Plasma Very-Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy: Diagnostic Insights From a Clinical Laboratory...

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, leading to accumulation of very long-chain fatty acids (VLCFAs). Plasma VLCFA measurement is central to diagnosis, but its value for prognostic stratification remains uncertain. This study explored the association between biochemical profiles, ABCD1 variants, and clinical phenotypes, and assessed the clinical utility of plasma VLCFA levels.

We performed a retrospective study of 31 genetically confirmed X-ALD patients from Western Andalusia evaluated between 2005 and 2025. Clinical data, lipid profiles, and VLCFA parameters were analyzed. Patients were stratified by sex, clinical phenotype, genotype, and lipid status. Associations were assessed using Spearman correlation and non-parametric tests, and ROC curves were used to evaluate discrimination for cerebral ALD (CALD).

Symptomatic patients showed higher C26:0 levels and C26:0/C22:0 ratios than asymptomatic individuals, with the highest values in patients with cerebral involvement. VLCFA levels differed across clinically defined groups, although substantial overlap was observed. Truncating ABCD1 variants were associated with higher C26:0 levels and C26:0/C22:0 ratios, but not with cerebral involvement. ROC analysis showed moderate discrimination for CALD (AUC = 0.84). No significant longitudinal changes in VLCFA levels were observed.

Plasma VLCFA profiling remains essential for X-ALD diagnosis and shows moderate group-level associations with clinical phenotypes, particularly in cerebral involvement. However, its utility for individual prognostic stratification is limited, supporting the need for complementary biomarkers such as C26:0-LPC.