Fabry disease (FD) is a multi-systemic X-linked lysosomal disorder caused by the deficient activity of α-galactosidase-A enzyme, which leads to accumulation of glycosphingolipids in various body tissues. The N215S mutation is a known variant of FD, with a late onset cardiac phenotype. Consensus guidelines acknowledged the use of globotriaosylsphingosine (Lyso-Gb) as a diagnostic marker for classical FD but its utility for cardiac variant FD is not clear. We aim to characterize the clinical features and evaluate the diagnostic accuracy of plasma and urinary Lyso-Gb levels in N215S cardiac variant FD patients. Thirty-four FD patients with the late-onset N215S cardiac variant mutation were enrolled along with 62 classical FD patients and 109 healthy controls. Plasma and urinary Lyso-Gb and its analogues were analyzed by LC-MS/MS. Both FD males and females with N215S mutation showed Lyso-Gb levels of (mean ± SEM) 9.7 ± 1.0 and 5.4 ± 0.8 nM, respectively. These levels were significantly higher than healthy control and lower than classical FD patients (p < 0.0001). Plasma Lyso-Gb levels equal to or higher than 2.7 nM yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p < 0.0001). Cardiac involvement was frequent with 16/34 (47%) developing left ventricular hypertrophy. Three patients who underwent renal biopsy had the characteristic sphingolipid deposition in the podocytes while 6/19 (32%) had evidence of white matter changes or infarct on brain MRI. Taken together, cardiac variant N215S mutation is rather an attenuated form of classical FD. Plasma Lyso-Gb is a diagnostic hallmark to differentiate N215S variant phenotype from subjects with no FD.

No abstract

The use of 256-slice CCTA performed with the FLASH protocol has a better objective and subjective image quality as well as lower radiation exposure when compared with the use of prospective electrocardiography gating.

Fabry Disease (FD) has been a diagnostic challenge since it was first recognised in 1898, with patients traditionally suffering from considerable delay before a diagnosis is made. Cardiac involvement is the current leading cause of death in FD. A combination of improved enzyme assays, availability of genetic profiling, together with more organised clinical services for rare diseases, has led to a rapid growth in the prevalence of FD. The earlier and more frequent diagnosis of asymptomatic individuals before development of the phenotype has focussed attention on early detection of organ involvement and closer monitoring of disease progression. The high cost of enzyme replacement therapy at a time of constraint within many health economies moreover, has challenged clinicians to target treatment effectively. This article provides an outline of FD for the general physician and summarises the aetiology and pathology of FD, the cardiovascular (CV) consequences thereof, modalities used in diagnosis, and then discusses current indications for treatment, including pharmacotherapy and device implantation.