title: Platelet hexosaminidase a enzyme assay effectively detects carriers missed by targeted DNA mutation analysis.
abstract: Biochemical testing of hexosaminidase A (HexA) enzyme activity has been available for decades and has the ability to detect almost all Tay-Sachs disease (TSD) carriers, irrespective of ethnic background. This is increasingly important, as the gene pool of those who identify as Ashkenazi Jewish is diversifying. Here we describe the analysis of a cohort of 4,325 individuals arising from large carrier screening programs and tested by the serum and/or platelet HexA enzyme assays and by targeted DNA mutation analysis. Our results continue to support the platelet assay as a highly effective method for TSD carrier screening, with a low inconclusive rate and the ability to detect possible disease-causing mutation carriers that would have been missed by targeted DNA mutation analysis. Sequence analysis performed on one such platelet assay carrier, who had one non-Ashkenazi Jewish parent, identified the amino acid change Thr259Ala (A775G). Based on crystallographic modeling, this change is predicted to be deleterious, as threonine 259 is positioned proximal to the HexA alpha subunit active site and helps to stabilize key residues therein. Accordingly, if individuals are screened for TSD in broad-based programs by targeted molecular testing alone, they must be made aware that there is a more sensitive and inexpensive test available that can identify additional carriers. Alternatively, the enzyme assays can be offered as a first tier test, especially when screening individuals of mixed or non-Jewish ancestry.
authors: Human Genetics Laboratory, Department of Pathology, Jacobi Medical Center, 1400 Pelham Parkway S., Building 1, 6N28B, Bronx, NY, 10461, USA.
authors: Sachiko
authors: S
authors: Nakagawa
authors: Jie
authors: J
authors: Zhan
authors: Wei
authors: W
authors: Sun
authors: Jose Carlos
authors: JC
authors: Ferreira
authors: Steven
authors: S
authors: Keiles
authors: Tina
authors: T
authors: Hambuch
authors: Anja
authors: A
authors: Kammesheidt
authors: Brian L
authors: BL
authors: Mark
authors: Adele
authors: A
authors: Schneider
authors: Susan
authors: S
authors: Gross
authors: Nicole
authors: N
authors: Schreiber-Agus