Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the subsequent deposition of glycosylsphingolipids in tissues throughout the body; in particular, the kidney, heart, and brain. Fabry disease is caused by mutations within the GLA gene and more than 150 mutations have been identified in individuals diagnosed with Fabry disease. Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic form of Fabry disease occurs in males with <1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include acroparesthesias (pain crises in the extremities), multiple angiokeratomas, reduced or absent sweating, and corneal opacity. In addition, progressive renal involvement leading to end-stage renal disease typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The estimated incidence is 1 in 40,000 males.
Males with residual alpha-Gal A activity may present with either a renal or cardiac variant form of Fabry disease with onset of symptoms later in life. Individuals with the renal variant typically present in the third decade with the development of renal insufficiency and, ultimately, end-stage renal disease. These individuals may or may not share other symptoms with the classic form of Fabry disease. Individuals with the cardiac variant are often asymptomatic until they present with cardiac findings such as cardiomyopathy, mitral insufficiency, or conduction abnormalities in the fourth decade. The cardiac variant is not associated with renal failure. Variant forms of Fabry disease may be underdiagnosed.
Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected and may have alpha-Gal A activity in the normal range. Therefore, additional studies including molecular genetic analysis of the GLA gene (FABMS / Fabry Disease, Full Gene Analysis) are recommended to detect carriers.
Reduced or absent alpha-Gal A in blood spots, leukocytes (AGA / Alpha-Galactosidase, Leukocytes), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. Molecular sequence analysis of the GLA gene (FABMS / Fabry Disease, Full Gene Analysis) allows for detection of the disease-causing mutation in affected patients and carrier detection in females.
See Fabry Disease Testing Algorithm in Special Instructions.
Diagnosis of Fabry disease in males
Serum testing is the preferred screen for Fabry disease
Deficiency (<0.016 U/L) of alpha-galactosidase in properly submitted specimens is diagnostic for Fabry disease in males. If concerned about specimen integrity, please recheck using leukocyte testing (AGA / Alpha-Galactosidase, Leukocytes).
Urine sediment analysis (CTSA / Ceramide Trihexoside/Sulfatide Accumulation in Urine Sediment, Urine) for the accumulating trihexoside substrate is also recommended.
Carriers usually have alpha-galactosidase levels in the normal range and molecular sequence analysis of the GLA gene is recommended (FABMS / Fabry Disease, Full Gene Analysis).
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Carrier detection using enzyme levels is unreliable; mutation analysis (FABMS / Fabry Disease, Full Gene Analysis) is the recommended test.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Note: Results from this assay are not useful for carrier determination. Carriers usually have levels in the normal range.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Desnick RJ, Ioannou YA, Eng CM: Chapter 150: Alpha-galactosidase A deficiency: Fabry disease. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle, AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Available at www.ommbid.com. Accessed 02/21/2014
2. De Schoenmakere G, Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant 2008;23:4044-4048
3. Spada M, Pagliardini S, Yasuda M, et al: High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40
4. Mehta A, Hughes DA: Fabry Disease. GeneReviews. Edited by RA Pagon, TD Bird, CR Dolan, et al. University of Washington, Seattle. Last updated October 2013