Implementation of high-throughput screening for Fabry disease in Toronto dialysis patients.

Sir,

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (α-gal A) gene. Affected hemizygous males have impaired or abrogated activity of α-gal A enzyme that leads to a buildup of neutral glycosphingolipids, particularly globotriaosylceramide (Gb3), in many tissues and organs [1]. Symptoms include acroparesthesias, angiokeratomas, corneal opacities, and cardiovascular and renal complications, with death usually occurring by the fifth decade of life [1]. Females that are heterozygous carriers of an α-gal A enzyme mutation show a wide variety in the range and severity of their symptoms.

The kidney is of particular pathological importance in Fabry disease, as kidney failure due to Gb3 buildup is a major complication; along with cardiac failure it is a leading cause of death [2]. In recent years, it has been proposed that some dialysis patients could be suffering from undiagnosed Fabry disease and therefore there would be benefits to screening dialysis patients for this disease [3,4]. We carried out a pilot screening study at the Toronto General Hospital in Ontario, Canada, to implement our previously published high-throughput blood spot assay for Fabry disease [5]. Informed consent was obtained from 147 forthcoming. dialysis patients to screen their blood for levels of α-gal A enzyme. Based on our blood spot assay, 141 of these patients had whole blood α-gal A enzyme activity levels within the normal range compared to normal and Fabry controls [5, and unpublished data]. For those six patients with activity below 1.5 nmol/h/ml (<65% of average enzyme activity in normal controls), secondary plasma α-gal A enzyme assays showed that all patients were within the normal range.

While no Fabry patients were identified in the relatively small participating patient population, this study shows application of our previously published high-throughput screening method. Our assay is a rapid and low-cost method for screening patients that may be suffering from undiagnosed Fabry disease. This initial screening study did not exclude any patients willing to participate, so both males and females were included. As with other symptoms, α-gal A enzyme levels in female Fabry patients vary with the individual and can even approach normal levels. We thus cannot discount the possibility that there remain undiagnosed female Fabry patients in this population. For this male dialysis population. With the availability of enzyme replacement therapy (ERT) for lysosomal storage disorders such as Fabry disease, standardized screening for particular biomarkers is beginning to be considered a useful tool for diagnostics [6]. Future screening studies may help to identify Fabry patients that would gain immediate benefit from diagnosis. Screening for this disease is particularly timely in Canada, where a comparative clinical trial of currently approved ERT drugs is ongoing.