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 630 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 who have less than 1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal opacity, and proteinuria. In addition, progressive renal involvement leading to end-stage renal disease typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The estimated incidence varies from 1 in 3,000 infants detected via newborn screening to 1 in 10,000 males diagnosed after onset of symptoms.
Males with residual a-Gal A activity greater than 1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in life: a renal variant associated with end stage renal disease (ESRD) but without the pain or skin lesions; a cardiac variant typically presenting in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; and a cerebrovascular variant presenting as stroke or transient ischemic attack. The 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. Measurement of alpha-Gal A activity is not generally useful for identifying carriers of Fabry disease, as many of these individuals have normal levels of alpha-Gal A. Therefore, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) is recommended to detect carriers.
Unless irreversible damage has already occurred, treatment with enzyme replacement therapy (ERT) has led to significant clinical improvement in affected individuals. For this reason, early diagnosis and treatment are desirable, and in a few US states early detection of Fabry disease through newborn screening has been implemented.
Absent or reduced 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 (FABRZ / Fabry Disease, Full Gene Analysis) allows for detection of the disease-causing mutation in males and females.
See Fabry Disease Testing Algorithm and Fabry Disease: Newborn Screen-Positive Follow-up in Special Instructions.
Diagnosis of Fabry disease in males
Preferred screening test (serum) 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, recheck using leukocyte testing (AGA / Alpha-Galactosidase, Leukocytes).
Urine sediment analysis (CTSA / Ceramide Trihexosides and Sulfatides, Urine) for the accumulating trihexoside substrate is also recommended.
Carrier females usually have alpha-galactosidase levels in the normal range; therefore, molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) is recommended as the appropriate diagnostic test for females.
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 in females. Mutation analysis (FABRZ / Fabry Disease, Full Gene Analysis) is the recommended test.
Individuals with pseudodeficiency alleles can show reduced alpha-galactosidase A enzyme activity with this assay.
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. Accessed 01/23/15. Available at www.ommbid.com
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. Mehta A, Hughes DA: Fabry Disease. In GeneReviews. 2002 Aug 5, Updated 2013 Oct 17. Edited by RA Pagon, MP Adam, HH Ardinger, et al: Seattle, WA. University of Washington, Seattle; 1993-2015. Accessed 1/23/17. Available at www.ncbi.nlm.nih.gov/books/NBK1292/
4. Laney DA, Bennett RL, Clarke V, et al: Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns 2013;22:555-564
5. Laney DA, Peck DS, Atherton AM, et al: Fabry disease in infancy and early childhood: a systematic literature review. Genet Med 2014;Epub ahead of print. Accessed 1/23/15. Available at www.nature.com/gim/journal/vaop/ncurrent/pdf/gim2014120a.pdf