Alpha-Galactosidase, Blood Spot
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Fabry disease is an X-linked recessive lysosomal storage disorder resulting from deficient activity of the enzyme alpha-galactosidase A (a-Gal A) and the subsequent deposition of glycosylsphingolipids in tissues throughout the body, in particular, the kidney, heart, and brain. More than 150 mutations in the GLA gene 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% a-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 a-Gal A activity above 1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in life. These include 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.
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.
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. Additional studies including molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) are recommended to detect carriers.
Reduced or absent a-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.
Evaluation of patients with a clinical presentation suggestive of Fabry disease
Follow-up to an abnormal newborn screen for Fabry disease
In male patients, results less than 1.2 nmol/mL/hour in properly submitted specimens are consistent with Fabry disease. Normal results (> or =1.2 nmol/mL/hour) are not consistent with Fabry disease.
In female patients, normal results (> or =2.8 nmol/mL/hour) in properly submitted specimens are typically not consistent with carrier status for Fabry disease; however, enzyme analysis, in general, is not sufficiently sensitive to detect all carriers. Because a carrier range has not been established in females, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) should be considered when alpha-galactosidase A activity is less than 2.9 nmol/mL/hour, or if clinically indicated.
Pseudodeficiency results in low measured alpha-galactosidase A, but is not consistent with Fabry disease; FABRZ / Fabry Disease, Full Gene Analysis should be performed to resolve the clinical question.
See Fabry Disease Testing Algorithm in Special Instructions.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
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.
Males: > or =1.2 nmol/mL/hour
Females: > or =2.8 nmol/mL/hour
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Chamoles NA, Blanco M, Gaggioli D: Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta 2001;308:195-196
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. Matern D, Gavrilov D, Oglesbee D, et al: Newborn screening for lysosomal storage disorders. Semin Perinatol 2015 Apr;39(3):206-216
5. Mehta A, Hughes DA: Fabry Disease. In GeneReviews. Accessed 1/23/2017. Available atwww.ncbi.nlm.nih.gov/books/NBK1292/