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

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.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/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.N215S patients showed later symptom onset (males: p< 0.0001, females: p