Mutations and polymorphisms of the alpha-galactosidase A gene in patients with hypertrophic cardiomyopathy

Abstract

Aims: Anderson-Fabry disease (AFD) is a rare cause of hypertrophic cardiomyopathies (HCM). Clinical signs alone do not allow distinguishing a cardiac manifestation of AFD from sarcomeric forms of HCM. Enzyme activity analysis and genetic testing of the α-galactosidase A (α-GAL) gene (GLA) are therefore important for diagnosis and verification of disease causing mutations. Methods and results: We enrolled 108 adults (76 males, 32 females) with a referral diagnosis of HCM with a left ventricular wall thickness of ≥15 mm on echocardiography. Laboratory analyses included the measurement of α-GAL activity in leukocytes and sequencing of the GLA gene in all patients. Symptoms were evaluated using a specified questionnaire. Mutation analyses confirmed AFD in two patients (p.G35R and g.5092A>G; 1.9%). One female patient (0.98%) had a rare polymorphism (p.D313Y) previously described as disease causing for AFD. In 31 patients (28.7%) various combinations of polymorphisms were detected. The g.1170C>T polymorphism was found in 9 patients (7 males) and was associated with a significantly decreased α-GAL activity in leukocytes among male subjects compared to the wild type GLA gene (p=0.003). Clinically these patients showed higher frequencies of non-sustained ventricular tachycardias (nsVTs, p=0.009). Conclusion: Specific testing of the GLA gene in patients with HCM confirmed AFD in two patients and revealed various polymorphisms in almost one third of patients. The g.1170C>T polymorphism was found in 8% and is associated with a reduced α-GAL activity and a higher incidence of nsVTs in males.