Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Abstract

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.

Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease

“…Lyso-Gb3 has been described as a helpful tool for newborn 22 and high-risk group screening, 21 25 for diagnosis, [26][27][28][29] as a biomarker for phenotypic assignment, 14 a tool reflecting disease severity 4 and therapeutic monitoring. [30][31][32] As a result of enzymatic deficiency, Gb3 accumulation occurs in classic phenotype males, already before symptom manifestation.…”

Review and Proposal of Alternative Technologies for Comprehensive and Reliable Newborn Screening Using Paper Borne Urine Samples for Lysosomal Storage Disorders: Glycosphingolipid Disorders

“…A couple of 2018 papers that had dealt with reviews of the issue [52,53] did not deal with analytical procedures; nor did those that had dealt with decisions to implement such detection methods [54,55] or those that had dealt with the follow up and management of detected cases [56,57]. Those that had studied biomarkers [57,58] and the consensus guidelines for neonatal screening, diagnosis, and treatment [59,60] as well as those that had studied costs [61] did not consider the possibility of using what has been exposed, which should improve what has been done so far, on a few diseases.…”

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

“…Lyso-Gb3 is involved in cardiac and renal dysfunction [31,32], for example by promoting the release of pro-inflammatory cytokines [1]. Hence, lyso-Gb3 may serve as a biomarker to distinguish FD phenotypes from subjects without FD [33,34], monitor disease progression [30], and may be used as a factor indicating prognosis and disease burden [35,36]. Lyso-Gb3 was found higher in men with FD when compared to women and in patients with classical FD phenotype than in those with nonclassical phenotype [37].…”