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Background  Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described “Classic” and “late onset” which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of  N215S  patients and compare this to patients with other mutations.    Methods  In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84  N215S  mutation (37 males) and 167  non-N215S  mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m 2.7 ). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m 2.7 ), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.    Results   N215S  patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 ( non-N215S ) vs. 64 ( N215S ) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non- N215S ) vs 71 years ( N215S ), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years ( non-N215S ) vs. not reached ( N215S) , p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m 2  (median survival: 56  (non-N215S)  vs. 72  (N215S)  years, p< 0.01), and greater overall survival (median survival 81  (N215S)  vs. 66  (non-N215S)  years, p< 0.0006). Lyso-Gb3 was found to be less elevated in  N215S  compared to  non-N215S  male and female patients. However, the  N215S  population eventually reached an overall severity measured by MSSI comparable to the  non-N215S  without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition,  N215S  patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals’ life time exposure to lyso-Gb3 (calculated as [lyso-Gb3]*age): MSSI (r 2  = 0.88, p< 0.0001), LVMI (r 2  = 0.59, p< 0.005), and GFR (r 2  = 0.75, p = 0.0001).    Conclusion  These results demonstrate that the  N215S  mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.

Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation