Disturbances in bile acid metabolism of infants with the Zellweger (cerebro-hepato-renal) syndrome

Monnens, L.A.H.; Bakkeren, J. A. J. M.; Parmentier, G.; Janssen, G.; Haelst, U. van; Trijbels, Frans J.M.; Eyssen, H.

doi:10.1007/bf00444751

Cited by 65 publications

(36 citation statements)

References 14 publications

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“…The significance of this 1973 find ing was not fully appreciated until it was shown that Zellweger patients had deficient activities of three sets of enzymes that had been localized to the peroxisome. These en zymes control certain steps in the synthesis of plasmalogens [50][51][52][53], oxidation of very long chain fatty acids [54] and certain steps in bile acid synthesis [55][56][57]. The consonance of the morphological (absence of peroxisome) and biochemical (deficient activities of peroxi somal enzymes) led to the realization that the Zellweger syndrome is a model of the effects of a lack of this subcellular organelle.…”

Section: Generalized Peroxisomal Disordersmentioning

confidence: 99%

New Approaches in Peroxisomal Disorders

Moser

1987

Dev Neurosci

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The peroxisome is a subcellular organelle with important functions in plants and protozoa, which during the last decade has also been shown to have a role in mammalian lipid and amino acid metabolism. These functions include steps in the synthesis of ether lipids and bile acids and fatty acid beta-oxidation, particularly those of very long chain fatty acids. The proposition that the peroxisome carries out significant functions in man is highlighted by the fact that lack of this organelle is associated with severe abnormalities in many human organs. Human peroxisomal disorders are now grouped into three general categories. In the first group, peroxisomes are lacking or reduced in number. This group includes the Zellweger cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum''s disease and hyperpipecolic acidemia. These patients lack the capacity to synthesize ether lipids and to oxidize very long chain fatty acids or phytanic acid, and they show abnormally high levels of pipecolic acid and bile acid intermediates. These patients rarely survive early childhood, have severe neurological deficits and multiple malformations. A second group includes the ''pseudo-Zellweger'' syndrome and the rhizomelic form of chondrodysplasia punctata. Here the peroxisomal structure is intact, but there is deficient function of several peroxisomal enzymes. The third group includes X-linked adrenoleukodystrophy, acatalasemia and ''adult'' Refsum''s disease. The peroxisomal structure is intact, and the defect in each instance is thought to involve a mutation which affects a single peroxisomal enzyme. Peroxisomal disorders are of current interest because they occur more commonly than had been recognized and show phenotypic and genotypic heterogeneity. Their study provides the opportunity to learn more about the role of the peroxisome in normal brain function and development.

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Section: Generalized Peroxisomal Disordersmentioning

confidence: 99%

New Approaches in Peroxisomal Disorders

Moser

1987

Dev Neurosci

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“…It is characterized by a reduced number or absence of peroxisomes (3) and regarded as the prototype of peroxisomal deficiency disorders. Multiple peroxisomal biochemical processes are defective, including @-oxidation of very long chain fatty acids (4), phytanic acid oxidation (5,6), pipecolic acid oxidation (7), plasmalogen biosynthesis (8), and bile acid metabolism (9).…”

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confidence: 99%

The 22-kD Peroxisomal Integral Membrane Protein in Zellweger Syndrome—Presence, Abundance, and Association with a Peroxisomal Thiolase Precursor Protein

et al. 1991

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ABSTRACT. The primary genetic defect of Zellweger syndrome may be related to defective synthesis or impaired import of peroxisomal proteins. We analyzed the presence and measured the abundance of the 22-kD peroxisomal integral membrane protein (PMP) in patients with Zellweger syndrome. We determined the intracellular localization of the 22-kD PMP and compared it with the localization of a peroxisomal 44-kD thiolase precursor protein.The 22-kD P M P was quantified by immunoblot analyses in liver tissue (n = 7 patients). Immunoblot signals were evaluated using transmission photometry. The intracellular localization of the 22-kD P M P and the peroxisomal 44-kD thiolase precursor protein were determined by immunoblot analyses on fibroblast subcellular fractions prepared by Nycodenz (n = 5 patients) or sucrose density gradient centrifugation (n = 2 patients). The 22-kD P M P was present and associated with membrane fractions in all patients. Its abundance varied in patients as compared with normal human liver controls. The 22-kD P M P was located in subcellular membrane fractions having a lower density than normal peroxisomes or mitochondria. Using two different gradient techniques, the 22-kD P M P and the peroxisomal 44-kD thiolase precursor protein were found in the same low-density gradient fractions. These results suggest that in Zellweger syndrome peroxisome-like elements containing both the 22-kD P M P and a 44-kD thiolase precursor protein are formed.

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“…Zellweger syndrome is also characterized by an increased urinary excretion of trihydroxycoprostanic acid and dihydroxycoprostanic acid (6,9).…”

Section: Patientsmentioning

confidence: 99%

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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Disturbances in bile acid metabolism of infants with the Zellweger (cerebro-hepato-renal) syndrome

Cited by 65 publications

References 14 publications

New Approaches in Peroxisomal Disorders

New Approaches in Peroxisomal Disorders

The 22-kD Peroxisomal Integral Membrane Protein in Zellweger Syndrome—Presence, Abundance, and Association with a Peroxisomal Thiolase Precursor Protein

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

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