C26:0-lysophosphatidylcholine in X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a progressive neurometabolic disorder caused by pathogenic variants in the ABCD1 gene, resulting in the systemic accumulation of very-long-chain fatty acids (VLCFAs). C26:0-lysophosphatidylcholine (LPC(26:0)) is the primary biochemical marker of ALD and the basis for newborn screening programs worldwide. LPC(26:0) arises from the accumulation of VLCFA-CoA species that are incorporated into phosphatidylcholine via the lysophospholipid acyltransferase LPLAT10, followed by phospholipase A2-mediated hydrolysis. Compared to conventional plasma VLCFA analysis, measurement of LPC(26:0) by liquid chromatography or flow injection tandem mass spectrometry in plasma or dried blood spots offers superior sensitivity and specificity, even in female patients, for whom VLCFA analysis yields false-negative results in 15-20% of cases. Beyond diagnosis, accumulating evidence indicates that LPC(26:0) and the broader landscape of VLCFA-containing lipids correlate with disease severity. Higher levels are associated with cerebral ALD, adrenal insufficiency, and severe spinal cord disease, and data from newborn screening cohorts suggest that neonatal LPC(26:0) levels may also stratify risk for early-onset disease manifestations. LPC(26:0) accumulates in CNS lipoproteins and exhibits direct neurotoxic and proinflammatory properties in experimental models. This implicates LPC(26:0) not only as a biomarker, but also as a potential mediator of ALD pathology. Furthermore, LPC(26:0) shows promise as a pharmacodynamic biomarker of biochemical correction across therapeutic strategies, from hematopoietic stem cell transplantation to emerging approaches including ELOVL1 inhibition. However, key questions remain regarding the cell type and tissue origin of circulating LPC(26:0), its precise contribution to neuroinflammation, and the threshold levels that reliably predict clinical outcomes in individual patients.