Clinical Information

Fabry disease is an X-linked recessive disorder with an incidence of approximately 1 in 50,000 males. Symptoms result from a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). Reduced alpha-Gal A activity results in accumulation of glycosphingolipids in the lysosomes of both peripheral and visceral tissues.

Severity and onset of symptoms are dependent on the residual alpha-Gal A activity. Males with less than 1% alpha-Gal A activity have the classic form of Fabry disease. Symptoms can appear in childhood or adolescence and usually include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, and corneal opacity. By middle age, most patients develop renal insufficiency leading to end-stage kidney disease, as well as cardiac and cerebrovascular disease. Males with greater than 1% alpha-Gal A activity may present with a variant form of Fabry disease. The renal variant generally has onset of symptoms in the third decade. The most prominent feature in this form is renal insufficiency and, ultimately, end-stage kidney disease. Individuals with the renal variant may or may not have other symptoms of classic Fabry disease. Individuals with the cardiac variant are often asymptomatic until they present with cardiac findings such as cardiomyopathy or mitral insufficiency later in life. The cardiac variant is not associated with renal failure.

Female carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severe. 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.

Variants in the GLA gene result in deficiency of alpha-Gal A. Most of the disease causing variants identified to date are family specific. Full sequencing of the GLA gene identifies over 98% of the sequence variants in the coding region and splice junctions. In addition, this assay detects the intron 4 alteration common in the Taiwanese population.(1)

The recommended first-tier test for males with suspected Fabry disease is biochemical testing that measures alpha-galactosidase enzyme activity in blood or serum: AGAW / Alpha-galactosidase, Leukocytes or AGAS / Alpha-galactosidase, Serum. Additionally, testing for the glycosphingolipid, globotriaosylsphingosine (LGb3) may aid in further clarifying disease status in both males and females with suspected Fabry disease (LGB3S / Globotriaosylsphingosine, Serum). Individuals with decreased or absent enzyme activity and elevated LGb3 are more likely to have an identifiable disease-causing variants in the GLA gene by molecular genetic testing. However, enzymatic testing alone is not reliable to detect female carriers.

The following algorithms are available:

-Fabry Disease: Newborn Screen-Positive Follow-up algorithm

-Fabry Disease Diagnostic Testing Algorithm