Lipidomics Analysis of Peroxisomal Disorders: Discovery of Deficits in Phosphatidyglycerol Levels in Rhizomelic Chondrodysplasia Type 1

Paul L Wood and Nancy E Braverman

Objectives: Decreases in the levels of plasmalogens, have been consistently demonstrated in rhizomelic chondrodysplasia type 1 (RCDP1), a genetic disorder of peroxisomal function. However, an in-depth lipidomics analysis has not been undertaken. We undertook such an analysis. Study Design: We performed a high-resolution mass spectrometric shotgun lipidomics analyses of plasma and lymphoblasts from RCDP1 patients. Results: We report for the first time, decrements in phosphatidylglycerol levels in plasma and lymphoblasts from RCDP1 patients. Phosphatidylinositol and phosphatidylserine levels also were unaltered in plasma and lymphoblasts. These data suggested that decrements in phosphatidylglycerol were due to increased catabolism, possibly in failed cellular attempts to restore deficient plasmalogen levels. This conclusion was further supported by supplementation of RCDP1 lymphoblasts with ether lipid plasmalogen precursors that bypass dysfunctional peroxisomes. These precursors augmented cellular levels of plasmalogens in control and RCDP1 lymphoblasts but only augmented phosphatidylglycerols in RCDP1 lymphoblasts. Conclusions: Overall, our results indicate that the peroxisomal disorder, RCDP1, which is characterized by plasmalogen deficits, also possess decrements in phosphatidylglycerol levels, thereby also compromising mitochondrial function and pulmonary surfactant synthesis. Given the role pf phosphatidylglycerols in surfactant, these new data potentially explain the severe respiratory compromise in RCDP children and may add a new parameter of mitochondrial dysfunction in these patients.