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R J Wanders

Publications and source records attributed to R J Wanders.

At least 397 records · Page 22Linked to original sources
PubMed1990

The inborn errors of peroxisomal beta-oxidation: a review.

In recent years a growing number of inherited diseases in man have been recognized in which there is an impairment in peroxisomal beta-oxidation. In some diseases this is due to the (virtual) absence of peroxisomes leading to a generalized loss of peroxisomal functions including peroxisomal beta-oxidation. In most inborn errors of peroxisomal beta-oxidation, however, peroxisomes are normally present and the impairment in peroxisomal beta-oxidation is due to the single or multiple loss of peroxisomal beta-oxidation enzyme activities. In all these disorders there is accumulation of very-long-chain fatty acids in plasma, which allows biochemical diagnosis of patients affected by an inborn error of peroxisomal beta-oxidation to be done via gas-chromatographic analysis of plasma very-long-chain fatty acids. Subsequent enzymic and immunological investigations are required to identify the precise enzymic defects in these patients. In all inborn errors of peroxisomal beta-oxidation known today there are multiple abnormalities, especially neurological with death usually occurring in the first decade of life. Prenatal diagnosis of these disorders has recently become possible.

Fatty Acids↗
PubMed1990

Excessive urinary oxalate excretion after combined renal and hepatic transplantation for correction of hyperoxaluria type 1.

A 4.5-year-old boy received a combined liver and kidney transplant for correction of hyperoxaluria type 1. Both organs were from the same donor and functioned primarily. Three months after transplantation, urine oxalate excretion reached a maximum of 10,500 mumol/24 h and remained above 2300 mumol/24 h for the next 2 months. Two months later, oxalate excretion decreased to about 565 mumol/24 h, indicating exhaustion of a large oxalate pool. Six months after transplantation plasma oxalate is near normal (4.9 mumol/l). With the exception of one episode of acute rejection of the renal transplant, both organs were tolerated well and continue to have a unimpaired function 9 months after transplantation. However, there is increased echogenity on renal ultrasound, indicating oxalate deposits in the grafted kidney. This case illustrates that successful combined transplantation of both liver and kidney can be performed in infants, resulting in cure of the metabolic defect. The prolonged or acute excretion of oxalate may lead to oxalate deposition in the grafted kidney without impaired graft function or early graft loss.

Child, Preschool↗
PubMed1990

Peroxisomal beta-oxidation defect with detectable peroxisomes: a case with neonatal onset and progressive course.

A progressive demyelinating cerebral disorder is described in a normally-appearing female infant with neonatal seizures, progressive psychomotor deterioration, deafness, retinopathy, peripheral neuropathy and loss of myelin observed on magnetic resonance imaging (MRI) scanning. MRI also showed the absence of macroscopic neocortical dysplasia which is usually found in Zellweger syndrome (ZS). Adrenal cortical function was normal. The patient died at the age of 37 months. Extensive biochemical investigations of peroxisomal functions in the patient revealed an impairment of peroxisomal beta-oxidation resulting in elevated levels of very long (greater than C22) chain fatty acids in plasma and fibroblasts. Moreover, elevated plasma levels of intermediates of bile acid biosynthesis such as tri- and dihydroxycholestanoic acid were found. Other peroxisomal functions were normal. Immunoblotting of the peroxisomal beta-oxidation enzyme proteins in liver from the patient revealed normal responses with antisera against acyl-CoA oxidase, bifunctional protein and thiolase respectively. From these data we conclude that the patient had a deficiency of a single peroxisomal beta-oxidation enzyme at the level of either the bifunctional protein or peroxisomal thiolase with retained immunoreactivity against these enzymes.

Demyelinating Diseases↗
PubMed1990

Infantile phytanic acid storage disease, a disorder of peroxisome biogenesis: a case report.

The infantile and classic forms of phytanic acid storage disease belong to the newly recognized group of peroxisomal disorders. In this paper we report the full clinical, morphological and biochemical results in a patient with infantile phytanic acid storage disease. The results indicate a generalized loss of peroxisomal functions due to a deficiency of peroxisomes as demonstrated in hepatocytes and cultured skin fibroblasts.

Acyl Coenzyme A↗
PubMed1990

Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.

The rhizomelic form of chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized biochemically by an impairment of plasmalogen biosynthesis and phytanate catabolism. We have now found that the maturation of peroxisomal 3-oxoacyl-CoA thiolase is impaired in fibroblasts from RCDP patients. To establish the subcellular localization of the 3-oxoacyl-CoA thiolase precursor protein, cultured skin fibroblasts were fractionated on a continuous Nycodenz gradient. Only a small amount of 3-oxoacyl-CoA thiolase activity was present in the catalase-containing (peroxisomal) fractions of RCDP fibroblasts in comparison with control fibroblasts. Moreover, the amount of thiolase protein in immunoblots of the catalase-containing fractions was below the limit of detection. Finally, the beta-oxidation of [14C]palmitoyl-CoA was found to be reduced in these fractions. We conclude that the mutation in RCDP leads to a partial deficiency of 3-oxoacyl-CoA thiolase activity in the peroxisomes and, concomitantly, an impairment in the ability to convert the precursor of this protein to the mature form. The reduction of 3-oxoacyl-CoA thiolase activity results in a decrease in the rate of peroxisomal beta-oxidation of palmitoyl-CoA. However, the capacity of the peroxisomes to oxidize very-long-chain fatty acids must be sufficient to prevent excessive accumulation of these compounds in vivo.

