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Reversal of First-Degree Atrioventricular Block in Fabry Disease

Reversal of First-Degree Atrioventricular Block in Fabry Disease Fabry disease is an X-linked disorder of glycosphingolipid catabolism that results from deficient activity of the lysosomal enzyme α-galactosidase A in the vascular smooth muscle, the myocardium, the central nervous system, and epithelial cells of the glomeruli, causing accumulation of globotriaosylceramide, the glycosphingolipid substrate for this enzyme. Five years ago we published a case report of a 26-year-old man with Fabry disease who had first-degree atrioventricular (AV) block with right bundle branch block and diastolic dysfunction with a restrictive pattern. In the last few years he was treated with α-galactosidase A. Recently he was readmitted for left leg cellulitis, and surprisingly we found that his electrocardiogram and echocardiogram patterns were improved, with the disappearance of the AV block and diastolic dysfunction. Report of a Case A 34-year-old patient was admitted for recurrent left leg cellulitis. He was hospitalized in our department 5 years ago with the same clinical presentation, and we noticed at that time that he had a first-degree AV block with a restrictive physiologic pattern and a diastolic dysfunction (as demonstrated by echocardiography).1 On admission he had a high fever (38°C) without chills and pain in his left swollen leg. Findings from physical examination were unremarkable except for his swollen, sensitive left leg. His heart sounds were clear with no pathological sounds or murmurs, and the peripheral pulses were normal. His erythrocyte sedimentation rate was high (80 mm/first hour), and his hemoglobin level was 14.5 g/dL (to convert to grams per liter, multiply by 10), with a high leukocyte count (15 000/μL [to convert to ×10/L multiply by 0.001]) with a left shift. Blood chemistry values were normal, with normal electrolyte and normal renal function test results, but he had mild proteinuria. Chest x-ray films showed a normal cardiac shadow with no abnormalities in the peripheral lung fields or in the mediastinum. The electrocardiogram demonstrated a normal sinus rhythm (80 beats/min), with normal PR and QT intervals, a normal axis (+60°), and a right bundle branch pattern with borderline criteria for left ventricular hypertrophy without strain. Echocardiography demonstrated a normal structure and function of both the left and the right ventricles, with normal physiological flow patterns and no diastolic dysfunction or signs of restrictive physiologic pattern and without signs of left or right ventricular hypertrophy or valvular disease. These were interesting findings because 5 years ago his electrocardiogram showed a first-degree AV block with right bundle branch block and the echocardiogram showed diastolic dysfunction with a restrictive pattern. Over the last few years he was treated on a regular basis (every 3 weeks) with α-galactosidase A, the enzyme that catalyzes the hydrolysis of globotriaosylceramide. Comment Fabry disease is an X-linked recessive disorder of glycosphingolipid catabolism caused by a deficiency of the lysosomal enzyme galactosidase A as a consequence of 1 or more than 4 dozen mutations.2 The disease is characterized by an intracellular accumulation of a neutral glycolipid with prominent involvement of the skin