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The disease is caused by mutations in the <jats:italic>ABCD1<\/jats:italic> gene resulting in a defect in peroxisomal degradation of very long\u2010chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life\u2010time risk to develop myelopathy. The life\u2010time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype\u2010phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single\u2010celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC\u2010derived technologies could improve the understanding of this highly complex disorder.<\/jats:p>","DOI":"10.1002\/jimd.12357","type":"journal-article","created":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T23:55:06Z","timestamp":1609286106000},"page":"544-553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evolution of adrenoleukodystrophy model systems"],"prefix":"10.1002","volume":"44","author":[{"given":"Roberto","family":"Montoro","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam Neuroscience University of Amsterdam  Amsterdam The 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