Correspondence

PR Interval and the Response to Enzyme-Replacement Therapy for Fabry's Disease

N Engl J Med 2003; 348:1186-1187March 20, 2003

Article

To the Editor:

Fabry's disease is a rare, X-linked disorder characterized by subnormal or absent activity of the lysosomal hydrolase α-galactosidase A. A deficiency of α-galactosidase A leads to progressive lysosomal accumulation of glycosphingolipids (particularly globotriaosylceramide), causing renal and cardiac damage.

Electrocardiographic abnormalities are frequently observed in patients with Fabry's disease. In 1973, Roudebush et al. reviewed the first reported cases of an “abbreviated PR interval” in Fabry's disease.1 In patients with the disorder, a shortened PR interval may lead to tachyarrhythmias and sudden death.2

Progressive accumulation of glycosphingolipids in cardiac tissue is the most probable cause of the progressive reduction in the PR interval in patients with Fabry's disease.3 Agalsidase beta (recombinant human α-galactosidase A; Fabrazyme, Genzyme) is an enzyme-replacement therapy for Fabry's disease that reduces globotriaosylceramide levels in infiltrated tissues throughout the body.4 In phase 3 studies and phase 3 extension studies, patients treated with agalsidase beta (1 mg per kilogram of body weight every 2 weeks) for 6 or 12 months had significant and sustained clearance of globotriaosylceramide from the vascular endothelium of the kidney, heart, and skin.4

One patient in the trial, a woman who was 46 years old at the start of the study, had a PR interval of 118 msec, assessed with the use of a 12-lead electrocardiogram, and a cardiac globotriaosylceramide level of 34,944 ng per milligram at base line. Within the first six months of agalsidase beta therapy, the patient's PR interval had returned to a normal value (132 msec; normal range, 120 to 200 msec), and the globotriaosylceramide level in cardiac tissue had declined by more than 90 percent, to 3279 ng per milligram. The patient's PR interval remained above 120 msec during the 24 months after the start of the study (Figure 1Figure 1Effect of Treatment for 24 Months with Agalsidase Beta on the PR Interval, Ejection Fraction, and Globotriaosylceramide (GL-3) Level in a Woman with Fabry's Disease.). The left ventricular ejection fraction, determined by echocardiography, increased from 52.9 percent to 70.7 percent after two years of agalsidase beta therapy. The patient now reports that pain in the extremities has been almost eliminated.

This patient had a favorable response to enzyme-replacement therapy; the PR interval and cardiac globotriaosylceramide level were restored to normal values, with an improvement in cardiac function shown by the increase in the left ventricular ejection fraction. The rapid increase in the PR interval coincided with a dramatic decline in the cardiac globotriaosylceramide level, suggesting that the duration of the PR interval may be a useful marker of both the severity of cardiac disease and the response to treatment in patients with Fabry's disease.

Stephen Waldek, B.Ch., F.R.C.P.
Hope Hospital, Manchester M6 8HD, United Kingdom
steve.waldek@srht.nhs.uk

4 References

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   Full Text | Web of Science | Medline

Citing Articles (11)

Citing Articles

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   Raymond Y. Wang, Olaf A. Bodamer, Michael S. Watson, William R. Wilcox. (2011) Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genetics in Medicine 13:5, 457-484
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   Julian F. Guest, Trond Jenssen, Gunnar Houge, Willy Aaseboe, Camilla Tøndel, Einar Svarstad. (2010) Modelling the resource implications of managing adults with Fabry disease in Norway favours home infusion. European Journal of Clinical Investigation 40:12, 1104-1112
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   Mehdi Namdar, Christoph Kampmann, Jan Steffel, Daniel Walder, Johannes Holzmeister, Thomas Felix Lüscher, Rolf Jenni, Firat Duru. (2010) PQ Interval in Patients With Fabry Disease. The American Journal of Cardiology 105:5, 753-756
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   Jami C. Levine, Priya S. Kishnani, Y. T. Chen, J. Rene Herlong, Jennifer S. Li. (2008) Cardiac Remodeling After Enzyme Replacement Therapy with Acid α-Glucosidase for Infants with Pompe Disease. Pediatric Cardiology 29:6, 1033-1042
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   C. Serratrice, G. Serratrice. (2007) Lipidosi (II). Malattia di Fabry. EMC - Neurologia 7:2, 1-7
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   Annette K. Ansong, Jennifer S. Li, Eva Nozik-Grayck, Richard Ing, Richard M. Kravitz, Salim F. Idriss, Ronald J. Kanter, Henry Rice, Y T. Chen, Priya S. Kishnani. (2006) Electrocardiographic response to enzyme replacement therapy for Pompe disease. Genetics in Medicine 8:5, 297-301
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   Sudheera Magage, Ales Linhart, Jan Bultas, Jan Vojacek, Martin Mates, Tomas Palecek, Jana Popelová, Jaroslav Tintera, Michael Aschermann, Martin E. Goldman, Robert J. Desnick. (2005) Fabry Disease: Percutaneous Transluminal Septal Myocardial Ablation Markedly Improved Symptomatic Left Ventricular Hypertrophy and Outflow Tract Obstruction in a Classically Affected Male. Echocardiography 22:4, 333-339
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   M. Beck, R. Ricci, U. Widmer, F. Dehout, A. Garcia de Lorenzo, C. Kampmann, A. Linhart, G. Sunder-Plassmann, G. Houge, U. Ramaswami, A. Gal, A. Mehta. (2004) Fabry disease: overall effects of agalsidase alfa treatment. European Journal of Clinical Investigation 34:12, 838-844
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    L Spinelli, A Pisani, M Sabbatini, M Petretta, MV Andreucci, D Procaccini, N Lo Surdo, S Federico, B Cianciaruso. (2004) Enzyme replacement therapy with agalsidase β improves cardiac involvement in Fabry's disease. Clinical Genetics 66:2, 158-165
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    W WILCOX, M BANIKAZEMI, N GUFFON, S WALDEK, P LEE, G LINTHORST, R DESNICK, D GERMAIN, FORTHEINTERNATIONALFABRYDISEA. (2004) Long-Term Safety and Efficacy of Enzyme Replacement Therapyfor Fabry Disease. The American Journal of Human Genetics 75:1, 65-74
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