Long survival in a case of peroxisomal biogenesis disorder with peroxisome mosaicism in the liver.
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Child↗
Biomedical subjects
F Roels
Publications and source records attributed to F Roels.
Isolated dihydroxyacetonephosphate-acyl-transferase deficiency in rhizomelic chondrodysplasia punctata: clinical presentation, metabolic and histological findings.
UNLABELLED: Rhizomelic chondrodysplasia punctata (RCDP) is clinically characterized by symmetrical shortening of the proximal limbs, contractures of joints, a characteristic dysmorphic face, and cataracts. In the classical form an impairment of several peroxisomal functions and enzymes (plasmalogen synthesis, phytanic acid oxidation, 3-oxoacyl-CoA thiolase) has been repeatedly shown. Recently a variant involving only the peroxisomal dihydroxyacetonephosphate acyltransferase (DHAP-AT) has been described. We present a patient with isolated DHAP-AT deficiency and all clinical, radiological and pathological features of classical RCDP. For the first time, microscopy and immunocytochemistry of hepatocytes could be performed. CONCLUSION: In contrast to studies on classical rhizomelic chondrodysplasia punctata which have shown enlarged peroxisomes in numbers varying from hepatocyte to hepatocyte, the peroxisomes in our patient seem to be normal in size, number and shape.
Acyltransferases↗
Hyperoxaluria with hyperglycoluria not due to alanine:glyoxylate aminotransferase defect: a novel type of primary hyperoxaluria.
Considering the clinical heterogeneity of primary hyperoxaluria type I (PH1) and the fact that in many instances this diagnosis was made without enzymatic and immunohistochemical investigation, other disturbances of oxalate metabolism than those presently known can be expected in PH1. Using a gaschromatographic/mass spectrometric method that allows quantification of these acids, hyperoxaluria and hyperglycoluria was found repeatedly in two unrelated patients. The hyperoxaluria was unresponsive to pyridoxine. There was no nephrocalcinosis or urolithiasis. In the liver biopsy normal AGT activity and normal localization of this enzyme in the peroxisome was found. In one patient abnormal Km and maximal activity and mozaicism of AGT were excluded. Hyperoxaluria and hyperglycoluria were also found in other family members, suggesting autosomal dominant transmission. Although the underlying defect leading to hyperoxaluria and hyperglycoluria could not be identified in these patients, it is probable that they represent a separate type of primary hyperoxaluria.
Alanine Transaminase↗
Subtypes of active cell death in the granulosa of ovarian atretic follicles in the quail (Coturnix coturnix japonica).
Follicular atresia in the ovaries of Japanese quail was studied by cytochemistry and electron microscopy. Three different types of cell death coexisted in the granulosa. A large number of cells showed signs of apoptosis. The DNA fragmentation in these cells was demonstrated in a previous study using in situ end-labeling. A second and non-negligible type of cell death consisted of extensive autophagocytosis of the cytoplasm occurring simultaneously with late nuclear alterations. Finally, a few detached cells displayed cytoplasmic disintegration and small irregular clumps of chromatin condensation indicative of primary cell necrosis. Apoptotic versus autophagic cell death revealed a different pattern of acid phosphatase activity (lysosomal versus cytoplasmic). We propose that these observations may be linked to the existence of distinct subpopulations in the granulosa as has been shown by others. This study confirms the biochemical data on granulosa cell death, but demonstrates that apoptosis is not the exclusive mode of active cell death in follicular atresia.
Acid Phosphatase↗
Severe Smith-Lemli-Opitz syndrome with prolonged survival and lipid abnormalities.
We have studied a girl with multiple congenital anomalies, growth and mental deficiency, characteristic facial anomalies, cataracts, cerebellar atrophy, and severe hypocholesterolemia. Death occurred at age 7 years. After excluding several syndromes, i.e., peroxisomal disorders, mevalonic acidaemia, and Marinesco-Sjögren syndrome, it is concluded that this girl had severe Smith-Lemli-Opitz Syndrome (SLOS) with exceptionally long survival. This diagnosis was confirmed through assay of 7-dehydrocholesterol in cultured fibroblasts.
Abnormalities, Multiple↗
Liver and chorion cytochemistry.
Microscopic visualization of peroxisomes in chorionic villus cytotrophoblast and in biopsy and autopsy samples of liver and kidney, the presence of enlarged liver macrophages containing lipid droplets insoluble in acetone and n-hexane as well as polarizing inclusions formed by stacks of trilamellar sheets are of diagnostic value in peroxisomal disorders. Methods are presented for evaluating these structures by light microscopy; trilamellar inclusions are only detected by electron microscopy. Macrophage features are preserved in archival paraffin blocks. In adrenal cortex, insoluble lipid, polarizing inclusions and trilamellar structures should be looked for. The stains are easily reproducible, and all reagents are commercially available.
