Adrenoleukodystrophy

Schaumburg, Herbert H.

doi:10.1001/archneur.1975.00490510033001

Cited by 432 publications

(24 citation statements)

References 22 publications

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“…Cytoplasmic trilamellar structures, presumed morphologic evidence of lipid accumulation, have been observed in brain, peripheral nerves, testes, and adrenal cortex (1,3,5). Recent studies have demonstrated that these tissues (6)(7)(8) and skin fibroblasts (9,10) cultured from patients having either disease accumulate long-chain saturated fatty acids, especially hexacosanoic acid (C26:0).…”

Section: Introductionmentioning

confidence: 99%

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

Knazek¹,

Rizzo²,

Schulman³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are related X-linked disorders characterized by adrenal, gonadal, and nervous system dysfunction. While the pathologic finding common to these tissues appears to be the accumulation of excessive amounts of very long chain fatty acids, the mechanism leading to functional impairment in these tissues is unclear.Measurements of fluorescence polarization (P), using the lipid probe diphenylhexatriene, demonstrate a highly significant increase in the microviscosity of erythrocyte membranes in affected patients (P = 0.286±0.012) vs. normals (P = 0.239±0.020). Analyses of these membranes by gas-liquid chromatography revealed 1.9-, 1.6-, and 1.3-fold increases above normal values in the C25:0, C26:0, and C27:0 fatty acids, respectively.These observations are compatible with previously obtained data in animals that correlate membrane microviscosity with the number of hormone receptors in target tissues. The present data support the thesis that a decrease in responsiveness to trophic hormones in ALD and AMN is secondary to changes in the membrane microviscosity of the target tissues and suggest a mechanism by which adrenal and gonadal failure occur in such patients.

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Section: Introductionmentioning

confidence: 99%

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

Knazek¹,

Rizzo²,

Schulman³

et al. 1983

J. Clin. Invest.

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“…In neonatal ALD, clinical symptoms are present at birth and an autosomal recessive mode of inheritance is followed (4). This differs from the better known childhood form of ALD, an X-linked recessive disorder, in which symptoms appear after 3-5 years of normal development (2). The cytoplasmic lipid inclusions observed in these disorders were shown to be cholesterol esterified to very long chain fatty acids (VLCFA) (5); both disorders are characterized biochemically by increased levels of VLCFA in both plasma and cultured skin fibroblasts (6).…”

mentioning

confidence: 95%

“…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.…”

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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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“…The lack of peroxisomes would also explain the increased blood level of bile acid precursors (7,8) and possibly of pipecolic acid (9), assuming it reflects a deficiency in glutaryl-CoA oxidation (10). Adrenoleukodystrophy constitutes another hereditary disorder in which the accumulation of very longchain fatty acids (11) and also myelin degeneration (12,13) apparently reflect a peroxisomal defect. As new findings increase the scope of the possible peroxisomal involvement in metabolic inherited disorders, their participation is being considered for hyperpipecolatemia (8,14), glutaric aciduria (10), dicarboxylic aciduria (15,16), hyperoxaluria (14,17), glycinuria (17), testicular feminization (18), and cerebrotendinous xanthomatosis (8,14).…”

mentioning

confidence: 99%

Peroxisomal organization in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts.

Santos¹,

Ojeda²,

Garrido³

et al. 1985

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

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The reported absence of morphologicafly detectable peroxisomes in liver and kidney tissue cells from patients affected by the autosomic recessive, inherited metabolic disease known as cerebrohepatorenal, or Zeflweger, syndrome was studied in fibroblasts, assuming it to be a generalized defect.Normal cultured fibroblasts were shown to contain peroxisomes according to morphological, biochemical, and subcellular fractionation criteria: particle-bound catalase and fatty acyl-CoA oxidase copurify in subcellular fractionation by differential centrifugation or isopycnic equilibrium in continuous density gradients and peroxidase-positive organelles of =O.1 ,um in diameter are detected in the cytoplasm. In Zellweger cultured fibroblasts, these peroxisomal enzymes are present; however, they behave as cytosolic enzymes in the different subcellular fractionation procedures employed and peroxisomes are not detected cytochemically. These rindings support the hypothesis that the lack of peroxisomes in this genetic disease is the consequence of a defect in the assembly of the peroxisomal constituents. Furthermore, the value offibroblasts for subcellular analysis of peroxisomal defects is illustrated.Recent evidence supports the hypothesis that in some inherited metabolic disorders, defects in peroxisomal function are pathogenic. The initial observation that peroxisomes are absent in liver and kidney from children affected with the cerebrohepatorenal (Zellweger) syndrome (1) later correlated with the greatly reduced plasmalogen content found in their tissues (2), a phenomenon attributed to a lack of peroxisomal enzymes involved in plasmalogen biosynthesis (2, 3). It has also been correlated with the accumulation in fibroblasts of very long-chain fatty acids (4), supposedly the consequence of a defect in the peroxisomal fatty acid oxidation system capable of oxidizing very long-chain fatty acids (5, 6). The lack of peroxisomes would also explain the increased blood level of bile acid precursors (7,8) and possibly of pipecolic acid (9), assuming it reflects a deficiency in glutaryl-CoA oxidation (10). Adrenoleukodystrophy constitutes another hereditary disorder in which the accumulation of very longchain fatty acids (11) and also myelin degeneration (12, 13) apparently reflect a peroxisomal defect. As new findings increase the scope of the possible peroxisomal involvement in metabolic inherited disorders, their participation is being considered for hyperpipecolatemia (8,14), glutaric aciduria (10), dicarboxylic aciduria (15, 16), hyperoxaluria (14, 17), glycinuria (17), testicular feminization (18), and cerebrotendinous xanthomatosis (8,14). A single enzymatic defect might explain some of these conditions; however, in the Zellweger syndrome the whole organelle would be missing, perhaps reflecting the deficit of a protein essential for the assembly of peroxisomes. Consequently, as already suggested (14, 19-24), this pathologic condition would constitute a unique example of a genetic disorder expressed as absence of a cell o...

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Adrenoleukodystrophy

Cited by 432 publications

References 22 publications

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

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

Peroxisomal organization in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts.

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