Adreno-leukodystrophy (Sex-Linked Schilder Disease)

Schaumburg, Herbert H.; Powers, James M.; Suzuki, Kinuko; Raine, Cedric S.

doi:10.1001/archneur.1974.00490390092013

Cited by 75 publications

(9 citation statements)

References 7 publications

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“…The demyelination begins usually in the splenium of corpus callosum where the white matter fiber bundles are most tightly packed and spreads outward into the periventricular white matter Schaumburg, Powers, Raine, Suzuki, & Richardson, 1975;Schaumburg, Powers, Suzuki, & Raine, 1974). This is the area where the oligodendrocytes express the highest levels of ABCD1 (Lauer et al, 2017).…”

Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

“…There are marked changes in the lipid profile of ALD brain tissue when active demyelinating areas are analyzed in postmortem tissue. The VLCFA are enriched in cholesterol esters, predominately located in invading monocytes/macrophages entering the brain following the opening of the blood-brain barrier (Schaumburg et al, 1974). The myelin lipids, the phospholipids, sphingomyelin, cerebrosides, sulfatides, gangliosides and the proteolipid protein show an increased VLCFA (Bizzozero, Zuniga, & Lees, 1991;Kishimoto et al, 1984;Theda et al, 1992).…”

Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

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X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

130

113

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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 roles 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 USA. 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.

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Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

130

113

View full text Add to dashboard Cite

show abstract

“…The term adrenoleukodystrophy (ALD) refers to a group of degenerative neurological disorders characterized by demyelination and by cytoplasmic lipid inclusions in the central nervous system, adrenal cortical cells, and Schwann cells (1)(2)(3). Several forms of the disorder have been described.…”

mentioning

confidence: 99%

Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.

Chen

Watkins

Osumi

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Very long chain fatty acids, which accumulate in plasma and tissues in X-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger cerebrohepatorenal syndrome, are degraded by the peroxisomal ,8-oxidation pathway, consisting of acyl-CoA oxidase, the bifunctional enoylCoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and 13-ketothiolase. A marked deficiency of all three enzyme proteins was reported in livers from patients with the Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in X-linked ALD. Immunoblot analysis of the peroxisomal 13-oxidation enzymes revealed an almost complete lack of the bifunctional enzyme in neonatal ALD liver, similar to the finding in Zellweger tissue. In contrast, acyl-CoA oxidase and f3-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature enzyme) in neonatal ALD. Unlike either neonatal ALD or Zellweger syndrome, all three peroxisomal 13-oxidation enzymes were present in X-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional enzyme protein, its mRNA was detected by RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional enzyme protein in neonatal ALD results from either abnormal translation of the mRNA or degradation of the enzyme prior to its entry into peroxisomes.

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“…Within such areas, VLCFA are strongly enriched in cholesterol esters [25,27]. It is believed that the cholesterol esters containing VLCFA are predominantly located in invading monocytes/macrophages, entering the CNS after the opening of the blood–brain barrier occurs, and within activated microglia [28]. ABCD1 deficient macrophages/microglia are unable to degrade VLCFA from phagocytosed myelin debris during the inflammatory demyelinating process.…”

Section: Lipidomic Aspects Of the Pathophysiology Of X-aldmentioning

confidence: 99%

Pathophysiology of X-linked adrenoleukodystrophy

2014

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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.

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Adreno-leukodystrophy (Sex-Linked Schilder Disease)

Cited by 75 publications

References 7 publications

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.

Pathophysiology of X-linked adrenoleukodystrophy

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