Serum metabolomics indicates ferroptosis in patients with pantothenate kinase associated neurodegeneration.

The core syndrome among NBIA disorders is pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene. There is no therapy for PKAN; only symptomatic treatment is available. Our work aimed to identify the mechanisms induced by biochemical disturbances in the cell cycle and identify potential pharmacological targets to improve patient quality of life. Mass spectrometry (MS) (metals) and NMR spectroscopy (hydrophilic and hydrophobic compounds) were used for profile analyses of the sera of 12 PKAN patients and 12 controls to study the compounds involved in PKAN pathomechanisms. We performed ANOVA and multivariate analysis using orthogonal partial least squares discriminant analysis. We have shown for the first time that patients have 100-500-fold greater serum citrate levels than controls do, which may contribute to Fe transport and ferroptosis. Ferroptosis may be indicated by disturbances in the levels of many metals, oxidative stress, disturbances in energy production and neurotransmission or dysfunction of biological membranes. Our findings suggest that ferroptosis could be a primary cause of cell death in PKAN patients. This could be indicated by serum metabolomics.