Fabry disease is a rare and progressive genetic disease caused by mutations in the GLA gene, which contains the information necessary to make the enzyme alpha-galactosidase A. This enzyme is required to break down a type of fat molecule called globotriaosylceramide (Gb3 or GL-3). The mutations cause the alpha-galactosidase A enzyme not to function properly, which leads to the accumulation of GL-3 inside cells. That causes damage and results in symptoms that include pain, opaque corneas, kidney disease, and risk of heart attacks.
The primary blood test for the diagnosis of Fabry disease assesses the activity of the alpha-galactosidase A enzyme. Another blood test, which detects the presence of a fatty substance called lyso-Gb3, also can be performed and may indicate the severity of the disease. Finally, the blood sample can be used for genetic testing that looks for mutations in the GLA gene and may help confirm Fabry disease.
Alpha-galactosidase A activity
The activity of the alpha-galactosidase A enzyme can be measured using liquid blood or dried blood spots (DBS).
Symptoms of classical or type 1 Fabry disease usually occur when alpha-galactosidase A activity drops below 1% (less than 0.016 U/L). Enzyme activity may be greater than 1% in patients with late-onset or type 2 Fabry disease.
Alpha-galactosidase A enzyme activity is unreliable in the case of female carriers of Fabry disease, so genetic testing is mandatory to confirm the presence of the disease in women.
Gb3 concentration is elevated in the blood of Fabry disease patients and serves as an important diagnostic marker. Levels of a form of Gb3 known as globotriaosylsphingosine (lyso-Gb3) also may be an indicator of the severity of Fabry disease.
Lys0-Gb3 levels can be measured using a technique called electrospray ionization liquid chromatography-mass spectrometry (ESI LC-MS/MS). Mass spectrometry is a niche diagnostic test with several testing procedures yet to be validated by the U.S. Food and Drug Administration (FDA), so not all laboratories provide this service.
More than 370 different mutations in the GLA gene that can cause Fabry disease have been identified. These mutations can be different in nature and range from single DNA letter changes to chunks of DNA missing from or being added to the gene. Genetic testing can identify any of these mutations and help confirm a diagnosis of Fabry disease.
Last updated: Oct. 9, 2019
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