and kidneys as well as the myocardium. The cardiac manifestations include angina pectoris and myocardial infarction despite angiographically normal coronary arteries (due to the accumulation of lipid moieties in coronary endothelial cells), left ventricular dysfunction and failure, and mitral regurgitation.3 The echocardiogram usually shows increased left ventricular wall thickness as a result of glycolipid deposition, which may simulate hypertrophic cardiomyopathy.3 In a cohort study of 47 kindred members from 3 families with Fabry disease, 12 affected male patients were studied. Ten male patients had electrocardiographic evidence of left ventricular hypertrophy and 5 had ST-T changes. One patient had a short PR interval. Of the 16 heterozygous female patients, none had electrocardiographic evidence of left ventricular hypertrophy and 4 had decreased PR interval, while 2 had a delayed conduction (prolonged PR interval).4 Enzyme replacement therapy with recombinant human α-galactosidase A enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. In a study that followed up for 2 years the effects of therapy on renal function and cardiac function of 26 treated patients with Fabry disease, the condition of patients with renal failure who started the study continued to deteriorate despite the enzymatic treatment. However, patients without impairment of renal function had a better outcome with improved renal function (nonsignificant) but with a decrease in posterior wall thickness (P = .04).5 The important message in our case is the disappearance of the first-degree AV block and the disappearance of the diastolic dysfunction with the restrictive type of physiologic abnormality. We assume that these favorable changes were secondary to treatment with the enzyme α-galactosidase A. Correspondence: Dr Blum, Department of Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee 15208, Israel (ablum@poria.health.gov.il). Author Contributions:Study concept and design: Blum and Khasin. Acquisition of data: Blum, Podovitzky, and Sheiman. Analysis and interpretation of data: Blum. Drafting of the manuscript: Blum, Sheiman, and Khasin. Critical revision of the manuscript for important intellectual content: Blum and Podovitzky. Obtained funding: Blum. Administrative, technical, and material support: Blum, Podovitzky, and Sheiman. Study supervision: Blum and Khasin. Financial Disclosure: None reported. References 1. Blum AAshkenazi HHaromankov IKhazim KSheiman J First degree atrioventricular block and restrictive physiology as cardiac manifestations of Fabry's disease. South Med J 2003;96 (2) 212- 213PubMedGoogle ScholarCrossref 2. Ishii SKase RSakuraba HSuzuki Y Characterization of a mutant alpha-galactosidase gene product for the late onset cardiac form of Fabry disease. Biochem Biophys Res Commun 1993;197 (3) 1585- 1589PubMedGoogle ScholarCrossref 3. Eng CMResnick-Silverman LANiehaus DJAstrin KHDesnick RJ Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet 1993;53 (6) 1186- 1197PubMedGoogle Scholar 4. Sheth KJThomas JP Jr Electrocardiocardiograms in Fabry's disease. J Electrocardiol 1982;15 (2) 153- 156PubMedGoogle ScholarCrossref 5. Breunig FWeidemann FStrotmann JKnoll AWanner C Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int 2006;69 (7) 1216- 1221PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Reversal of First-Degree Atrioventricular Block in Fabry Disease

