Fabry Disease, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 <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 renal disease, as well as cardiac and cerebrovascular disease. Males with >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 renal 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 a clinical presentation 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.
Mutations in the GLA gene result in deficiency of alpha-Gal A. Most of the mutations 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. Full gene sequencing of the GLA gene is available by ordering FABMS/88264 Fabry Disease Full Gene Analysis.
Site-specific testing (this test) for mutations that have already been identified in an affected patient is useful for confirming a suspected diagnosis in a family member. It is also useful for determining whether at-risk individuals are carriers of the disease and, subsequently, at risk for having a child with Fabry disease
The following algorithms are available in Special Instructions:
-Fabry Disease: Newborn Screen-Positive Follow-up
-Fabry Disease Testing Algorithm
Diagnostic confirmation of Fabry disease when a familial mutation has been previously identified
Carrier screening of at-risk individuals when a mutation in the GLA gene has been identified in an affected family member
Prenatal testing when 2 familial mutations have been previously identified in an affected family member
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order FABMS/88264 Fabry Disease, Full Gene Analysis.
Analysis is performed for the familial mutation(s) provided only. This assay does not rule-out the presence of other mutations within this gene or within other genes that may be associated with Fabry disease.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false paternity, could lead to an erroneous interpretation of results.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
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.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300
2. Germain DP: Fabry disease. Orphanet J Rare Dis. 2010 Nov 22;5:30
3. Wang RY, Lelis A, Mirocha J, Wilcox WR: Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007 Jan;9(1):34-35
4. Hwu WL, Chien YH, Lee NC, et al: Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G->A (IVS4+919G->A). Hum Mutat 2009;30:1397-1405