Untargeted Metabolomic Analysis of Sjögren–Larsson Syndrome Reveals a Distinctive Pattern of Multiple Disrupted Biochemical Pathways

Sjögren–Larsson syndrome (SLS) is a rare inherited neurocutaneous disease characterized by ichthyosis, spastic diplegia or tetraplegia, intellectual disability and a distinctive retinopathy. SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal lipid metabolism. The biochemical abnormalities in SLS are not completely known, and the pathogenic mechanisms leading to symptoms are still unclear. To search for pathways that are perturbed in SLS, we performed untargeted metabolomic screening in 20 SLS subjects along with age- and sex-matched controls. Of 823 identified metabolites in plasma, 121 (14.7%) quantitatively differed in the overall SLS cohort from controls; 77 metabolites were decreased and 44 increased. Pathway analysis pointed to disrupted metabolism of sphingolipids, sterols, bile acids, glycogen, purines and certain amino acids such as tryptophan, aspartate and phenylalanine. Random forest analysis identified a unique metabolomic profile that had a predictive accuracy of 100% for discriminating SLS from controls. These results provide new insight into the abnormal biochemical pathways that likely contribute to disease in SLS and may constitute a biomarker panel for diagnosis and future therapeutic studies.