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Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2009.334
Publisher site
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Abstract

Fabry disease is an X-linked disorder of glycosphingolipid catabolism that results from deficient activity of the lysosomal enzyme α-galactosidase A in the vascular smooth muscle, the myocardium, the central nervous system, and epithelial cells of the glomeruli, causing accumulation of globotriaosylceramide, the glycosphingolipid substrate for this enzyme. Five years ago we published a case report of a 26-year-old man with Fabry disease who had first-degree atrioventricular (AV) block with right bundle branch block and diastolic dysfunction with a restrictive pattern. In the last few years he was treated with α-galactosidase A. Recently he was readmitted for left leg cellulitis, and surprisingly we found that his electrocardiogram and echocardiogram patterns were improved, with the disappearance of the AV block and diastolic dysfunction. Report of a Case A 34-year-old patient was admitted for recurrent left leg cellulitis. He was hospitalized in our department 5 years ago with the same clinical presentation, and we noticed at that time that he had a first-degree AV block with a restrictive physiologic pattern and a diastolic dysfunction (as demonstrated by echocardiography).1 On admission he had a high fever (38°C) without chills and pain in his left swollen leg. Findings from physical examination were unremarkable except for his swollen, sensitive left leg. His heart sounds were clear with no pathological sounds or murmurs, and the peripheral pulses were normal. His erythrocyte sedimentation rate was high (80 mm/first hour), and his hemoglobin level was 14.5 g/dL (to convert to grams per liter, multiply by 10), with a high leukocyte count (15 000/μL [to convert to ×10/L multiply by 0.001]) with a left shift. Blood chemistry values were normal, with normal electrolyte and normal renal function test results, but he had mild proteinuria. Chest x-ray films showed a normal cardiac shadow with no abnormalities in the peripheral lung fields or in the mediastinum. The electrocardiogram demonstrated a normal sinus rhythm (80 beats/min), with normal PR and QT intervals, a normal axis (+60°), and a right bundle branch pattern with borderline criteria for left ventricular hypertrophy without strain. Echocardiography demonstrated a normal structure and function of both the left and the right ventricles, with normal physiological flow patterns and no diastolic dysfunction or signs of restrictive physiologic pattern and without signs of left or right ventricular hypertrophy or valvular disease. These were interesting findings because 5 years ago his electrocardiogram showed a first-degree AV block with right bundle branch block and the echocardiogram showed diastolic dysfunction with a restrictive pattern. Over the last few years he was treated on a regular basis (every 3 weeks) with α-galactosidase A, the enzyme that catalyzes the hydrolysis of globotriaosylceramide. Comment Fabry disease is an X-linked recessive disorder of glycosphingolipid catabolism caused by a deficiency of the lysosomal enzyme galactosidase A as a consequence of 1 or more than 4 dozen mutations.2 The disease is characterized by an intracellular accumulation of a neutral glycolipid with prominent involvement of the skin and kidneys as well as the myocardium. The cardiac manifestations include angina pectoris and myocardial infarction despite angiographically normal coronary arteries (due to the accumulation of lipid moieties in coronary endothelial cells), left ventricular dysfunction and failure, and mitral regurgitation.3 The echocardiogram usually shows increased left ventricular wall thickness as a result of glycolipid deposition, which may simulate hypertrophic cardiomyopathy.3 In a cohort study of 47 kindred members from 3 families with Fabry disease, 12 affected male patients were studied. Ten male patients had electrocardiographic evidence of left ventricular hypertrophy and 5 had ST-T changes. One patient had a short PR interval. Of the 16 heterozygous female patients, none had electrocardiographic evidence of left ventricular hypertrophy and 4 had decreased PR interval, while 2 had a delayed conduction (prolonged PR interval).4 Enzyme replacement therapy with recombinant human α-galactosidase A enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. In a study that followed up for 2 years the effects of therapy on renal function and cardiac function of 26 treated patients with Fabry disease, the condition of patients with renal failure who started the study continued to deteriorate despite the enzymatic treatment. However, patients without impairment of renal function had a better outcome with improved renal function (nonsignificant) but with a decrease in posterior wall thickness (P = .04).5 The important message in our case is the disappearance of the first-degree AV block and the disappearance of the diastolic dysfunction with the restrictive type of physiologic abnormality. We assume that these favorable changes were secondary to treatment with the enzyme α-galactosidase A. Correspondence: Dr Blum, Department of Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee 15208, Israel (ablum@poria.health.gov.il). Author Contributions:Study concept and design: Blum and Khasin. Acquisition of data: Blum, Podovitzky, and Sheiman. Analysis and interpretation of data: Blum. Drafting of the manuscript: Blum, Sheiman, and Khasin. Critical revision of the manuscript for important intellectual content: Blum and Podovitzky. Obtained funding: Blum. Administrative, technical, and material support: Blum, Podovitzky, and Sheiman. Study supervision: Blum and Khasin. Financial Disclosure: None reported. References 1. Blum AAshkenazi HHaromankov IKhazim KSheiman J First degree atrioventricular block and restrictive physiology as cardiac manifestations of Fabry's disease. South Med J 2003;96 (2) 212- 213PubMedGoogle ScholarCrossref 2. Ishii SKase RSakuraba HSuzuki Y Characterization of a mutant alpha-galactosidase gene product for the late onset cardiac form of Fabry disease. Biochem Biophys Res Commun 1993;197 (3) 1585- 1589PubMedGoogle ScholarCrossref 3. Eng CMResnick-Silverman LANiehaus DJAstrin KHDesnick RJ Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet 1993;53 (6) 1186- 1197PubMedGoogle Scholar 4. Sheth KJThomas JP Jr Electrocardiocardiograms in Fabry's disease. J Electrocardiol 1982;15 (2) 153- 156PubMedGoogle ScholarCrossref 5. Breunig FWeidemann FStrotmann JKnoll AWanner C Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int 2006;69 (7) 1216- 1221PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Nov 9, 2009

Keywords: fabry disease,first degree atrioventricular block

References