Lipid signature in X-ALD: a comparison between phenotypes.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) has highly variable phenotypes with no known genotype/phenotype correlation or method for predicting the course of the disease. Screening for X-ALD allows for early, potentially lifesaving treatment of adrenal insufficiency and cerebral demyelination, possibly useful to detect pre-clinical differences in patients and extend treatments to pre-symptomatic subjects. In this study, we analyzed the lipid signature in fibroblasts of patients with Adrenomyeloneuropathy (AMN), the late onset and slowly progressive form of X-ALD, and in patients with Cerebral Adrenoleukodystrophy (CALD), the cerebral inflammatory demyelinating form of early childhood, in order to identify specific lipid molecules as potential early predictors for CALD.

METHODS: We analyzed lipidomic profiles in fibroblasts obtained from n = 4 clinically affected (and genetically proven) X-ALD patients (two CALD and two AMN) and n = 4 age-matched controls, using a Dionex UltiMate 3000 UHPLC system, coupled to a Q-Exactive mass spectrometer.

RESULTS: Our results highlight alterations in lipid metabolism both in AMN and in CALD fibroblasts relative to controls, further confirming the role of LPC 26:0 as a potential biomarker of X-ALD. However, the extent and pattern of lipid remodeling differ substantially between the two phenotypes, with a contribution of neutral lipids in CALD patients, along with a selective involvement of gangliosides.

CONCLUSION: Although both AMN and CALD fibroblasts share some disease-associated lipid alterations, CALD samples exhibited a broader and more pronounced perturbation in multiple lipid classes, particularly in LPCs and steryl esters. The identification of phenotype-associated lipid signatures may represent a step forward toward precision medicine in X-ALD, in order to improve patient phenotypic evaluation.