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

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...

Storage diseases with hypertrophic cardiomyopathy phenotype

“…Whereas missense mutations appear to be less prone to cause disease, it has also been suggested that some missense variants can be cause of late onset forms or in some cases are associated with particular phenotypes. This is the case of the p.N215S pathogenic variant, which presents with cardiomyopathy in the absence of renal involvement 71 . Disease expression may vary among members of the same family, even between males, which makes treatment decisions and counselling more difficult.…”

Diagnostic strategy for females suspected of Fabry disease

“…In recent years, lyso‐GL‐3 has emerged as a useful biomarker in FD, even allowing to differentiate between classic and later‐onset FD . However, lyso‐GL‐3 is not solely specific to FD, so diagnosis cannot be based on lyso‐GL‐3 elevations alone.…”

“…In contrast, primarily genetic testing leads to the identification of variants of unknown significance (VUS), and above all, to frequent benign variants, such as p.D313Y and p.A143T. [6][7][8][9] In recent years, lyso-GL-3 has emerged as a useful biomarker in FD, [10][11][12][13][14][15][16] even allowing to differentiate between classic and later-onset FD. 17 However, lyso-GL-3 is not solely specific to FD, 18 so diagnosis cannot be based on lyso-GL-3 elevations alone.…”

Fabry cardiomyopathy: missing links from genotype to phenotype

“…Lin et al 6 have reported that 1 in 1600 newborns in Taiwan harbour an intronic variant in GLA associated with late-onset cardiomyopathy. More than 500 individuals worldwide have been diagnosed with the c.644A>G mutation,7 which again is primarily associated with a late-onset cardiomyopathy.…”