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Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Fabry Disease

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
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Background

Fabry disease results from the build-up of fatty substances in the walls of blood vessels, particularly the small vessels in the skin, kidneys, heart, and nervous system. The channels of these vessels become narrowed, leading to decreased blood flow. Symptoms associated with Fabry disease include an inability to sweat, fever attacks, atrophy of the cornea, and purple skin lesions called angiokeratomas. As the disease progresses, kidney, heart and neurological complications may develop.

The fatty substances, called glycosphingolipids, accumulate because patients are unable to produce a-galactosidase A, an enzyme needed to break down these fats. The enzyme is lacking due to mutations in the a-galactosidase A (GLA) gene on the X chromosome (Xq22.1). Males normally have one X chromosome in each cell. If that X chromosome carries the mutation in the GLA gene, the boy will have Fabry disease. Females normally have two X chromosomes in each cell. If one X chromosome carries the mutation in the GLA gene and the other one does not, the girl will be a carrier of Fabry disease. In rare cases, a female carrier will show some symptoms of the disease (manifesting carrier), although most carriers do not have and will not develop Fabry disease. Carrier females may, however, pass the mutation on to their children. If a female is a carrier, her sons have a 50 per cent chance of inheriting the mutation and being affected with Fabry disease. Her daughters are unlikely to be affected by Fabry disease but have a 50 per cent chance of inheriting the mutation and being carriers themselves.

An accurate biochemical test is available for the diagnosis of Fabry disease consisting of the analysis of a-galactosidase A activity in plasma, leucocytes or cultured cells. This test should be considered before molecular analysis is undertaken. Molecular identification of the mutation in individuals with a confirmed diagnosis can be used for carrier testing and prenatal diagnosis in the family. The biochemical test is not reliable for identifying carriers.

Who should be tested

  • individuals clinically and/or biochemically suspected of being affected with Fabry disease
  • women with a family history of Fabry disease, to determine the carrier status of unaffected individuals
  • pregnancies at risk due to a family history of Fabry disease

Testing Methodology

Direct Mutation Analysis: This assay consists of two stages

  • Direct sequence analysis to identify any point mutations or small insertions/deletions.
  • Dosage analysis to detect large scale deletion in the GLA gene

Potential Outcomes & Interpretation of Test Results

Sex of Patient

GLA Gene Mutation

Explanation

Male

none detected

  • This result does not support a diagnosis of Fabry disease.

Male

mutation detected

  • This result confirms a diagnosis of Fabry disease.

 

 

 

Female

none detected /
none detected

  • This individual is unlikely to be affected with, or a carrier of Fabry disease.

Female

mutation detected /
none detected

  • This individual is a carrier of Fabry disease and may transmit a mutation to offspring.

Cautions

  • Current molecular testing will not detect all possible mutations in this gene. A negative test, therefore, does not rule out the diagnosis of Fabry disease, or eliminate the possibility the individual is a carrier.
  • We strongly recommend that biochemical analysis be done on these patients as it can be a useful complement to molecular testing.
  • Linkage analysis may be used to assess carrier risk when mutations are not detected in families with a clear clinical history of Fabry disease. Linked markers provided an assessment of risk, but are not an absolute diagnosis, due to the possibility of recombination between the marker loci and the disease locus.
  • It is often helpful to first identify the mutations(s) in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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