gene at Xq22.1 locus.

– Over 150 mutations at this locus have been linked to a deficiency in the enzyme α-galactosidase A.


• Genetic counseling and prenatal chorionic villus sampling (10–12 weeks) or amniocentesis (15–18 weeks).

• Early treatment may prevent secondary complications of Fabry disease.


• The glycosphingolipid metabolic pathway is responsible for breaking down glycosphingolipid components of the plasma membrane of cells. In this pathway, α-galactosidase A (α-GAL) converts globotriaosylceramide (GL-3) to lactosyl ceramide.

• Mutation of GAL gene causes α-GAL deficiency, which causes an accumulation of the upstream substrate GL-3 within lysosomes.

• High levels of GL-3 are found throughout the body and in the fluids of patients with Fabry disease, most notably in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels.


Mutation in gene coding for α-GAL causes enzyme deficiency and build-up of toxic substrate.


• Dermatologic

– Clusters of angiokeratomas (non-blanching, individual, punctuate, dark red to blue-black telangiectasias) most dense between the umbilicus and knees

– Hypo/anhydrosis

• Neurologic

– Acroparesthesias (periodic crises of severe pain in the extremities) appear early

– Early TIA or stroke

– Hearing loss (CN VIII)

• Ocular

– Cornea verticillata (whorl-like inferior corneal subepithelial deposits)-–an early finding

– Distinctive spoke-like posterior cataracts; wedge-shaped anterior cataracts

– Vascular tortuosity and aneurismal dilation of the bulbar conjunctiva and retina

• Cardiac

– Mitral insufficiency, left ventricular hypertrophy

– Dysrhythmias

– Cardiomyopathy

• Renal

– Mild proteinuria appears in childhood/adolescence

– Progressive renal insufficiency leading to end-stage renal disease



• Classically, symptom onset in childhood or adolescence (acroparesthesias, angiokeratomas, ocular findings, hypohidrosis).

• Gradually progressive renal insufficiency in the 3rd to 5th decade and eventually death due to renal disease, heart failure, or cerebrovascular accident (55% of males, 45% of females).

– Later-onset patients’ initial presentation may be for renal, cardiovascular, and/or cerebrovascular symptoms.


• Ocular findings are visible early (as early as age 1)

– Cornea verticillata (95% of males, 88% of females)

– Spoke-like posterior cataracts (70% of males, 35% of females)

– Vascular tortuosity and aneurismal dilation of the bulbar conjunctiva and retina (77% of males, 19% of females)

• Skin

– Angiokeratomas between the umbilicus and knees (66% of males, 36% of females). Occasionally seen intraperiorally and periorally

– Hypo/anhydrosis (almost constant finding)

• Cardiac

– Arrhythmias, murmurs, chest heave, laterally displaced PMI

• Abdomen

– Tenderness, hyperactive bowel sounds



Initial lab tests

• α-GAL enzyme activity assay of both plasma and leukocytes

• Heterozygous females may have normal enzyme activity, so molecular genetic testing may be necessary

• During childhood and adolescence, urinalysis


Initial approach

No special imaging necessary for diagnosis.

Follow-up & special considerations

• Additional confirmation can be made by identifying mutation in α-GAL gene with molecular genetic testing.

• CBC, CMP for systemic manifestations.

• Secondary complications of Fabry disease may require imaging

– Cardiac: ECG, chest X-ray, echo

– Vascular: Duplex Doppler, angiogram

– Neurologic: CT, MRI

– Skin: electron microscopy of Fabry angiokeratomas demonstrate characteristic electron-dense, lamellar (zebra-like) inclusions within endothelial and other cell types

Diagnostic Procedures/Other

• Decreased α-GAL enzyme activity is diagnostic of Fabry disease, and confirmation can be made with molecular genetic testing.

• Any patient with a constellation of intermittent acroparesthesias, anhydrosis, angiokeratomas, left ventricular hypertrophy, corneal and/or lenticular opacities, and renal insufficiency of unknown etiology should be worked up for Fabry disease.

Pathological Findings

• Early on, urinalysis demonstrates protein, casts, red cells, and characteristic “Maltese crosses” in sediment, progressing to end-stage renal disease with electrolyte disturbances and anemia.

