Author + information
- Gabor E. Linthorst, MD, PhD⁎ (, )
- Ben J.H.M. Poorthuis, PhD and
- Carla E.M. Hollak, MD, PhD
- ↵⁎Department of Endocrinology and Metabolism, Academic Medical Center, F4-224, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
The availability of enzyme replacement therapy for Fabry disease, deficiency of alpha-galactosidase (αGal) A, has increased awareness for this disorder and stimulated the conduction of additional screening (1). Several studies have shown that patients with renal insufficiency, cerebral infarctions, or left ventricular hypertrophy of unknown etiology might suffer from Fabry disease. One such study is that of Monserrat et al. (2), reported in the Journal, in which they showed the prevalence of Fabry disease to be 1% in Spanish patients with hypertrophic cardiomyopathy. In this study, plasma αGal A activity was used as the primary screening method. Fabry disease is an X-linked disorder, and random X-inactivation results in highly variable activity of αGal A in female patients with Fabry disease (heterozygotes). We previously reported that screening for Fabry disease with enzyme αGal A activity analysis on dried whole blood samples failed to detect one-third of female Fabry patients (3). Monserrat et al. (2) found that an αGal A activity of <50% of the normal mean value in plasma was a reason to perform deoxyribonucleic acid mutation analysis of the GLA gene in women. They thoughtfully stated that in female carriers plasma enzymatic activity might be within the normal range and that mutation analysis of the αGal A gene should be performed in patients with additional symptomatology suggestive of Fabry disease irrespective of the level of residual enzyme activity. Nevertheless, they argued that the chance for false negatives would be minimal, because they failed to detect disease-causing mutations in 7 women with a borderline activity (30% to 50% of the control). We analyzed αGal A levels in 40 women who were obligate carriers by family screening or with a proven diagnosis of Fabry disease by mutation analysis. In all patients the αGal A was performed in leukocytes, not plasma. Previous studies have shown that the number of women with activity >50% is comparable with either leukocytes or plasma (4). Leukocyte αGal A activity ranged from 5% to 131%. Although the majority of female Fabry patients would have been detected (24 of 40, 60%) with a cutoff of <50%, 16 patients—including 4 patients with hypertrophic cardiomyopathy—had a leukocyte αGal A activity >50% (40%). This indicates that the number of false negatives might have been higher than anticipated by Monserrat et al. (2). More importantly, such a “negative” screening result might delay a diagnosis of Fabry disease in the future. Therefore, we would like to stress that Fabry disease screening studies that use αGal A activity analysis in women should be interpreted with caution.
- American College of Cardiology Foundation
- Monserrat L.,
- Gimeno-Blanes J.R.,
- Marin F.,
- et al.
- Rietra P.J.,
- Tager J.M.