Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history

Abstract

X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome

“…The most severe phenotype of X-ALD is childhood cerebral ALD (CCALD), which is accompanied by acute inflammatory demyelination of the central nervous system that leads to a vegetative state or death within 3–5 years of onset8. On the other hand, adrenomyeloneuropathy (AMN), the most prevalent phenotype, manifests as a slowly progressive myelopathy in the adulthood79.…”

“…Nevertheless, abnormal accumulation of VLCFA is considered as a biochemical trigger for the pathophysiology of CCALD including cerebral inflammatory response10. Furthermore, the pathogenesis of cerebral ALD could be affected by a range of genetic and environmental factors9. Although Abcd1 -deficient mice exhibited an increased level of VLCFA in the brain and adrenal gland, these mice did not show any characteristics of CCALD phenotypes including the cerebral pathology11.…”

Novel <b><i>ABCD1</i></b> Gene Mutation in Adrenomyeloneuropathy with Hypoplasia and Agenesis of the Corpus Callosum

“…More than 100 mutations have been reported in the ABCD1 gene, but no correlation has been found between phenotypes and genotypes [1]. In the present study, patients carried a nonsense mutation which results in a short truncated protein (p.W77X) with possible severe loss of function.…”

“…Adrenoleukodystrophy (ALD, OMIM# 300100) is a progressive neurodegenerative disease characterized by the accumulation of saturated very long-chain fatty acids (VLCFAs) in all tissues of the body [1]. Mutations of the ATP-binding cassette subfamily D member 1 (ABCD1) gene result in abnormal peroxisomal transport or catabolism of VLCFAs [2].…”

Psychiatric disease in an adolescent as a harbinger of cerebral X-linked adrenoleukodystrophy

“…Cerebral adrenoleukodystrophy is typically fatal within 2 years after the onset of symptoms if untreated. While cerebral adrenoleukodystrophy most often presents in childhood, it is increasingly recognised to occur in adolescence and adulthood 1. There is some evidence that head trauma (as in this case) and other environmental factors may trigger progression to cerebral adrenoleukodystrophy 1…”