• Cardiac dysrhythmias including ST segment changes, T-wave inversion, and intermittent supraventricular tachycardia

• Left ventricular hypertrophy

• Multifocal cerebral small vessel involvement with thromboses, aneurisms, intracranial bleeds and areas of ischemia


• Angiokeratomas of Fabry

– Can be confused with petechiae, pyogenic granulomas, eruptive angiomas, or angiokeratomas of Fordyce spots

– Other metabolic syndromes that cause angiokeratomas include fucosidosis, aspartylglycosaminuria, galactosialidosis, Schindler/Kanzaki disease, mannosidosis

• Cornea verticillata

– Long-term therapy with amiodarone, aminoquinolines, atovaquone, clofazimine, gold, ibuprofen, indomethacin, mepacrine, monobenzone, naproxen, perhexiline maleate, phenothiazines, suramin, tamoxifen, tilorone hydrochloride

– Environmental exposure to silica dust.

– Multiple myeloma

• Pain crises

– Rheumatic fever, neurosis, erythromelalgia, rheumatoid arthritis, juvenile arthritis, SLE, “growing pains,” Raynaud syndrome, multiple sclerosis



First Line

• Enzyme replacement therapy (ERT) as early as possible in all males and in females carriers with significant disease:

– Agalsidase beta (Fabrazyme) 1 mg/kg body weight infused every 2 weeks as an IV infusion. The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/h).

• For acroparesthesias:

– Diphenylhydantoin

– Carbamazepine

– Gabapentin

• For renal disease:

– ACE inhibitor (benazepril 40 mg per day) and ARB (losartan 100 mg PO per day)

• Antiplatelet agents (clopidogrel 75 mg PO per day) may be recommended for prophylaxis against stroke and central retinal artery occlusion.

• Lipid- (simvastatin 40 PO per day) and blood pressure (diltiazem 360 mg PO per day) lowering agents may be recommended for those with cardiac ischemia

Second Line

• Thiazide diuretic (hydrochlorothiazide 25–50 mg PO per day)

• Beta-blocker (atenolol 100 mg PO per day)

• Hydralazine


General Measures

Chronic hemodialysis, if needed.

Issues for Referral

• Fabry disease is a rare, complex, and serious disease that requires consultation with and coordination amongst many specialists:

– Pediatricians

– Nephrologists

– Neurologists

– Cardiologists

– Dermatologists

– Ophthalmologists

– Geneticists

– Psychiatrists and psychologists

– Social workers

Additional Therapies

• Mental health consultations for psychosocial impact of disease on patient

• Nutrition and exercise to decrease risk of cardiovascular disease


Antioxidants and omega-3 fatty acids may have benefit by reducing vascular damage.


• Allograft kidney transplant can be curative of renal dysfunction (engrafted kidney has normal enzyme activity)

• For angiokeratomas:

– Laser therapy



Annual (or more frequent) renal, cardiology, and hearing evaluations.

Patient Monitoring

• Patient should be followed by specialists in the organ systems most affected by Fabry disease.

– Cardiology: ECG, echo, BNP

– Neurology: Diphenylhydantoin levels (if prescribed)

– Nephrology: CMP, urinalysis, creatinine

• Siblings and female offspring of affected patients should be tested for Fabry disease.


Low-fat, low salt diet may reduce or delay cardiovascular and renal dysfunction.


Lifelong care from various specialists will be required to maintain health beyond middle age.


• Without treatment for end-stage renal disease, mean age of death is 41 years.

• With enzyme replacement therapy, patients can expect stabilization of their renal function, improved cardiac function, and decreases in neuropathy and gastrointestinal symptoms.


1. Eng CM, Ioannou YA, Desnick RJ. Alpha-Galactosidase a deficiency: Fabry disease. The Metabolic and Molecular Bases of Inherited Disease. In: Scriver C, Beaudet A, Sly W, et al, eds. New York: McGraw Hill, 2001:3733–3774.

2. Pinto LLC, Vieira TA, Giugliani R, Schwartz IVD. Expression of the disease on female carriers X-linked lysosomal disorders: A brief review. Orphanet J Rare Dis 2010;5(1):14.

3. Samiy N. Ocular features of fabry disease: Diagnosis of a treatable life-threatening disorder. Surv Ophthalmol 2008;53(4):416–423.

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Nov 9, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Disease

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