1/12. Enhanced expression of a-series gangliosides in fibroblasts of patients with peroxisome biogenesis disorders.Peroxisome biogenesis disorders (PBD) are classified into zellweger syndrome (ZS), infantile refsum disease (IRD) and neonatal adrenoleukodystrophy. Disturbances in the differentiation of neural cells such as migration arrest are characteristic of PBD. So far the pathogenesis of these disturbances is not clearly understood. We describe an altered metabolism of glycosphingolipids in PBD which has not yet been investigated. We observed an increased amount of a-series gangliosides, GM2, GM1 and GD1a, in the fibroblasts of patients with ZS and IRD. gangliosides GM1 and GD1a were not present in detectable amounts in normal subjects. A key step in the synthesis of a-series gangliosides is a transfer of GalNAc to ganglioside GM3, so we determined the level of ganglioside GM3 by immunohistochemical methods. We found a granular structure, which was positive toward anti-ganglioside GM3 antibody in the cytoplasm of the patients' fibroblasts. In control cells, the cell membrane was slightly positive toward anti-GM3 antibody. These results may help to clarify the pathogenesis of PBD with respect to the functional roles of glycosphingolipids in cell differentiation, proliferation and apoptosis.- - - - - - - - - - ranking = 1keywords = adrenoleukodystrophy (Clic here for more details about this article) |
2/12. pathology of hepatic peroxisomes and mitochondria in patients with peroxisomal disorders.The morphology of hepatic peroxisomes in five patients with metabolic disorders believed to be due to inherited defects of peroxisomal function or biogenesis is described. Electron microscopy and cytochemical staining for catalase were used to identify peroxisomes in two boys with infantile Refsum's disease (IRD), a girl with autopsy confirmed neonatal adrenoleukodystrophy (NALD), and two boys with pseudo-zellweger syndrome (PZS). In the patients with IRD and NALD hepatic peroxisomes were significantly reduced in size and number and contained electron dense centres. In the liver of the patients with PZS the peroxisomes were enlarged. Morphologically abnormal peroxisomes were also detected in autopsy tissue from one boy with PZS using electron microscopy. Lamellar-lipid inclusions and mitochondria with crystalline inclusions and/or abnormal cristae are also described in two patients, one with IRD, the other with NALD.- - - - - - - - - - ranking = 1keywords = adrenoleukodystrophy (Clic here for more details about this article) |
3/12. glyceryl ethers in peroxisomal disease.1-O-Alkyl and 1-O-alk-1-enyl (plasmalogens) glyceryl ether lipid levels were measured in post-mortem brain and/or liver biopsies from 7 patients with ultrastructural and biochemical evidence of a defect in peroxisomal biogenesis and/or enzymological evidence of a disturbance in ether lipid synthesis. Near normal levels of both species of glyceryl ether lipids were found in neonatal adrenoleukodystrophy and infantile Refsum's disease but marked deficiencies were found in Zellweger's syndrome and rhizomelic chondrodysplasia punctata, the latter manifesting the most profound reduction in ether lipid levels. These observations suggest that little ether lipid biosynthesis occurs in vivo in rhizomelic chondrodysplasia punctata or Zellweger's syndrome. However, in some phenotypes with apparently gross reductions in peroxisomal numbers, e.g. neonatal adrenoleukodystrophy and infantile Refsom's disease, there is significant ether lipid synthesis in liver and brain.- - - - - - - - - - ranking = 2keywords = adrenoleukodystrophy (Clic here for more details about this article) |
4/12. Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease: plasma changes and skin fibroblast phytanic acid oxidase.Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease patients can be divided into at least five distinct groups, according to the nature of their plasma changes and their fibroblast phytanic acid oxidase activities. The biochemical changes in the plasma vary from an increase in a single metabolite or group of structurally related metabolites, such as in X-linked adrenoleukodystrophy (ALD) and classical Refsum's disease, to an increase in a number of structurally distinct metabolites, as in neonatal ALD/zellweger syndrome, and infantile Refsum's disease. All patients, with the exception of those with the X-linked form of adrenoleukodystrophy are deficient in phytanic acid oxidase activity. The great similarity observed in neonatal adrenoleukodystrophy/zellweger syndrome and infantile Refsum's disease suggests that the basic biochemical lesion in each may be similar or at least closely related.- - - - - - - - - - ranking = 8keywords = adrenoleukodystrophy (Clic here for more details about this article) |
5/12. Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia: studies in four children.We describe a relatively new syndrome in four children with characteristic facial dysmorphism, sensorineural hearing loss, severe visual impairment with retinitis pigmentosa, hypotonia, hepatomegaly, and severe developmental delay. Two patients had intracranial hemorrhage secondary to a vitamin k-responsive clotting defect; both had steatorrhea. Liver biopsy specimens in two children showed an accentuated lobular architecture with prominent fibrous bands in the portal area. In one, the ultrastructure showed accumulation of abnormal substances and occasional trilaminar structures in hepatocytes and other cells. All four patients had elevated serum phytanic acid concentrations (0.3 to 2.7 mg/dl, normal less than 0.2 mg/dl) and deficient fibroblast phytanic acid oxidase activity (0.1 to 6.7 pmol/mg protein/hr, normal 23 to 87 pmol/mg protein/hr). serum pipecolic acid was 7 to 55 times normal, and the ratio of C26/C22 very long chain fatty acids was increased (0.10 to 0.22; normal less than 0.03). This characteristic syndrome has been described in several children and called infantile refsum disease or phytanic acid storage disease. Its relationship to neonatal adrenoleukodystrophy, hyperpipecolic acidemia, and zellweger syndrome is discussed.- - - - - - - - - - ranking = 1keywords = adrenoleukodystrophy (Clic here for more details about this article) |
