α-半乳糖苷酶A基因N215S基因型诱导法布里病的一种特定心脏变异型。
α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease.
作者信息
Oder Daniel, Liu Dan, Hu Kai, Üçeyler Nurcan, Salinger Tim, Müntze Jonas, Lorenz Kristina, Kandolf Reinhard, Gröne Hermann-Josef, Sommer Claudia, Ertl Georg, Wanner Christoph, Nordbeck Peter
机构信息
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.).
出版信息
Circ Cardiovasc Genet. 2017 Oct;10(5). doi: 10.1161/CIRCGENETICS.116.001691.
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/m) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in (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.
背景
肥厚型心肌病是最常见的心肌病类型，但许多患者缺乏肌节/肌丝突变。我们研究了由于缺乏心外器官受累，心脏特异性α-半乳糖苷酶A基因变异是否被误诊为肥厚型心肌病。
方法与结果
在这项前瞻性单中心纵向队列研究中，对所有N215S基因型检测呈阳性的受试者（n = 26，13名女性，平均年龄49±17[范围，14 - 74]岁）进行特征分析，以确定N215S（c.644A>G [p.Asn215Ser]）α-半乳糖苷酶A基因变异的基因型特异性临床特征。所有受试者最初因怀疑遗传性肥厚型心肌病而被转诊。心脏肥厚（室间隔，12±4[7 - 23]mm；左心室后壁，11±4[7 - 21]mm；左心室质量，86±41[46 - 195]g/m）呈进行性发展，收缩功能主要保留（心脏指数2.8±0.6[1.9 - 3.9]L/min per m），舒张功能轻度异常。心脏磁共振成像显示18/26（69%）存在替代性纤维化，尤其是年龄>50岁的受试者。老年受试者出现晚期心力衰竭，6名（23%）建议接受植入式心脏复律除颤器治疗。19名受试者白细胞α-半乳糖苷酶A酶活性轻度降低，溶酶体球三糖神经酰胺略有升高（中位数，4.9；四分位间距，1.3 - 9.1 ng/mL）。神经和肾脏损害（血清肌酐，0.87±0.20；中位数，0.80；四分位间距，0.70 - 1.01 mg/dL；肾小球滤过率，102±23；中位数，106；四分位间距，84 - 113 mL/min）不明显。仅2名受试者出现临床相关蛋白尿。
结论
α-半乳糖苷酶A基因型N215S不会导致典型的法布里表型的发展，但会诱发一种模仿非梗阻性肥厚型心肌病的法布里病特异性心脏变异型。缺乏明显的心外损害导致诊断和法布里特异性治疗的显著延迟。
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