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R J Wanders

Publications and source records attributed to R J Wanders.

At least 415 records · Page 23Linked to original sources
PubMed1989

Prenatal and perinatal diagnosis of peroxisomal disorders.

Peroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified into three groups: (1) disorders of peroxisome biogenesis with a generalized loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidaemia); (2) disorders with a loss of multiple peroxisomal functions (rhizomelic chondrodysplasia punctata and Zellweger-like syndrome; (3) disorders with loss of a single peroxisomal function (X-linked adrenoleukodystrophy, peroxisomal thiolase deficiency, bifunctional protein deficiency, acyl-CoA oxidase deficiency, classic Refsum disease, hyperoxaluria type I and acatalasaemia). Prenatal diagnosis is indicated in all these genetic disorders with the exception of classic Refsum disease, most types of hyperoxaluria type I and acatalasaemia. A variety of techniques is available now for the prenatal diagnosis of peroxisomal disorders in the first or second trimester of gestation. Prenatal diagnosis was performed by us in 70 pregnancies at risk for a disorder of peroxisome biogenesis, three for rhizomelic chondrodysplasia punctata, four for X-linked adrenoleukodystrophy and two for a defect in peroxisomal beta-oxidation. Fourteen affected fetuses were identified; no false negative cases were obtained.

Female↗
PubMed1989

Deficient oxidation of trihydroxycoprostanic acid in liver homogenates from patients with peroxisomal diseases.

The activation of palmitate and trihydroxycoprostanic acid and the peroxisomal oxidation of palmitate, trihydroxycoprostanic acid and their CoA esters were measured in homogenates prepared from fresh liver tissue of patients undergoing hepatic surgery and from frozen postmortem liver specimens of controls, patients with Zellweger syndrome and a patient with pseudo-Zellweger syndrome, a deficiency of peroxisomal 3-oxoacyl-CoA thiolase. In contrast to the findings in control livers, peroxisomal beta-oxidation of palmitate and of palmitoyl-CoA was severely impaired, and oxidation of trihydroxycoprostanic acid and its CoA ester could not be detected in the livers of the patients affected by peroxisomal diseases. The finding in this paper, that the oxidation of trihydroxycoprostanoyl-CoA can be measured reliably in small amounts of human liver, will be of valuable help in the differential diagnosis and classification of peroxisomal disorders and will help to elucidate the exact nature of some of the defects present in these disorders.

Acetyl-CoA C-Acetyltransferase↗
PubMed1989

Studies on the formation of lactate and pyruvate from glucose in cultured skin fibroblasts: implications for detection of respiratory chain defects.

We investigated the time course of the formation of lactate and pyruvate from glucose in cultured skin fibroblasts from controls, from a patient with a cytochrome c oxidase deficiency and from controls treated with inhibitors of the individual respiratory chain complexes. Fibroblasts from the patient and inhibitor treated fibroblasts produced more lactate and less pyruvate; this resulted in a significant increase in the lactate to pyruvate ratio, reflecting an increased cytosolic NADH/NAD+ redox state. We conclude that measurement of lactate and pyruvate production from glucose in cultured skin fibroblasts can be of value in the diagnosis of inherited diseases of the mitochondrial respiratory chain.

Cells, Cultured↗
PubMed1989

[X-linked adrenoleukodystrophy and other peroxisomal diseases caused by a failing peroxisomal beta-oxidation system: clinical expression, diagnosis and treatment].

X-linked adrenoleukodystrophy (ALD) is a sex-linked, neurodegenerative disorder which in its most stereotypic form manifests itself in a boy who progresses normally for the first years of life and then presents with CNS signs and symptoms such as behavioural abnormalities, visual and auditory disturbances and an abnormal gait. The course of the disease is progressive, culminating within a few years in dementia, blindness, quadriplegia and death. Recently it has become clear that ALD is caused by an impairment in the peroxisomal beta-oxidation system leading to the accumulation of very-long-chain fatty acids. Accumulation occurs not only in plasma but also in brain giving rise to increasing myelin instability and subsequent demyelination. Apart from X-linked ALD there are a number of other disorders all characterized by a deficient peroxisomal beta-oxidation activity. It is remarkable that the clinical presentation of these different inborn errors of peroxisomal beta-oxidation differs markedly. In this paper the inborn errors of peroxisomal beta-oxidation known at present will be discussed with particular emphasis on ALD.

Adrenoleukodystrophy↗
PubMed1988

Sigmoidal relation between mitochondrial respiration and log ([ATP]/[ADP])out under conditions of extramitochondrial ATP utilization. Implications for the control and thermodynamics of oxidative phosphorylation.

