ABCD1 and X‐linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models

摘要

Abstract X‐linked adrenoleukodystrophy (X‐ALD) is a phenotypically heterogeneous disorder involving defective peroxisomal β‐oxidation of very long‐chain fatty acids (VLCFAs), due to mutation in the ABCD1 gene. X‐ALD is the most common peroxisomal inborn error of metabolism and confers a high degree of morbidity and mortality. Remarkably, a subset of patients exhibit a cerebral form with inflammatory invasion of the central nervous system and extensive demyelination, while in others only dying‐back axonopathy or even isolated adrenal insufficiency is seen, without genotype–phenotype correlation. X‐ALD's biochemical signature is marked elevation of VLCFAs in blood, a finding that has been utilized for massive newborn screening for early diagnosis. Investigational gene therapy approaches hold promises for improved outcomes. However, the pathophysiological mechanisms of the disease remain poorly understood, limiting investigation of targeted therapeutic options. Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage. Most strikingly, however, cerebral invasion of leukocytes and demyelination were not observed in any animal model for X‐ALD, reflecting upon pathological processes that are yet to be discovered. This review summarizes the current disease models in animals, the lessons learned from these models, and the gaps that remained to be filled in order to assist in therapeutic investigations for ALD.