Acetone↗
Diagnostic work-up of a peroxisomal patient.
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Clinical Laboratory Techniques↗
Homology between mitochondriogenesis in the avian and amphibian oocyte.
Cytochrome oxidase cytochemistry was used to unequivocally identify the spread of mitochondria during oogenesis in the adult Japanese quail. This enabled us to compare their distribution with the distribution in the Xenopus laevis oocyte (Tourte et al, 1984). In the quail the paranuclear mitochondrial cloud initially disperses homogeneously but afterwards segregates into 2 populations: (i) a population localized in the basophilic cortical layer (surrounding the vegetal pole); and (ii) clusters of mitochondria distributed geometrically around the germinal vesicle in the animal pole. The mitochondria in these clusters have a high cytochrome oxidase activity, which reflects their functionality. This perinuclear crown of mitochondrial clusters actively replicates mtDNA in both animal species and builds up most of the stock of the mitochondria in the full-grown oocyte. Our study suggests that the perinuclear group of mitochondria will segregate in the somatic cells of the future embryo, whilst the original subcortical group will become localized in the primordial germ cells.
Animals↗
Peroxisome mosaicism in the livers of peroxisomal deficiency patients.
Peroxisomal deficiency disorders, which are genetically transmitted, are assumed to be expressed in all cells, and the use of cultured skin fibroblasts for diagnosis and research is based on this assumption. We describe three patients with clinical, biochemical, and microscopic evidence of a peroxisomal disorder. However, their liver displays mosaicism, i.e., parenchymal cells with peroxisomes are adjacent to cells without peroxisomes. Ten percent (volume), 8%, and less than 1% of the parenchyma possessed peroxisomes that can be identified in immunocytochemical tests for six matrix and membrane proteins performed by light and electron microscopy. In the bulk of the parenchyma, catalase is localized in the cytoplasm, and in such cells no peroxisomes are evident by electron microscopy and immunolabeling for the 43-kd peroxisomal membrane protein (PMP) in two patients; in the third case, peroxisomal membrane ghosts are present. Immunoblots of peroxisomal beta-oxidation enzymes show a pattern similar to that from patients with a generalized peroxisomal deficiency. In contrast to the clinical and biochemical signs of peroxisomal dysfunction and hepatic histopathology, cultured fibroblasts from two patients demonstrate normal peroxisomal functions, including very-long-chain fatty acid oxidation and plasmalogen synthesis.
Bile Acids and Salts↗
Immunolocalization of a 43 kDa peroxisomal membrane protein in the liver of patients with generalized peroxisomal disorders.
The presence of peroxisomal membrane ghosts was examined in liver biopsies from eleven patients presenting the clinical and biochemical picture of a generalized peroxisomal disorder (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and variants of these syndromes). A polyclonal antibody raised against the membrane of human liver peroxisomes and recognizing a 43 kDa peroxisomal membrane protein (PMP) was used. In human control liver the antibodies react in a distinct and specific way with the peroxisomal membrane. Two types of organelles with an immunoreactive membrane were identified in the liver parenchymal cells of the patients: organelles containing an electron-dense core and organelles with electron transparent contents. Both types may co-occur in the same patient; in two patients they were found in the same cell. The organelles are rare, and their number varies between patients. The first type possibly corresponds to the previous morphological description of aberrant peroxisomes in the liver of patients with Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The empty looking organelles have not been reported previously in the liver, some of the "empty" organelles seem to be enclosed by a double membrane. Morphometrical analysis in three patients indicated that both types of organelles (corrected mean d-circle 0.271-0.306 micron for the "empty" and the dense core organelles, respectively) are smaller than the peroxisomes in postnatal control liver and in fetal liver. In one patient (infantile Refsum disease) immunoreactive organelles were not detected. The organelles with the electron-dense core were not found in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Automated cytometry of fibre size and spatial distribution in the superficial masseter muscle of the rat at three ages.