Acetyl-CoA C-Acyltransferase↗
PubMed1990

Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood.

A child presented in early childhood with episodes of coma and hypoglycemia and a rapidly evolutive myopathy and cardiomyopathy leading to death at 9 mo of age. Ketosis was decreased (blood beta-hydroxybutyrate: 0.07 mmol/L) despite normal plasma levels of fatty acids (0.81 mmol/L). The patient's urine contained excessive amounts of the C6 to C10 dicarboxylic acids present in almost all defects of fatty acid mitochondrial oxidation. More specifically, gas chromatography-mass spectrometry identified an accumulation of medium- and long-chain (C8 to C14) 3-hydroxy-dicarboxylic acids, suggesting a defect of the mitochondrial enzyme that normally dehydrogenates these 3-hydroxyacyl-CoA esters. Biochemical studies in the patient's cultured fibroblasts confirmed the impairment of medium- and long-chain fatty acid oxidation, and allowed the recognition of the deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. The activities of long-, medium-, and short-chain acyl-CoA dehydrogenases and 3-ketoacyl-CoA thiolase were normal. These results describe a disorder of fatty acid metabolism that affects the liver, skeletal muscles, and myocardium. It is important to point out that long-chain 3-hydroxyacyl-CoA deficiency shares many clinical similarities with systemic carnitine deficiency, as well as with carnitine-palmityl-CoA transferase and long-chain acyl-CoA dehydrogenase deficiencies. The differential diagnosis of this disease relies on the demonstration of long-chain urinary dicarboxylic acids with a hydroxyl group in 3-position and the study of the enzyme activity in cultured fibroblasts.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1990

Menadione partially restores NADH-oxidation and ATP-synthesis in complex I deficient fibroblasts.

In this paper we report our studies on the effects of menadione in cultured fibroblasts treated with rotenone to block complex I. A normalization of the lactate to pyruvate ratio after incubation with glucose, an increased production of 14CO2 from [6-14C]glucose and an increased intra-cellular concentration of ATP was observed in the presence of micromolar concentrations of menadione. These results not only demonstrate the potential value of menadione in complex I deficient patients but also suggest that this system can be used advantageously for the in vitro assessment of therapeutic agents for disorders of the mitochondrial respiratory chain.

Adenosine Triphosphate↗
PubMed1990

Genetic relationship between the Zellweger syndrome and other peroxisomal disorders characterized by an impairment in the assembly of peroxisomes.

The peroxisomal diseases can be divided into three categories: 1) diseases in which morphologically distinguishable peroxisomes are virtually absent (Zellweger syndrome; infantile Refsum disease; Hyperpipecolic Acidaemia; neonatal Adrenoleukodystrophy); 2) diseases in which peroxisomes are present but several peroxisomal functions are impaired (rhizomelic Chondrodysplasia punctata; Zellweger-like syndrome?); and 3) diseases in which a single peroxisomal function is impaired. We have used complementation analysis after somatic cell fusion in order to investigate the genetic relationship between diseases in category 1. The activity of acyl-CoA: dihydroxyacetonephosphate acyltransferase, which is deficient in these diseases and in rhizomelic Chondrodysplasia punctata, was used as an index of complementation. The cell lines studied, all of which complemented with rhizomelic Chondrodysplasia punctata, could be divided into at least 4 and possibly 5 complementation groups. This indicates that at least 5 and possibly 6 genes are involved in the assembly of peroxisomes. One of the complementation groups is comprised of cell lines from patients with the Zellweger syndrome, infantile Refsum disease and Hyperpipecolic Acidaemia. Thus mutations in the same gene can lead to clinically distinguishable diseases. On the other hand, the Zellweger cell lines studied fall into 3 complementation groups and the infantile Refsum disease cell lines into 2 groups. Thus mutations in different genes can lead to the same clinical phenotype. Fusion of complementary cell lines lacking morphologically distinguishable peroxisomes leads to assembly of peroxisomes, which can be monitored by measuring particle-bound catalase biochemically or by immunofluorescence. In two combinations of cell lines assembly of peroxisomes was rapid and cycloheximide insensitive. Thus the components required for peroxisome assembly must be present in a stable form in the parental cell lines, at least one of which must contain peroxisomal ghost-like structures.

Alleles↗
PubMed1989

L-pipecolate oxidase: a distinct peroxisomal enzyme in man.

We investigated the oxidation of L-pipecolate in human liver. The results obtained with L-pipecolate from which traces of D-pipecolate had been removed by a preincubation with D-aminoacid oxidase indicate that a distinct L-pipecolate oxidase rather than D-aminoacid oxidase is responsible for the L-pipecolate dependent H2O2-production in human liver. Importantly, L-pipecolate oxidase was found to be localized in peroxisomes which adds to the growing number of enzymes and metabolic functions which can be ascribed to peroxisomes.

Animals↗