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A deeper understanding of its natural history and the relationship between biochemical markers and clinical phenotypes is essential for improving disease monitoring, patient counseling, and optimizing clinical trial design. In particular, the predictive value of very long\u2010chain fatty acids (VLCFA) for clinical phenotypes has recently garnered increased attention. In this longitudinal, mixed prospective\/retrospective, single\u2010center study, we analyzed clinical and biochemical data from 364 patients with X\u2010ALD (255 males). Parameters included clinical scores (EDSS, AACS), age at symptom onset, and disease manifestations, which were correlated with individual VLCFA levels. Patients with adrenal insufficiency (AI) exhibited significantly elevated VLCFA concentrations. Higher C26:0 levels were associated with faster progression (measured by EDSS); however, effect sizes were small and inter\u2010individual variability considerable. Although initial symptom severity was comparable between sexes, males presented earlier and progressed faster. Among patients seen in early clinical stages (EDSS \u2264\u20094.5), disease progression rates were higher (males: 0.34\u2009\u00b1\u20090.77; females: 0.11\u2009\u00b1\u20090.11) than in those presenting at more advanced stages (EDSS &gt;\u20094.5; males: 0.23\u2009\u00b1\u20090.33; females: 0.09\u2009\u00b1\u20090.10). We provide comprehensive data on the prevalence of disease manifestations and the natural course of X\u2010ALD in a large adult cohort. The observed association between elevated VLCFA levels and adrenal insufficiency should be considered in future clinical monitoring and trial design. However, due to the small effect sizes and variability, VLCFA levels offer limited prognostic utility for individual patients.<\/jats:p>","DOI":"10.1002\/jimd.70176","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:28:45Z","timestamp":1773912525000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Natural History of Clinical Phenotypes and Their Biochemical Correlates in Adult X\u2010Linked Adrenoleukodystrophy"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-9425","authenticated-orcid":false,"given":"Julia","family":"Lier","sequence":"first","affiliation":[{"name":"Department of Neurology University Medical Center  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Ponleitner","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center  Leipzig 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