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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 due to 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 in 10,000 males diagnosed after onset of symptoms.
Males with residual alpha-Gal A activity may present with either a renal or cardiac 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 (FABRZ / Fabry Disease, Full Gene Analysis) is recommended as the most appropriate diagnostic test 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 (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
Verifying abnormal serum alpha-galactosidase results in males with a clinical presentation suggestive of Fabry disease
Deficiency of alpha-galactosidase A (alpha-Gal A) is diagnostic for Fabry disease in males.
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.
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.
> or =23.1 nmol/hour/mg protein
An interpretative report will be provided.
Note: Results from this assay do not reflect carrier status because of individual variation of alpha-galactosidase enzyme levels.
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