https://pmc.ncbi.nlm.nih.gov/articles/PMC13234235
X-linked adrenoleukodystrophy (X-ALD) is a disorder caused by changes in the ABCD1 gene. These changes disrupt adrenoleukodystrophy protein (ALDP), a protein involved in transporting very long-chain fatty acids (VLCFAs) into peroxisomes, where they are normally broken down. As a result, VLCFAs build-up throughout the body including in lipids. However, serious effects of X-ALD often occur in the central nervous system (CNS), and it remains difficult to predict how quickly the disease will progress. In this study, researchers investigated whether patterns of fatty acids and lipids could provide better biomarkers. A biomarker is a measurable biological sign, such as a blood test result, scan finding, or protein level, that helps doctors and researchers understand, diagnose, monitor, or treat a disease. They compared samples from different human tissues and body fluids, including blood and cerebrospinal fluid (CSF), as well as tissues from ABCD1 knockout mice. The researchers found differences in lipid composition between blood and CNS tissues. This may help explain why VLCFA levels measured in blood, although useful for diagnosing X-ALD, do not reliably reflect neurological disease progression. In contrast, CSF showed lipid patterns more closely resembling those found in CNS tissues. Notably, lipidomic analysis (study of the lipids in a cell) of CSF from children with cerebral X-ALD identified several VLCFA-containing lipids that were strongly associated with disease severity, measured using the Loes score. These included ceramides, sphingomyelins, hexosylceramides and sulfatides, which are important components of myelin. The findings identify promising candidate biomarkers that could help monitor disease progression and evaluate treatment responses. Further research is needed to validate these markers and determine whether related proteins or lipid changes could eventually be detected through blood-based tests, providing less invasive ways to monitor X-ALD.