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Non-invasive high-risk screening for Fabry disease hemizygotes and heterozygotes

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Abstract

The most appropriate time for screening for Fabry disease (FD) is school age. For this reason, we developed non-invasive methods for measuring urinary α-galactosidase A (α-gal A) protein, using enzyme-linked immunosorbent assay (ELISA), and for globotriaosylceramide (GL-3), using tandem mass spectrometry (MS/MS). We measured these two biomarkers in the urine of previously diagnosed FD hemizygotes and heterozygotes, and in controls. All the classic FD hemizygotes were clearly distinguished from controls by either method alone, and combining the two assays produced 96% sensitivity for detecting heterozygotes. To assess the utility of these methods for screening school children and adults at high risk of FD, a pilot study was conducted. To distinguish FD from 432 controls, cut-off values for α-gal A protein and GL-3 were set at the 5th and 95th centile values of the controls, respectively. Among the high-risk patients, the measurements exceeded the cut-off values for both biomarkers in male and female subjects and were strong indicators for Fabry hemizygotes and heterozygotes. However, we recommend that if the results of the first measurements exceed the cut-off values for only one of these biomarkers, another urine sample should be requested for re-assay to confirm the result.

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Abbreviations

FD:

Fabry disease

ERT:

enzyme replacement therapy

α-gal A:

α-galactosidase A

GL-3:

globotriaosylceramide

MS/MS:

tandem mass spectrometry

M/F ratio:

male-to-female ratio

PBS:

phosphate-buffered saline

Cr:

creatinine

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Acknowledgments

This work was supported, in part, by a grant for the Research on Measures for Intractable Disease, Japanese Ministry of Health, Welfare and Labor (2001–2007), and by a grant for the development of a screening method for lysosomal storage disorders, from Genzyme Corporation (2002–2007).

We thank the doctors and their associates who sent us the urine samples to measure urinary α-gal A protein, as well as GL-3, and who were known to us the final diagnosis of the subjects at high risk for FD. We thank Ms. Joan Keutzer of Genzyme Corp., Cambridge MA, USA, for providing rabbit anti-human α-gal A polyclonal antibody, anti-human α-gal A monoclonal antibody, and C-17GL-3. We thank Dr. Gabriel Symonds for his help with correcting the English in this paper.

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Correspondence to Teruo Kitagawa.

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Kitagawa, T., Suzuki, K., Ishige, N. et al. Non-invasive high-risk screening for Fabry disease hemizygotes and heterozygotes. Pediatr Nephrol 23, 1461–1471 (2008). https://doi.org/10.1007/s00467-008-0846-6

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