From gene to therapy: a review of deciphering the role of ABCD1 in combating X-Linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic disorder caused by ABCD1 mutations, resulting in the buildup of very-long-chain fatty acids, leading to significant neurological decline and adrenal insufficiency. Despite advancements in understanding the mechanisms of X-ALD, its pathophysiology remains incompletely understood, complicating the development of effective treatments. This review provides a comprehensive overview of X-ALD, with a focus on the genetic and biochemical roles of ABCD1 and the impacts of its mutations. Current therapeutic approaches are evaluated, discussing their limitations, and emphasizing the need to fully elucidate the pathogenesis of X-ALD. Additionally, this review highlights the importance of international collaboration to enhance systematic data collection and advance biomarker discovery, ultimately improving patient outcomes with X-ALD.

Keywords: ABCD1; Gene therapy; Genetic mutations; Neurological decline; Very-long-chain fatty acids (VLCFAs); X-linked adrenoleukodystrophy (X-ALD).

Fig. 1

Distribution of Mutations of ABCD1 and Functional Domains of ABCD1. The top panel depicts the distribution of mutations in ABCD1 (excluding introns), categorized as pathogenic or likely pathogenic mutations (colored red), benign or likely benign mutations (colored green), or variants of uncertain significance (VUSs) (colored gray). The middle panel contains a variant density plot based on a 50-base-pair sliding window across ABCD1, with the x-axis representing the positions of amino acids. The bottom panel highlights the protein domains encoded by ABCD1. CDS = Coding Sequence, UTR = Untranslated Region. Mutation data was obtained from https://adrenoleukodystrophy.info/

Fig. 2

Therapeutic Targets in X-ALD Linked to ABCD1 Mutations. The mutation disrupts normal ABCD1 functioning, leading to decreased β-oxidation of very-long-chain fatty acids (VLCFAs). This reduction leads to the accumulation of VLCFA-CoAs and thus an increase in concentrations of free VLCFAs. The accumulation of VLCFAs triggers oxidative stress and cellular damage. The figure indicates intervention points that must be addressed when developing treatments to target the underlying biochemical abnormalities in X-ALD. ROS = reactive oxygen species. The figure is created with BioRender.com