Fabry disease: a new approach for the screening of females in high-risk groups.

[fabry disease]

Fabry disease (FD ) is a rare X-linked inborn error of metabolism caused by deficient activity of lysosomal α-galactosidase A (α-GAL ). Due to random X inactivation , α-GAL activity in heterozygous females ranges from very low to overlapping normal values . Determining this specific range and altering assays cutoffs could become a valuable tool for minimizing the need in DNA sequencing for screening of all potential carriers . Therefore , the aim of this study was to establish the range of enzyme in dried blood spots (DBS ), plasma and leukocytes that suggests carrier status for FD .α-GAL gene was sequenced in 453 women with clinical suspicion and /or positive family history of FD . This data was compared to the α-GAL activity measured in DBS (dried blood spots ) and /or plasma and /or leukocytes .About 12 % of the samples had pathogenic mutations (c .30 _32 delG , c .718 _719 delAA , p .R 118 C , p .S 126 G , p .Y 152 X , p .A 156 D , p .C 2 02 Y , p .N 215 S , p .P 259 R , p .D 264 Y , p .V 269 M , p .R 342 Q and p .R 356 W ). When compared to genotype , DBS was the least reliable biochemical test for screening , with very low specificity . Plasma and leukocyte activities presented high AUC in ROC curve analysis , both over 84 %. When cutoffs were altered to identify all carriers , leukocyte specificity was higher than that of plasma (35 .2 % and 27 .6 %, respectively ). Moderated correlation and agreement coefficients were found between them , which reinforces the need for using both data combined .A combined approach involving plasma and leukocyte α-GAL activities , with distinct cutoffs for men and women , could represent a more accurate , faster and less expensive tool to screen women for FD in high -risk groups in middle - and low -income countries .