General aspects and neuropathology of X-linked adrenoleukodystrophy

Abstract

X-adrenoleukodystrophy (X-ALD) is a metabolic, peroxisomal disease affecting the nervous system, adrenal cortex and testis resulting from inactivating mutations in ABCD1 gene which encodes a peroxisomal membrane half-adenosine triphosphate (ATP)-binding cassette transporter, ABCD1 (or ALDP), whose defect is associated with impaired peroxisomal beta-oxidation and accumulation of saturated very long-chain fatty acids (VLCFA) in tissues and body fluids. Several phenotypes are recognized in male patients including cerebral ALD in childhood, adolescence or adulthood, adrenomyeloneuropathy (AMN), Addison's disease and, eventually, gonadal insufficiency. Female carriers might present with mild to severe myeloneuropathy that resembles AMN. There is a lack of phenotype-genotype correlations, as the same ABCD1 gene mutation may be associated with different phenotypes in the same family, suggesting that genetic, epigenetic, environmental and stochastic factors are probably contributory to the development and course of the disease. Degenerative changes, like those seen in pure AMN without cerebral demyelination, are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord, possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie, oxidative damage). Similar lesions are encountered following inactivation of ABCD1 in mice (ABCD1(-)). A different and more aggressive phenotype is secondary to cerebral demyelination, very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes, CD1 presentation and increased levels of cytokines, gamma-interferon, interleukin (IL)-1alpha, IL-2 and IL-6, Granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha, chemokines and chemokine receptors.

Figure 1

X‐ALD, childhood cerebral form (cALD). A. Loss of myelin and axons in the white matter of the temporal lobe. B. Inflammatory infiltrates in the white matter at the edge of the demyelinating lesion. C. Infiltrating reactive CD68⁺ cells in the intermediate zone between the edge of demyelination and the demyelinated area. D. Hypertrophic astrocytes in the demyelinated area. Paraffin sections: A, B, D. hematoxylin and eosin; C. CD68 immunohistochemistry. B, bar = 200 µm; C, D, bar = 50 µm.

Figure 2

Pure adult cerebral X‐ALD. Gross neuropathological examination of the cerebral hemispheres at the levels of the striatum and globus pallidus (A), mid‐thalamus (B) and posterior part of the parietal lobes (C) show demyelination of the cerebral white matter largely sparing the subcortical fibers. Note the thinning of the anterior part of the corpus callosum and internal capsule. Demyelination is better seen by using myelin stains (Spielmeyer‐Vogt) (D).

Figure 3

Pure adult cerebral X‐ALD. A, B. Perivascular infiltrates of round cells and macrophages filled with granular material that is stained with hematoxylin and eosin (A) and luxol fast blue (B). Bar = 50 µm.

Figure 4

The dorsal column of the spinal cord in wild type: WT (A, E); ABCD1^‐, ALD (B, F); ABCD2^‐, ALDR (C, G); and double mutant ABCD1 ^‐ /ABCD2 ^‐, 2KO (D, H) aged 20 months immunostained with anti‐synaptophysin (A–D) and anti‐ubiquitin (E–H) antibodies. Axonal swellings (arrows) are seen in ALD, ALDR and 2KO mice. Paraffin sections slightly counterstained with haematoxylin. Bar = 20 µm.