A metabolic disorder similar to Zellweger syndrome with hepatic acatalasia and absence of peroxisomes, altered content and redox state of cytochromes, and infantile cirrhosis with hemosiderosis

Versmold, Hans T.; Bremer, H. J.; Herzog, Volker; Siegel, G.; Bassewitz, D. B. v.; Irle, U; Voss, Hubertus von; Lombeck, I.; Brauser, B.

doi:10.1007/bf00441934

Cited by 71 publications

(21 citation statements)

References 46 publications

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“…We favor this hypothesis because I) long chain fatty acids are known to be oxidized in peroxisomes (14); 2) we presented evidence that the oxidation of C24:O in rat liver takes place in peroxisomes (1 3); 3) we recently showed that patients with the Zellweger cerebrohepatorenal syndrome have elevated levels of very long chain fatty acid levels (3) and impaired I4CO2 production from [l-I4C] C24:O (Singh, I. unpublished observation) similar to observations in ALD; and 4) patients with the Zellweger syndrome lack peroxisomes (6,29,39). Definition of the metabolic defect in ALD will require study of specified subcellular fractions, and analysis of the separate steps involved in fatty acid degradation.…”

Section: Resultsmentioning

confidence: 86%

Adrenoleukodystrophy: Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes

et al. 1984

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SummaryWe compared the formation of I4CO2 from [I-I4C]fatty acids in homogenates of cultured skin fibroblasts and white blood cells from 25 patients with adrenoleukodystrophy (ALD) and from 24 controls. The ALD group included 16 boys with childhood ALD, five men with adrenomyeloneuropathy (AMN), and two boys and two girls with neonatal ALD. The substrates were unbranched saturated fatty acids ranging in chain length from 16-26 carbons. From C24:0, the radioactive C 0 2 production by homogenates of ALD fibroblasts and white blood cells was 17% and 37% of control, respectively, and from C26:O it was 17% of control in ALD fibroblasts. The C 0 2 evolution from palmitate (C16:O) in the ALD was identical to the control group; for C18:0, the value for ALD cells was 76% of control, and fatty acids with chain lengths between C18:O and C24:O gave intermediate results.Results for childhood ALD patients were similar to those for the AMN patients. More limited studies with cultured amniocytes of fetuses with childhood ALD gave results similar to those obtained with cultured skin fibroblasts, and results with neonatal ALD patients appeared to be the same as for childhood ALD and AMN. Studies of three women who were carriers for childhood ALD gave values intermediate between ALD and control. The total C26:O levels in ALD cultured skin fibroblasts and white blood cells were 4-6 times that of control; the total C24:O levels were increased 10-30%, whereas the C22:O levels were unchanged.The results suggest that ALD patients have a defect in the oxidation of very long chain fatty acids (C24:O and longer) but not for the degradation of fatty acids with a chain length of 18 carbons or less. Such a defect could account for the accumulation of the very long chain fatty acids in a variety of tissues and lipid moieties. The accumulation of these fatty acids, coupled with the metabolic data presented here, suggests that normal catabolism of very long chain fatty acids involves a metabolic pathway which is distinct from that for other fatty acids, and that this pathway is genetically deficient in patients with ALD.Abbreviations ALD, adrenoleukodystrophy AMN, adrenomyeloneuropathy C22:0, docosanoic acid (behenic acid) C24:0, tetracosanoic acid (lignoceric acid) C26:0, hexacosanoic acid (cerotic acid) C27:0, heptacosanoic acid GLC, gas liquid chromatography WBC, white blood cell ALD is a genetically-determined, progressive disorder which affects mainly the adrenal cortex and the white matter of the nervous system (32). It is associated with the accumulation of saturated very long chain fatty acids (mainly C26:0, C25:0, and C24:O) in the cholesterol esters and gangliosides in these tissues (1 1, 17, 30). Accumulation of these same fatty acids has also been reported in sphingomyelin and other lipid moieties of plasma (23) and red blood cells (38) and in cultured skin fibroblasts (22), cultured muscle cells (I), and cultured amniocytes (24).Several types of ALD have been described. The most common type is the childhood form (32) that usually p...

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Section: Resultsmentioning

confidence: 86%

Adrenoleukodystrophy: Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes

et al. 1984

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“…Furthermore, we propose that the same damage has occurred at the interaction site of NADH dehydrogenase with ubiquinone. The abnormally high oxidation state of cytochrome b in the controlled state, as found by Versmold et al (15), might be a secondary consequence of the proposed damage of succinate-Q-oxidoreductase.…”

Section: [14c02]production Rate From [I-14c]-pymvate [U-14c]-malatmentioning

confidence: 75%

“…The findings of a normal cytochrome content in heart muscle mitochrondria as well as in liver mitochondria are in accordance with the suggestion that the defect is located before the oxidative step involving the cytochromes (4). Versmold et al (15) found a decreased cytochrome content (aas, b, and c) in liver mitochondria from a Zellweger-like syndrome patient'who also showed a deficiency of ~eroxisomes in he~atocvtes. The authors concluded that the de-…”

Section: Methodsmentioning

confidence: 98%

Biochemical Studies in the Liver and Muscle of Patients with Zellweger Syndrome

et al. 1983

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SummaryBiochemical studies have been performed in muscle, liver, leukocytes, and fibroblasts from patients suffering from the Zellweger syndrome. Oxidation rates of [l-14Cjpyruvate, [U-14Clmalate, and [l-14C12-oxoglutarate were strongly reduced in skeletal muscle homogenate. Oxygen consumption in isolated skeletal muscle mitochondria could only be stimulated by ADP in the presence of ascorbate and N,N,N1,N1-tetramethyl-p-phenylenediamine. Cytochrome contents in heart muscle and liver mitochondria were normal. A very low activity of succinate-ubiquinone oxidoreductase was found in liver homogenate of two patients. From the effect of 2-thenoyltrifluoroacetone on the succinate-phenazine methosulhate oxidoreductase activitv, a nearlv com~etitive inhibition with " . respect to phenazine methosulphate was demonstrated in contrast with a non-competitive inhibition in controls. Normal oxidation rate of 11-14Clpyruvate and 12-14Clpyruvate was found in leucocytes and fibroblasts. Lactate and pyruvate levels were normal in serum and cerebrospinal fluid and P-hydroxybutyrate and acetoacetate levels were normal in blood. The ratios lactate/pyruvate and Phydroxybutyrate/acetoacetate were normal as well. These findings point to a defect in the electron transport chain at the succinateubiquinone oxidoreductase level. This defect might be related to the absence of peroxisomes in the cells of Zellweger patients.

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“…DiMauro et al (1980) described deficiencies of cytochrome oxidase in both skeletal muscle and kidney associated with hypercalcaemia, lactic acidaemia and a generalized aminoaciduria. Deficiences of cytochrome oxidase have also been reported in the cerebro-hepato-renal syndrome (Versmold et al, 1977).…”

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confidence: 95%