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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 with <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 in10,000 males diagnosed after onset of symptoms.
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 exhibit other symptoms of 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. 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 yet they may have alpha-Gal A activity in the normal range. Therefore, molecular genetic analysis of the GLA gene (FABMS / Fabry Disease, Full Gene Analysis) is recommended to detect carriers.
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 (FABMS / Fabry Disease, Full Gene Analysis) allows for detection of the disease-causing mutation in males and 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 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 (FABMS / Fabry Disease, Full Gene Analysis) is recommended as the appropriate diagnostic test for females.
Carrier detection using enzyme levels is unreliable in females. Mutation analysis (FABMS / Fabry Disease, Full Gene Analysis) is the recommended test.
Note: Results from this assay are not useful for carrier determination. Carriers usually have levels in the normal range.
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