BIOCHEMICAL DIAGNOSTIC STRATEGY IN FEMALES SUSPECTED OF FABRY DISEASE

Study objective and method

To demonstrate

The benefits of adding lyso-GL-3

to ►

Primary diagnostic for testing

for ►

Improving detection rate of potential females with FD

Avoiding unnecessary genetic testing

First large prospective study

11,948 females with suspicion of FD

tested for

Biochemical tests

α-Gal A activity
Lyso-GL-3 levels

followed by

Genetic confirmatory testing in 883 females

Groups	01. Low α-Gal A activity High lyso-GL-3	02. Low α-Gal A activity Normal lyso-GL-3	03. Normal α-Gal A activity High lyso-GL-3	04. Normal α-Gal A activity Normal lyso-GL-3
	Classical FD very likely (n=61)	Classical FD unlikely (n=184)	FD very likely (n=256)	had normal results (n=11,447*)
	Genetic confirmatory test			No further testing required

Results

(184/883) females were identified with one or two GLA variants.

Distribution of genetically positive samples

Better indicator of FD

Elevated lyso-GL-3 levels (39% PPV)

Low α-Gal A activity (6% PPV)

Clearly negative results for both biochemical parameters:

Unlikely to have FD, even in clinically highly suspicious cases

Proposed diagnosis decision tree

STEP 2

Once enzyme deficiency is confirmed, molecular testing is performed to identify GLA genetic variants.

STEP 2

Once enzyme activity (deficient or not) together with elevated biomarker is confirmed, molecular testing is performed to identify GLA genetic variants.

Conclusion

*Mutation analysis performed in 389 cases.

α-Gal A: Alpha-galactosidase A; dbFGP: Fabry disease genotype–phenotype database; FD: Fabry disease; Lyso-GL-3: Globotriaosylsphingosine; PPV: Positive predictive value; DBS: Dried blood spotting; GLA: Galactosidase alpha; VUS: Variant of unknown significance.

Reference