Adrenomyeloneuropathy

Abstract

The neuropathologic features of adrenomyeloneuropathy (AMN) are reviewed by supplementing those few previously published cases with 5 additional cases collected over the years. The endocrine involvement in AMN is briefly presented to serve as a pathogenetic backdrop and to emphasize that most of the lesions in AMN, as in adreno-leukodystrophy (ALD), are noninflammatory in the traditional sense of the word. The myeloneuropathy is emphasized, but the dysmyelinative/inflammatory demyelinative lesions also are presented. The preponderance of available data indicates that the myeloneuropathy of AMN is a central-peripheral distal (dying-back) axonopathy, as was originally proposed. The severity of the myeloneuropathy does not appear to correlate with the duration or severity of endocrine dysfunction. Microglia are the dominant participating cells in the noninflammatory myelopathy. Abnormalities in the ALD gene, which encodes a peroxisomal ABC half-transporter, do not correlate with clinical phenotypes. The relationship of the gene product, ALDP, to the peroxisomal very long chain fatty acid (VLCFA) synthetase, the activity of which is deficient in ALD/AMN, is unclear. An ALD-knockout mouse model has developed axonal degeneration, particularly in spinal cord, and is therefore more reminiscent of AMN than ALD. We continue to postulate that the fundamental defect in the myeloneuropathy of AMN is an axonal or neuronal membrane abnormality perhaps due to the incorporation of VLCFA-gangliosides, which perturbs the membrane's microenvironment and leads to dysfunction and atrophy.

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…Importantly, ABCD1 deficiency in mice also leads to axonal degeneration, resembling findings in AMN patients 12. In AMN mice, previous studies have noted that microglial activation coincides with noninflammatory axonal degeneration13, 14; similar observations have been made in human AMN spinal cord 12.…”

“…In AMN mice, previous studies have noted that microglial activation coincides with noninflammatory axonal degeneration13, 14; similar observations have been made in human AMN spinal cord 12. Despite these findings, no detailed studies on the molecular and functional change of microglia in the absence of ABCD1 have been conducted, and the impact of microglia upon long‐tract degeneration remains unclear.…”

Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy

“…However, the pathogenesis and pathophysiology of ALD is very complex and not yet completely understood. Nevertheless, neuropathologic study has revealed a fundamental difference between AMN and cerebral ALD 16. Additionally, studies have shown that the clinical phenotypes thereof are not correlated with genotype, even in members of the same family with the same mutation 17,18.…”

Cytokine-mediated Induction of Ceramide Production Is Redox-sensitive

“…Several studies demonstrating the induction of proinflammatory cytokines at the protein or mRNA level in cerebrospinal fluid and brain tissue of MS patients have established an association of proinflammatory cytokines (TNF-␣, IL-1␤, IL-2, IL-6, and IFN-␥) with the inflammatory loci in MS (33)(34)(35). Recent documentation of the presence of TNF-␣, IL-1␤, and IFN-␥ in X-ALD brain has revealed the neuroinflammatory character of this disease (36,37). Therefore, to understand the underlying relationship among intracellular levels of GSH, levels of ceramide, and DNA fragmentation in cytokine-inflamed central nervous system of X-ALD and MS, we measured the levels of GSH and ceramide in homogenates and also studied the DNA fragmentation in nuclei from brains of patients with X-ALD and MS.…”