Navigating the lipidomic landscape of andrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a genetic disorder caused by ABCD1 mutations, leading to impaired peroxisomal β-oxidation and VLCFA accumulation. In males, ALD presents with variable symptoms, including adrenal insufficiency, spinal cord disease, and cerebral demyelination, while females develop progressive spinal cord disease later in life. Despite newborn screening enabling early detection, predicting disease course remains challenging due to the lack of prognostic biomarkers (Chapter 2).
Chapter 3 showed that LPC 26:0 analysis outperforms VLCFA analysis in detecting ALD and Zellweger spectrum disorder (ZSD) patients, offering a faster and less labour-intensive alternative for clinical use. Chapter 4 applied lipidomics to identify prognostic biomarkers, revealing that VLCFA are incorporated into various lipid classes, with higher levels correlating with more severe disease. Chapter 5 extended this to cerebrospinal fluid (CSF), showing similar VLCFA-associated lipid alterations. Chapter 6 investigated astrocytes in ALD pathogenesis, demonstrating impaired β-oxidation and VLCFA accumulation. Chapter 7 introduced 4D lipidomics to analyze ALD fibroblasts, identifying over 1,000 lipid species and detecting multiple VLCFA within complex lipids.
Overall, the findings in this work provide valuable insights into the lipidomic landscape of ALD. Refining and expanding these lipidomic approaches hold significant potential to further deepen our understanding of the underlying mechanisms of ALD and its clinical manifestations.