An image cytometry program was applied to sections of the superficial masseter muscle of female and male 21-, 42- and 105-day-old rats. Lesser diameter and spatial distribution of more than 6000 muscle fibres were automatically measured in digital images from muscle sections stained for myofibrillar ATPase activity. In this muscle, only type 2A, 2B and 2C fibres were observed. At the three ages and in both sexes, 2A fibres were found to have the largest diameter and were the most frequent (> 54%). In the 21-day-old animals, females presented larger diameters than did males; in contrast, in the 105-day-old animals, the three fibre types were larger in males than in females. At all ages and in both sexes, type 2A occupied 32 to 80% more cross-sectional area than type 2B. Most images (98%) showed a random spatial distribution of their fibre types. All fibre types grew in diameter with age. The coefficient of variation of the diameter was age-independent and remained under 23%. The finding of an age-independent variable could have a practical application: an increase of the coefficient of variation (> 25%) can be considered as pathological, even without a perfect age-matched control.
Aging↗
A new type of peroxisomal disorder with variable expression in liver and fibroblasts.
We describe two siblings, presently 5 and 9 years of age, who had neurodegenerative symptoms after the first year of life. Although they lacked clinical characteristics of a peroxisomal disorder, they had elevated levels of plasma very long chain fatty acids, pipecolic and phytanic acids, and abnormal bile acid intermediates, which suggested a generalized peroxisome deficiency disorder. Immunocytochemical study and electron microscopy of the liver disclosed absence of peroxisomes in approximately 90% of hepatocytes. However, the remaining 10% of the hepatocytes had numerous normal-looking peroxisomes containing catalase activity and catalase antigen. Alanine glyoxylate aminotransferase and the peroxisomal beta-oxidation enzymes acyl-coenzyme A oxidase and 3-ketoacyl coenzyme A thiolase were also present in the organelles. Both cell types were grouped in clusters. In contrast to most of the liver cells, fibroblasts cultured from skin biopsy specimens had normal peroxisomal functions. Thus this defect in peroxisome biogenesis is characterized by variable expression in different tissues (liver vs fibroblasts), as well as within individual cells in the same tissue (liver mosaicism). Awareness of the heterogeneity in tissue expression of peroxisomal disorders could be of critical importance in prenatal diagnosis.
Child↗
A peculiar distribution of peroxisomes in a patient with nodular regenerative hyperplasia of the liver.
In a patient with nodular regenerative hyperplasia of the liver, peroxisomes formed rows along the sinusoidal surface of the parenchymal cells, in contrast to their homogeneous distribution in the normal liver. In some cells, peroxisomes had a perinuclear configuration. Morphometric data were compared to those of seven control livers and revealed normal values of the peroxisomal diameter, axial ratio, volume density, numerical density and surface density. Peroxisomes with cytoplasmic invaginations, protrusions and gastruloid cisternae were rare. Angular profiles were frequently found. The peculiar distribution of the peroxisomes may be linked to the deficient blood supply to the liver in nodular regenerative hyperplasia.
Adult↗
Peroxisomes in liver, heart, and kidney of mice fed a commercial fish oil preparation: original data and review on peroxisomal changes induced by high-fat diets.
Male NMRI mice were fed a diet with 10% w/w Beromegan for up to three weeks. Beromegan is a commercial fish (salmon) oil preparation rich in eicosapentaenoic acid and docosahexaenoic acid. Peroxisomal beta-oxidation capacity, catalase activity, and ultrastructural morphometry of the hepatic peroxisomes were investigated. In myocardium and kidney, catalase activity, peroxisomal staining after catalase cytochemistry, peroxisomal morphology, and morphometry (in myocardium) were evaluated. In liver, we found a significant increase in peroxisomal beta-oxidation, catalase activity, and peroxisomal number already after 3 days of dietary treatment. These changes were more pronounced after 3 weeks. Peroxisomal size was not changed. Positive correlations were found between peroxisomal enzyme activities and the number but not the size of the peroxisomes, and between catalase activity and beta-oxidation capacity. The mean peroxisomal diameter per animal was inversely proportional to catalase activity measured in homogenate. In myocardium, catalase activity was increased with duration of fish oil feeding. Peroxisomal staining, number, and size were also increased when compared to controls. In kidney, no alterations were observed. Our results indicate a beneficial effect of a diet supplemented with fish oil on the peroxisomal metabolism in liver and myocardium; it differs from the changes induced by xenobiotic peroxisome proliferation.
Animals↗
Alterations of hepatocellular peroxisomes in patients with cancer. Catalase cytochemistry and morphometry.
