The α-galactosidase A N215S genotype causes a cardiac-specific variant of Fabry disease that mimics nonobstructive hypertrophic cardiomyopathy, often leading to delayed diagnosis due to the lack of prominent extracardiac involvement.
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 2 ) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 1.9–3.9 L/min per m 2 ), 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.
Oder et al. (Sun,) studied this question.