164 Chapter 5 Untreated lysoGb3 in plasma as a marker for disease phenotype All but one of the 237 FD patients had plasma lysoGb3 levels above the reference range (0.3-0.5 nmol/L). The one female patient with a normal plasma lysoGb3 level (0.3 nmol/L) had a pathogenic GLA variant associated with a non-classical phenotype in her male relatives. At her last evaluation (aged 39) she had no clinical signs or symptoms associated with FD. Plasma lysoGb3 levels >40 nmol/L separated male patients with classical disease from male patients with non-classical disease with 98 % sensitivity and 100 % specificity (P<0.001, PPV= 98%, NPV= 100%, fig 2). Plasma LysoGb3 levels > 2.3 nmol/L separated female patients with classical disease from female patients with nonclassical disease with 98% sensitivity and 83% specificity (P<0.001, PPV=94%, NPV= 94%). Figure 2: Plasma lysoGb3 levels in Fabry patients with different phenotypes. Dotted lines represent upper range of normal (0.5 nmol/L), best cut off value to differentiate between classical and non-classical FD in female patients (2.3 nmol/L) and the best cut off value to differentiate between classical and non-classical FD in male patients (40). Association of plasma lysoGb3 with renal manifestations in untreated FD patients Higher lysoGb3 levels were significantly associated with steeper eGFR slopes in all FD patients of 18 years and older (n= 202, median numbers of measurements 2 per patient, range 1-20) (fig 3a, p=0.04). As male patients with classical FD are known to be most at risk for accelerated decline in renal function, analyses were also performed after exclusion of this patient group. The association remained statistically significant (p=0.005). Higher lysoGb3 levels were also significantly
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