The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis.

X-linked adrenoleukodystrophy (X-ALD) is a complex disorder that affects the nervous, adrenocortical, and male reproductive systems. Although ABCD1 mutations are known to provide the genetic basis for X-ALD, its pathogenesis is not fully elucidated. Primary skin fibroblasts from two male patients with the childhood cerebral form of disease (CCALD) caused by ABCD1 mutations and three healthy donors were transduced with retroviral vectors expressing the OCT4, SOX2, KLF4, and c-MYC factors. Induced pluripotent stem cells (iPSCs) were subject to global gene expression, DNA methylation, DNA copy number variation, and genotyping analysis and tested for pluripotency through in vitro differentiation and teratoma formation. Unlike fibroblasts, CCALD patient iPSCs show differentially expressed genes relevant to both peroxisome abundance and neuroinflammation. The highlighted genes provide new leads for pathogenic mechanisms that can be explored in animal models and human tissue specimens. We suggest that these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes.