Abstract
Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific role of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials, and the advent of newborn screening in the United States. In ALD, very long chain fatty acid (VLCFA) chain-length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
Highlights
X-linked adrenoleukodystrophy, ALD, (MIM #300100) is the most common peroxisomal disorder affecting both males and females with an estimated birth incidence of about 1/14,700 (Bezman et al, 2001; Moser et al, 2016)
While some investigations into the involvement of cholesterol metabolism in ALD have been made, we propose that cholesterol transport dysfunction may play a pathogenic role in oxidative response and inflammatorymediated processes
Consistent with very long-chain saturated fatty acids ≥ C22:0 (VLCFA) induced endoplasmic reticulum (ER) stress seen in cell culture, the PERK pathway is shown to be activated in the spinal cord of ABCD1 knockout mice and brain and fibroblast samples from ALD patients
Summary
X-linked adrenoleukodystrophy, ALD, (MIM #300100) is the most common peroxisomal disorder affecting both males and females with an estimated birth incidence of about 1/14,700 (Bezman et al, 2001; Moser et al, 2016). Consistent with VLCFA induced ER stress seen in cell culture, the PERK pathway is shown to be activated in the spinal cord of ABCD1 knockout mice and brain and fibroblast samples from ALD patients (van de Beek et al, 2017). The increased VLCFA in the myelin lipids of the AMN spinal cord cause oxidative stress and impaired mitochondrial function that contribute to the myeloneuropathy through a failure of ATP-dependent axonal transport (Fourcade et al, 2008; Wanders, 2014). This leads to a distal dying-back axonopathy. Redirecting the synthesis of saturated VLCFA to monounsaturated VLCFA, which are less toxic to membranes, by upregulating the enzyme StearoylCoA Desaturase-1 is another current avenue of research (van de Beek et al, 2019)
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