BACKGROUND: Hepatic catalase activity is decreased in patients with malignant diseases, but little is known about the organelles that contain the bulk of catalase: the peroxisomes. METHODS: The authors studied the hepatocellular peroxisomes in patients with malignant diseases by means of catalase cytochemistry, light and electron microscopic study, and morphometry. RESULTS: Under the light microscope, a decrease in catalase staining was observed in 21 of 39 patients with extrahepatic tumors. A peculiar perinuclear concentration of peroxisomes was seen by light microscopic study in 15 of 39 patients and reflected an increase in number in most patients. In one of two hepatoma livers, peroxisomes also showed this perinuclear configuration. Ultrastructural and morphometric analysis of 20 livers of patients with extrahepatic tumors revealed a decreased mean peroxisomal diameter and an increase in number. Electron microscopic study also showed peroxisomes with transparent matrical spots, cytoplasmic invaginations, protrusions, and gastruloid cisternae. In each liver, at least one of these changes was observed. In hepatoma livers, one-third of the peroxisomes revealed empty matrical spots. In one patient, peroxisomes were smaller but more numerous. CONCLUSIONS: Alterations of the peroxisomal compartment are constant findings in the livers of patients with malignant diseases, but individual differences in peroxisomal alterations are frequent.
Adolescent↗
Catalase-negative peroxisomes in human embryonic liver.
Hepatic peroxisomes in human embryos with a menstrual age of 6 and 7 weeks have been examined via catalase cytochemistry. In the younger sample, the organelles show no catalase activity, their matrix being pale and coarsely reticular. In the 7-week specimen, the peroxisome population consists of catalase-positive and catalase-negative organelles. The latter have a morphology identical to that of the 6-week sample and represent 66% of the population. The positive organelles show a pronounced staining heterogeneity. Together with the simultaneous presence of negative organelles, this might reflect the onset of catalase import into the peroxisomes during this period. Catalase heterogeneity excludes a continuous exchange of matrix contents; moreover, interconnections between peroxisomes have not been observed, and no cluster formation occurs. The data therefore also suggest that catalase is imported into individual, preexisting organelles in embryonic liver. The three peroxisomal beta-oxidation enzymes become detectable by immunocytochemistry only later during development. Morphological indications for a rapidly dividing population, such as elongated and/or tailed organelles, have not been observed. Morphometry has revealed that, in these early stages, the organelles are significantly smaller than the peroxisomes of fetal and adult human liver.
Catalase↗
Peroxisomes in liver, kidney and duodenum of nude mice bearing xenografts of human pancreatic adenocarcinomas.
In the liver, kidney and duodenum of nude mice with xenografts of two human pancreatic adenocarcinomas differing in growth rate, catalase activity was assayed and peroxisomes were studied using catalase cytochemistry and light and electron microscopy. Hepatic and duodenal catalase activity were significantly decreased in tumour-bearing mice. Renal catalase activity was unchanged. At light microscopic level, a decrease in peroxisomal staining was evident in all duodenums and most livers of tumour-bearing mice. Only minor changes were observed in the kidneys. Ultrastructural morphometry of the hepatocellular peroxisomes revealed a decrease in size, volume density and surface density only in mice with fast-growing xenografts. These observations indicate that the two pancreatic adenocarcinomas exerted a different effect on the hepatic peroxisomes, and that catalase activity and peroxisomes in liver and duodenum are more affected than in kidney.
Adenocarcinoma↗
Peroxisomes in cirrhosis of the human liver: a cytochemical, ultrastructural and quantitative study.
Hepatocellular peroxisomes in 32 patients with cirrhosis were studied by means of catalase cytochemical and morphometric analysis. Seven normal human livers were used as controls. The severity of the cirrhosis was determined with the Child-Turcotte criteria. Under the light microscope, a decrease in catalase staining was observed in 12 livers. Staining showed a weak inverse correlation with severity of the cirrhotic process. Peroxisomes revealed a perinuclear configuration in 24 patients. Morphometric analysis of peroxisomes was performed on 14 cirrhotic livers and revealed a near doubling of the number of organelles, with a compensatory decrease in mean peroxisomal diameter: no appreciable change in total volume of the peroxisome compartment was found. Cytoplasmic invaginations, protrusions and gastruloid cisternae were sparse. Apparently, peroxisomal proliferation in liver cells appeared early in the cirrhotic process. In all 10 livers with a perinuclear configuration of the peroxisomes that were processed for electron microscopy, a morphometrically confirmed increase in the number of peroxisomes was observed. Peroxisomes frequently showed transparent matrical spots and angular profiles. In two patients nucleoid-containing peroxisomes were observed. Although variation between individual patients was high, peroxisomal changes were observed in each cirrhotic liver. No relationship between morphological or morphometric alterations in peroxisomal compartment on one side and the severity of the disease or the type of cirrhotic nodules on the other side was observed.
Adult↗