Background: XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK.

Objective: The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. Methods: We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls.

Results: In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N-acyl phosphatidylethanolamine was increased in the DLPFC. N-Acyl serine was reduced in all three regions.

Conclusions: Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease.