Studies in primary and iPSC-derived human Gaucher macrophages demonstrate impaired macrophage function and defective autophagy

Abstract

computerized tomography (HRCT) mainly in type I GD adults. So, this study will determine the clinical spectrum of severity of lung involvement in Egyptian children mainly type 3 GD, the radiological changes,assess clinical significance of these findings and their response to ERT. The study included 34 GD children diagnosed by enzyme assay and genotype and are on ERT, imiglucerase 30-60 IU/kg/2 weeks. 31 GD type 3 children (29L444P/L444P, 2 D409H/D409H) and 3 GD type I (1 R359Q/R359Q and 2 with unknown genotype) were followed over 7 years. Their pulmonary status was clinically and radiologically assessed by chest x-ray and HRCT and its response to ERT determined. Clinical variables and radiological findings were statistically correlated. Patients’ median age is 8.6 years and mean duration of ERT is 6.5 years. Twenty (59%) type 3 L4444P/L444P GD children, 13 males and 7 females had chest symptoms with 14 having recurrent chest infections, dyspnea and wheezing, 4 requiring intensive care admission and 1 died of severe pulmonary involvement. Children showed statistically significant higher prevalence of chest symptoms at younger age (p= 0.04). The chest xray and HRCT findings included coarse interstitial pulmonary thickening of variable severity in 26/34(76.5%) and in 90% of the symptomatic group. Other changes included bronchiectasis, gound glass veiling, hyperinflation, mediastinal lymphadenopathy, military infiltration, consolidation, atelectasis and air trapping. In 12/14 asymptomatic GD children findings varied from interstitial thickening to ground glass veiling and bronchiectactic changes. 3 children were splenectomised without worsening of their chest condition. In 13 symptomatic children there was dramatic clinical response to ERT but radiological findings were stationary. All L444P/L444P children showed moderate to severe neurological involvement, 4 had epilepsy, 8 mesenteric lymphadenopathy, 3 severe bone involvement, 2 severe skeletal deformities, aortic and mitral calcifications in D409H/D409H patients. Nearly all children with recurrent infections and significant chest findings have at least one other severe system involvement. Our study showed heterogeneity in clinical presentation and response of lung involvement to ERT in type 3 GD children. 76.5% had variable degrees of interstitial lung disease and nearly all children without clinical lung involvement had abnormal radiological findings. Chest symptoms showed improvement in 65%. Lung involvement can be among the determinants of severity of type 3 GD in children.