Except for close to state 3, mitochondrial respiration has been observed to vary almost linearly with the extramitochondrial phosphorylation potential. For the understanding of the control, thermodynamics, and stoichiometries of oxidative phosphorylation, it is important if this linearity corresponds to an extension of a near-equilibrium flow-force relationship. Using three methods to determine the extramitochondrial ATP/ADP ratio, we observed that at high ATP/ADP ratios the relationship between respiratory rate and log (ATP/ADP) deviated in a sigmoidal fashion from linearity, if the amount of hexokinase present was modulated. In a titration with uncoupler, the sigmoidicity at high ATP/ADP ratios was absent. This difference between the flow-force relationships of these two experiments suggests that the sigmoidicity in the former case reflects a nonproportional flow-force relationship of the adenine nucleotide translocator. In the latter case, one measures the flow-force relationship of the redox-driven proton pumps alone, which turns out to be virtually linear. We determined the flow-force relation of the adenine nucleotide translocator for two ways of varying the force and confirmed the sigmoidicity in both cases. The implication is that the near-linearity of the flow-force relationships at intermediary respiratory rates does not correspond to an Onsager-type (near equilibrium) linearity. We discuss that this phenomenon requires the application of nonclassical forms of nonequilibrium thermodynamics and may be responsible for some of the control over oxidative phosphorylation that is exerted by the cytosolic ATP consuming processes.

Adenosine Diphosphate↗
PubMed1988

Identification of L-pipecolate oxidase in human liver and its deficiency in the Zellweger syndrome.

The ability of human liver to oxidize L-pipecolic acid was investigated. Liver from control subjects was found to contain L-pipecolic acid oxidase, an H2O2-producing enzyme not previously demonstrated in mammals. In livers from patients with the cerebro-hepato-renal syndrome of Zellweger, a genetic disease characterized by the absence of morphologically distinguishable peroxisomes, L-pipecolic acid oxidase was found to be deficient. These results indicate that L-pipecolic acid oxidase is a peroxisomal enzyme in man and provide an explanation for the fact that elevated levels of L-pipecolic acid are found in body fluids of patients with the Zellweger syndrome.

Acyltransferases↗
PubMed1988

Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids.

A method was developed to prepare peroxisome-enriched fractions depleted of microsomes and mitochondria from cultured skin fibroblasts. The method consists of differential centrifugation of a postnuclear supernatant followed by density gradient centrifugation on a discontinuous Metrizamide gradient. The activity of hexacosanoyl-CoA synthetase was subsequently measured in postnuclear supernatants and peroxisome-enriched fractions prepared from cultured skin fibroblasts from control subjects and patients with X-linked adrenoleukodystrophy. Whereas the hexacosanoyl-CoA synthetase activity in postnuclear supernatants of X-linked adrenoleukodystrophy fibroblasts was only slightly decreased (77.8 +/- 4.4% of control (n = 15], enzyme activity was found to be much more markedly reduced in peroxisomal fractions isolated from the mutant fibroblasts (19.6 +/- 6.7% of control (n = 5]. This is a direct demonstration that the defect in X-linked adrenoleukodystrophy is at the level of a deficient ability of peroxisomes to activate very long chain fatty acids, as first suggested by Hashmi et al. [Hashmi, M., Stanley, W. and Singh, I. (1986) FEBS Lett. 86, 247-250].

Adrenoleukodystrophy↗
PubMed1988

Kinetics of the assembly of peroxisomes after fusion of complementary cell lines from patients with the cerebro-hepato-renal (Zellweger) syndrome and related disorders.

We have recently identified four complementation groups in fibroblasts from patients deficient in peroxisomes. Here we describe a kinetic analysis of the complementation process. The kinetics of peroxisome assembly was assessed in heterokaryons of complementary cell lines by measuring the rate of incorporation of catalase, initially present in the cytosol, into particles. In two combinations of cell lines assembly was rapid and insensitive to cycloheximide. Thus the components required for peroxisome assembly must have been present in the parental cell lines, at least one of which presumably contained peroxisomal ghosts. In three other combinations of cell lines assembly of peroxisomes was slow and sensitive to cycloheximide.

Brain Diseases↗
PubMed1988

3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method.

In this paper we studied the properties of 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) in human skin fibroblasts. The enzyme was found to exhibit an absolute requirement for divalent cations such as magnesium. Furthermore, dithiothreitol was necessary for full activity. The enzyme was found to be maximally active at pH 9.25. When measured at this pH in the presence of magnesium and dithiothreitol enzyme activity was high enough to be determined by simple spectrophotometry by measuring the amounts of acetoacetate produced. The results obtained suggest that the large variation in the values reported in literature for the activity of HMG-CoA lyase in human skin fibroblasts is due to the fact that the enzyme shows little activity at pH values below 8.

Fibroblasts↗