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α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease
Daniel Oder1, Dan Liu1, Kai Hu1
1From 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.).
Insights
A specific alpha-galactosidase A gene variant (N215S) can mimic hypertrophic cardiomyopathy. This cardiac variant of Fabry disease often delays diagnosis due to minimal non-cardiac symptoms.
Area of Science:
- Cardiology
- Genetics
- Metabolic Disorders
Background:
- Hypertrophic cardiomyopathy (HCM) is common, yet many patients lack sarcomeric mutations.
- Investigating cardio-specific alpha-galactosidase A (α-Gal A) gene variants as a cause of HCM misdiagnosis.
- Examining the role of extracardiac organ involvement in differentiating HCM mimics.
Purpose of the Study:
- To characterize the clinical presentation of the N215S α-Gal A gene variant.
- To determine if this variant causes a distinct cardiac phenotype.
- To understand diagnostic challenges associated with this variant.
Main Methods:
- Prospective monocentric longitudinal cohort study of 26 subjects with the N215S genotype.
- Clinical assessment including cardiac hypertrophy measurements, systolic/diastolic function, and cardiac MRI.
- Biochemical analysis of leukocyte α-Gal A enzyme activity and lyso-globotriaosylceramide levels.
- Evaluation of neurological and renal function.
Main Results:
- Progressive cardiac hypertrophy and preserved systolic function observed in N215S subjects.
- Cardiac MRI revealed significant replacement fibrosis in 69% of subjects.
- Mildly reduced α-Gal A activity and slightly elevated lyso-globotriaosylceramide in most subjects.
- Discreet neurological and renal impairments, with minimal proteinuria.
Conclusions:
- The N215S α-Gal A genotype induces a cardiac variant of Fabry disease, mimicking hypertrophic cardiomyopathy.
- The absence of significant non-cardiac symptoms delays diagnosis and Fabry-specific treatment.
- This genotype represents a specific cardiac phenotype distinct from classical Fabry disease.
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.
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