Abstract
BackgroundFabry 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.MethodsIn 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/m2.7). 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/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.ResultsN215S 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/1.73m2 (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 (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001).ConclusionThese 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.
Highlights
Fabry disease (OMIM 301500; FD) is an X-linked metabolic disorder caused by mutations in the GLA gene [1], of which over 900 mutations (HGMD1 July 2017) have been reported
N215S patients showed strong correlations between lyso-Gb3 levels and left ventricular mass index (LVMI), GFR, and Mainz severity score index (MSSI). These associations became stronger when we investigated individuals’ life time exposure to lyso-Gb3: MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001). These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs
Mutations of the GLA gene can be classified into three groups according to the resulting effect on the α-Galactosidase A (α-Gal A) activity [6]: variants which result in an enzyme activity below 10% of normal in males [7], variants with residual enzymatic activity in the range of 15–30% [8] and variants which code for enzymes whose residual activity is not significantly reduced, referred as non-pathogenic variants [6, 9]
Summary
Fabry disease (OMIM 301500; FD) is an X-linked metabolic disorder caused by mutations in the GLA gene [1], of which over 900 mutations (HGMD1 July 2017) have been reported. Two phenotypes are distinguished “Classic” and “Later Onset” The former has traditionally been associated with males and is characterized by an early onset, usually childhood, presenting with: periodic pain crisis (acroparesthesias), vascular cutaneous lesions (angiokeratomas), corneal and lenticular opacities, perspiration abnormalities, progressive proteinuric renal insufficiency, cardiac disease and cerebrovascular events. It is usually associated with mutations which result in very low (
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