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Unit Code 88264:
Fabry Disease, Full Gene Analysis

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Useful For

Confirmation of a diagnosis of classic or variant Fabry disease in affected

males with reduced alpha-Gal A enzyme activity

 

Carrier or diagnostic testing for asymptomatic or symptomatic females,

respectively

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

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. Renal insufficiency, leading to end-stage renal disease, and

cardiac and cerebrovascular disease generally occur in middle age.

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 share other symptoms with the

classic form of Fabry disease. Individuals with the cardiac variant are

often asymptomatic until they present with cardiac findings such as

cardiomyopathy or mitral insufficiency in the fourth decade. The cardiac

variant is not associated with renal failure.

 

Females who are carriers of Fabry disease can have clinical

presentations ranging from asymptomatic to severely affected.

Measurement of alpha-Gal A activity is not useful for identifying carriers

of Fabry disease, as many of these individuals have normal levels of

alpha-Gal A.

 

Deficiency of alpha-Gal A results from mutations in the GLA gene. Over

450 mutations have been identified in the GLA gene to date, most of

which are family-specific. Full sequencing of the GLA gene identifies

over 98% of the sequence variants in the coding region and splice

junctions.

Reference Values

An interpretive report will be provided.

Interpretation

An interpretive report based on the results, clinical presentation, and

family history will be provided.

Cautions

A small percentage of individuals who have a diagnosis of Fabry

disease may have a mutation that is not identified by the methods

described above (eg, large genomic deletions, promoter mutations).

The absence of a mutation, therefore, does not eliminate the possibility

of positive carrier status or the diagnosis of Fabry disease. Thus, for

presymptomatic testing, it is important to first document the presence

of a GLA gene mutation in an affected family member.

 

Any error in the diagnosis or in the pedigree provided to us, including

false paternity, could lead to an erroneous interpretation of results.

 

Test results should be interpreted in the context of clinical findings,

family history, and other laboratory data. Errors in our interpretation of

results may occur if information provided is inaccurate or incomplete.

 

Medical genetic consultation should be considered in complex cases

or when the diagnosis is atypical or uncertain.

 

In occasional cases, DNA alterations of undetermined significance may

be identified.

 

Rare polymorphisms could lead to false-negative or false-positive

results. If results obtained do not match the clinical and biochemical

findings, additional testing should be considered. A list of known

polymorphisms is available upon request.

Clinical Reference

1.   Shabbeer J, Yasuda M, Benson SD, Desnick RJ: Fabry disease:

      identification of 50 novel alpha-galactosidase A mutations causing the

      classical phenotype and three-dimensional structural analysis of 29

      missense mutations. Hum Genomics 2006 Mar;2(5):297-309

 

2.   Desnick RJ, Brady R, Barranger J, et al: Fabry disease, an under-

      recognized multisystemic disorder: expert recommendations for

      diagnosis, management, and enzyme replacement therapy. Ann

      Intern Med 2003 Feb;138(4):338-346

 

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

Key