Daniel Oder1, Dan Liu1, Kai Hu1, Nurcan Üçeyler1, Tim Salinger1, Jonas Müntze1, Kristina Lorenz1, Reinhard Kandolf1, Hermann-Josef Gröne1, Claudia Sommer1, Georg Ertl1, Christoph Wanner1, Peter Nordbeck2,3. 1. From the Department of Internal Medicine I and Comprehensive Heart Failure Center (CHFC) (D.O., D.L., K.H., T.S., J.M., K.L., G.E., C.W., P.N.), Fabry Center for Interdisciplinary Therapy (FAZIT) (D.O., D.L., K.H., N.Ü., T.S., J.M., C.S., G.E., C.W., P.N.), and Department of Neurology (N.Ü., C.S.), University Hospital Würzburg, Germany; West German Heart and Vascular Center Essen, University Hospital Essen, Germany (K.L.); Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany (K.L.); Department of Molecular Pathology, University Hospital of Tübingen, Germany (R.K.); and Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany (H.-J.G.). 2. From the Department of Internal Medicine I and Comprehensive Heart Failure Center (CHFC) (D.O., D.L., K.H., T.S., J.M., K.L., G.E., C.W., P.N.), Fabry Center for Interdisciplinary Therapy (FAZIT) (D.O., D.L., K.H., N.Ü., T.S., J.M., C.S., G.E., C.W., P.N.), and Department of Neurology (N.Ü., C.S.), University Hospital Würzburg, Germany; West German Heart and Vascular Center Essen, University Hospital Essen, Germany (K.L.); Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany (K.L.); Department of Molecular Pathology, University Hospital of Tübingen, Germany (R.K.); and Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany (H.-J.G.). nordbeck_p@ukw.de. 3. nordbeck_p@ukw.de.
Abstract
BACKGROUND: Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. METHODS AND RESULTS: All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) α-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7-23] mm; left ventricular posterior wall, 11±4 [7-21] mm; left ventricular mass, 86±41 [46-195] g/m2) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m2), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte α-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3-9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70-1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84-113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. CONCLUSIONS: α-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.
BACKGROUND:Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. METHODS AND RESULTS: All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) α-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7-23] mm; left ventricular posterior wall, 11±4 [7-21] mm; left ventricular mass, 86±41 [46-195] g/m2) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m2), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte α-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3-9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70-1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84-113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. CONCLUSIONS: α-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.
Authors: L Lavalle; A S Thomas; B Beaton; H Ebrahim; M Reed; U Ramaswami; P Elliott; A B Mehta; D A Hughes Journal: PLoS One Date: 2018-04-05 Impact factor: 3.240
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Authors: Dan Liu; Daniel Oder; Tim Salinger; Kai Hu; Jonas Müntze; Frank Weidemann; Sebastian Herrmann; Georg Ertl; Christoph Wanner; Stefan Frantz; Stefan Störk; Peter Nordbeck Journal: Open Heart Date: 2018-07-12