Increased levels of plasma lysosomal enzymes in patients with Lowe syndrome

Abstract

Lowe syndrome is an X-linked disorder that has a complex phenotype that includes progressive renal failure and blindness. The disease is caused by mutations in an inositol polyphosphate 5-phosphatase designated OCRL. It has been shown that the OCRL protein is found on the surface of lysosomes and that a renal tubular cell line deficient in OCRL accumulated substrate phosphatidylinositol 4, 5-bisphosphate. Because this lipid is required for vesicle trafficking from lysosomes, we postulate that there is a defect in lysosomal enzyme trafficking in patients with Lowe syndrome that leads to increased extracellular lysosomal enzymes and might lead to tissue damage and contribute to the pathogenesis of the disease. We have measured seven lysosomal enzymes in the plasma of 15 patients with Lowe syndrome and 15 age-matched male controls. We find a 1.6- to 2.0-fold increase in all of the enzymes measured. When the data was analyzed by quintiles of activity for all of the enzymes, we found that 95% of values in the lowest quintile come from normal subjects whereas in the highest quintile 85% of the values are from patients with Lowe syndrome. The increased enzyme levels are not attributable to renal insufficiency because there was no difference in enzyme activity in the four patients with the highest creatinine levels compared with the six patients with the lowest creatinine values.

Figure 1

Lysosomal enzyme activity in control vs. Lowe syndrome patients. The data are normalized so that the mean of the control samples for each enzyme is 1. The differences between control and Lowe syndrome values were evaluated by the Student’s t test. The mean control values and significance of the differences were β-d-glucuronidase, 0.67 nmol/min/ml, P = <0.05; α-l-fucosidase, 3.71 nmol/min/ml, P = <0.01; α-d-mannosidase, 0.07 nmol/min/ml, P = <0.01; N-acetyl-β-d-glucosaminidase, 0.30 nmol/min/ml, P = <0.001; N-acetyl-α-d-glucosaminidase, 0.19 nmol/min/ml, P = <0.1; β-d-galactosidase, 0.0017 nmol/min/ml, P = <0.01; and α-d-galactosidase, 0.015 nmol/min/ml, P = <0.01.

Figure 2

Enzyme levels by quintiles Lowe syndrome vs. controls. Enzyme activities for each enzyme measured were ranked from lowest to highest and then were divided into quintiles. The number of values from control subjects vs. patients with Lowe syndrome in each quintile is plotted.

Figure 3

Creatinine levels vs. age. The points plotted are those from patients with Lowe syndrome, and the line is from the least mean squares of these values. The line for controls is plotted from the equation creatinine = 0.35 + 0.03 × age in years.

Figure 4

Lysosomal enzyme activities vs. creatinine levels. Shown are plasma lysosomal enzyme activities of the Lowe syndrome patients with the six lowest creatinine levels vs. those with the four highest. The mean of the values of the lowest creatinines are normalized to 1.0. Error bars show standard deviations from the mean.