Pathophysiology of X-linked adrenoleukodystrophy

J Berger, S Forss-Petter, F S Eichler, J Berger, S Forss-Petter, F S Eichler

Abstract

Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.

Keywords: ABC transporter; Axonopathy; Demyelination; Inflammation; Leukodystrophy; Peroxisome.

Copyright © 2013 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Figures

Fig. 1
Fig. 1
Hypothetical model and pathology of AMN; (A) Model showing the sequential events leading to the dying-back axonopathy, the main clinical manifestation of AMN. (B) Quantitative magnetization transfer characteristics of the human cervical spinal cord in a severely affected patient with AMN. The arrows indicate the signal hyperintensity in the dorsal and lateral columns (Image was provided by Dr. Ali Fatemi, Department of Neurogenetics, The Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, USA). (C) Anti-phosphorylated neurofilament immunostaining of the cervical spinal cord of an AMN patients showing atrophy of the lateral columns (arrows; reproduced with permission from J. Neuropathol. Exp. Neurol.; Powers et al., 2000; 59:89–101). (D) T2-weighted magnetic resonance image of the brain in an AMN patient. The arrows indicate the symmetric lesions in the corticospinal tract.
Fig. 2
Fig. 2
Hypothetical model showing the sequential events leading to the inflammatory demyelination in CALD. The inset images are characteristic MRI features of a boy afflicted by CALD. The left panel shows a T2-weighted image with a symmetric and confluent demyelinating lesion within the parieto-occipital lobes. The right panel shows a T1-weighted image post gadolinium administration. Gadolinium enhancement indicates active inflammation and disruption of the blood brain barrier.

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