6/12. Peroxisomal very long-chain fatty acid beta-oxidation in human skin fibroblasts: activity in zellweger syndrome and other peroxisomal disorders.Since very long-chain fatty acids with a chain length of 24 carbons or more are known to accumulate in tissues and body fluids from patients with the cerebrohepato-renal (Zellweger) syndrome, infantile refsum disease, neonatal adrenoleukodystrophy and X-linked adrenoleukodystrophy, we studied very long-chain fatty acid oxidation in cultured skin fibroblasts from these patients. In this paper, we report that in accordance with earlier results the first step in the beta-oxidation of the very long-chain fatty acid lignoceric acid (C24:0) primarily occurs in peroxisomes in control human skin fibroblasts. Furthermore, it was found that peroxisomal lignoceric acid beta-oxidation was strongly deficient in fibroblasts from patients with zellweger syndrome, infantile Refsum disease, neonatal and X-linked adrenoleukodystrophy, which explains for the accumulation of very long-chain fatty acids in all four disease entities. In zellweger syndrome, infantile refsum disease and neonatal adrenoleukodystrophy the impairment in peroxisomal very long-chain fatty acid beta-oxidation is probably caused by a strong deficiency of all peroxisomal beta-oxidation enzyme proteins due to a deficiency of peroxisomes.- - - - - - - - - - ranking = 4keywords = adrenoleukodystrophy (Clic here for more details about this article) |
7/12. Infantile refsum disease: an inherited peroxisomal disorder. Comparison with zellweger syndrome and neonatal adrenoleukodystrophy.Three patients affected by infantile refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile refsum disease, neonatal adrenoleukodystrophy or zellweger syndrome who survived for several years. attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to zellweger syndrome.- - - - - - - - - - ranking = 7keywords = adrenoleukodystrophy (Clic here for more details about this article) |
8/12. Infantile Refsum's disease: a generalized peroxisomal disorder. Case report with postmortem examination.Infantile Refsum's disease (IRD) is a peroxisomal deficiency disease which is closely related to neonatal adrenoleukodystrophy (NALD) and the zellweger syndrome (ZS). Recent observations suggest that NALD and ZS are separate genetic disorders but the delimitation towards IRD remains uncertain. We present here the first autopsy report of a patient who was clinically and biochemically diagnosed as having IRD, and we compare the findings with those from NALD and ZS. The main gross and microscopic findings comprised micronodular liver cirrhosis, small hypoplastic adrenals without degenerative changes, and large groups of lipid macrophages in liver, lymph nodes and certain areas of the cerebral white matter. The brain showed no malformations except for a severe hypoplasia of the cerebellar granule layer and ectopic location of the purkinje cells in the molecular layer. A mild and diffuse reduction of axons and myelin was found in the corpus callosum and periventricular white matter, the corticospinal tracts, and the optic nerves. Large numbers of perivascular macrophages were present in the same areas but there was no active demyelination. The retina and cochlea showed severe degenerative changes. peripheral nerves, skeletal system and kidneys were normal. Electron microscopy showed characteristic cytoplasmic inclusions with bilamellar profiles in macrophages in the liver, lymph nodes and brain but not in the adrenals. Similar inclusions were found in liver cells and astrocytes. The findings differ from ZS which shows cortical renal cysts, skeletal changes, liver changes, cerebral micropolygyria, neuronal heterotopias, and demyelination of the white matter. Cases with NALD show mild cerebral malformations, active demyelination, degenerative changes of the adrenals, liver changes, and bilamellar electromicroscopic inclusions in macrophages. Our cases thus resembled NALD but lacked active demyelination, cerebral cortical malformations and adrenal degenerative changes. Further autopsy studies will be necessary to determine whether these changes are consistent findings in IRD.- - - - - - - - - - ranking = 1keywords = adrenoleukodystrophy (Clic here for more details about this article) |
9/12. Peroxisomal integral membrane proteins in livers of patients with zellweger syndrome, infantile Refsum's disease and X-linked adrenoleukodystrophy.Livers from seven patients with peroxisome disorders, three with zellweger syndrome, one with infantile Refsum's syndrome and three with X-linked adrenoleukodystrophy, were analysed by immunoblotting. The bifunctional protein catalysing two peroxisomal beta-oxidation reactions was deficient in all Zellweger livers and in the infantile Refsum's liver, consistent with the absence of morphologically recognizable peroxisomes. Three peroxisomal integral membrane proteins (IMPs) (69, 53 and 22 kDa) were present in normal amounts in all the Zellweger and adrenoleukodystrophy samples and they sedimented in a membrane fraction. These membrane proteins were also present in the infantile Refsum's liver. We suggest, on the basis of these results, that aberrant peroxisomal membranes may be present in zellweger syndrome and that the defect is in the transport of matrix proteins into the organelle.- - - - - - - - - - ranking = 6keywords = adrenoleukodystrophy (Clic here for more details about this article) |
10/12. Plasma and skin fibroblast C26 fatty acids in infantile Refsum's disease.In infantile and adult Refsum's disease, the activity of phytanic acid oxidase is low in skin fibroblasts, but plasma phytanic acid levels are high. Cultured skin fibroblasts and plasma from patients with the infantile, but not the adult, disorder show marked increases in the concentration of the long-chain fatty acid, hexacosanoic acid (C26), a feature once thought pathognomonic of adrenoleukodystrophy or Zellweger's syndrome.- - - - - - - - - - ranking = 1keywords = adrenoleukodystrophy (Clic here for more details about this article) |
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