Introduction and Objectives AFD is an X-linked lysosomal storage disorder caused by mutations of the GLA gene. Lack of enzyme results in storage material accumulation within lysosomes, leading to multi-organ pathology. Airflow obstruction has been reported, though there has been no systematic assessment of lung enzyme activity in affected individuals. We therefore undertook a controlled cohort review of UK AFD patients focussing in particular on the relationship between airway and blood intra- and extracellular GLA, and lung pathology.
Methods Study subjects and controls were recruited following local Ethics Committee approval. All underwent systematic pulmonary investigation, including lung function testing and sputum induction with 40 ml of 4% hypertonic saline over 20 min via an ultrasonic nebuliser. GLA activity was measured from AFD patients and healthy controls in induced sputum (IS) cells and supernatant using a fluorometric assay. In addition, in AFD patients, GLA activity was measured simultaneously in blood leucocytes and plasma.
Results 45 AFD patients with variable severity extra-pulmonary disease were recruited (20 males, 10 smokers). The population had a mean FEV1 of 89% predicted. 20 of 45 (44%) (13 males, 6 smokers) had evidence of airflow obstruction with FEV1/FVC ratio <70%. IS intra- and extracellular GLA activity was lower in AFD affected males compared to controls (n=18 and 13, median enzyme activity 18.8 vs 41.7 nmol/h/mg protein and 0.9 vs 10.0 nmol/h/ml, p<0.001 and p<0.01, respectively). No similar difference was found in females. Paired blood and sputum data from 22 AFD patients (13 males, 18 on enzyme replacement therapy) demonstrated greater GLA activity intracellularly in IS than peripheral blood, p=0.001 (see Abstract P179 Figure 1), and extracellularly in IS supernatant versus plasma in males alone (p<0.05).
Conclusions Sputum GLA activity is lower in male AFD patients than controls. However AFD subjects had significantly higher GLA activity in lung than blood. Measured airway obstruction in AFD was mild, though common. We speculate that the higher levels of lung enzyme found in AFD patients, on or off enzyme replacement, may contribute to the relative preservation of pulmonary function compared to other organ systems.