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PubMed1987

Pigmentary type of orthochromatic leukodystrophy (OLD): a new case with ultrastructural and biochemical study.

A 34-year-old woman with no family history of orthochromatic leukodystrophy (OLD) developed progressive intellectual deterioration, a frontal syndrome and spastic tetraparesis. She died four years after the onset of the clinical illness. Neuropathological studies included light and electron microscopy of cerebral and nerve biopsies, and a complete postmortem examination. Light microscopy demonstrated OLD with pigmented macrophages and glial cells. Electron microscopy showed electron-dense, membrane-bound intracytoplasmic lamellar inclusions with curved or straight parallel arrangement, or fingerprint pattern, in white matter macrophages, astrocytes and oligodendrocytes. Cortical cells contained lipofuscin which was normal in type and amount. This suggests that the material in white matter glial cells and macrophages is ceroid pigment, however, the distribution is not that seen in ceroid-lipofuscinosis. Similar inclusions have been found in oligodendrocytes in other forms of OLD. Biochemical study did not show evidence of demyelination. Galactolipids were normal. Polyunsaturated fatty acids were decreased. The most striking feature was an increase in plasmalogens.

Adult↗

PubMed1997

Rhizomelic chondrodysplasia punctata-like phenotype in a newborn male with normal peroxisomal function.

A newborn male with the characteristic phenotype of classic rhizomelic chondrodysplasia punctata (RCDP) and with the usual and severe radiographic skeletal abnormalities is described. The parents were young, healthy, and not consanguineous; the mother had not used licit or illicit drugs, alcohol, or tobacco during pregnancy and had not been exposed to radiation or teratogenic chemicals. The clinical phenotype led us to study peroxisomal function. Plasmalogen content in erythrocytes, membrane, and fibroblasts; dihydroxyacetone phosphate acyltransferase (DHAP-AT), alkyldehydroxyaceton phosphate synthetase (a gift from Professor Henk van der Boch, Utrech) in fibroblasts; and phytanic and pristanic acids in plasma showed normal values. Immunocytofluorescence study with antibodies against peroxisomal membrane showed normal organelles. We found no reference in the literature of a case of RCDP with normal peroxisomal functions, but non-CDP has been described with peroxisomal dysfunction. This phenotype (RCDP) may be due to other metabolic error.

Acyltransferases↗

PubMed1991

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.

Adrenoleukodystrophy↗

PubMed1985

Normal myelin composition and phospholipid synthesis in adrenalectomized rats with reduced brain myelin and glycerol 3-phosphate dehydrogenase activity.

The composition of CNS myelin was investigated in rats adrenalectomized at day 14 and killed 7 days later, previously shown to result in a 25% reduction in the amount of bulk-isolated myelin and a 40% decrease in brain glycerol 3-phosphate dehydrogenase activity. The proportions of the major myelin proteins, as well as the specific activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase, were the same in the myelin from both adrenalectomized and control animals. The amount of total phospholipid and the proportions of individual phospholipids were also normal in myelin from the adrenalectomized animals. The amount of nonmyelin phospholipid in whole brain was unchanged by adrenalectomy. Labeling studies carried out 4 days after adrenalectomy of 14-day-old animals showed no change in the synthesis rates of the major myelin phospholipids as compared with the synthesis rate of nonmyelin phospholipids. Furthermore, incorporation of [1,(3)-14C]glycerol into the glycerol moiety of ethanolamine plasmalogen, which requires glycerol 3-phosphate dehydrogenase, was also normal, showing that the reduced oligodendroglial glycerol 3-phosphate dehydrogenase activity following adrenalectomy was not rate-limiting for myelin phospholipid synthesis.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1989

Tellurium-induced neuropathy: metabolic alterations associated with demyelination and remyelination in rat sciatic nerve.

Rats fed a diet containing 1.25% elemental tellurium initiated on postnatal day 20 undergo a transient neuropathy characterized by synchronous demyelination of peripheral nerves. In sciatic nerve, the extent of demyelination was maximal after 5 days of tellurium exposure; there was a loss of 25% of the myelin, as assayed by concentration of myelin-specific P0 protein. Tellurium-induced alterations in the metabolic capacity of Schwann cells were examined by measuring the synthesis of myelin lipids in vitro in isolated sciatic nerve segments. Exposure to tellurium resulted in an early marked decrease of approximately 50% in overall incorporation of [14C]acetate into lipids, with a preferential depression in synthesis of cerebrosides, cholesterol, and ethanolamine plasmalogens (components enriched in myelin). Most dramatically, within 1 day of initiation of tellurium exposure, there was a profound increase in [14C]acetate-derived radioactivity in squalene; 23% of incorporated label was in this intermediate of cholesterol biosynthesis, compared to less than 0.5% in controls. In association with the remyelinating phase seen after 5 days of tellurium exposure, synthesis of myelin components gradually returned to normal levels. After 30 days, metabolic and morphologic alterations were no longer apparent. We suggest that the sequence of metabolic events in sciatic nerve following tellurium treatment initially involves inhibition of the conversion of squalene to 2,3-epoxysqualene, and that this block in the cholesterol biosynthesis pathway results, either directly or indirectly, in the inhibition of the synthesis of myelin components and breakdown of myelin.

Acetates↗

PubMed1979

Plasmenylethanolamine: growth factor for cholesterol-reducing Eubacterium.

A plasmalogen, plasmenylethanolamine, is required for in vitro growth of strains of Eubacterium which convert cholesterol to coprostanol. Plasmenylethanolamine was isolated from calf brain by selective saponification of lipid fractions separated by thin-layer or column chromatography. Cholesterol-containing thioglycolate broth plus purified plasmenylethanolamine or its 2-lyso derivative supported growth of Eubacterium ATCC 21408 and a cholesterol-reducing Eubacterium isolated from baboon feces. Plasmenylethanolamine obtained from commercial sources also supported growth of these organisms, but none of a number of other pure lipids would support growth. Metabolism of the alkenyl ether group of plasmenylethanolamine occurred during growth.

Cholesterol↗

PubMed1993

Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency.

An infant with the characteristic phenotype of classical rhizomelic chondrodysplasia punctata was found to have an isolated deficiency of the peroxisomal enzyme acyl CoA dihydroxyacetone phosphate acyltransferase (DHAP-AT). All other peroxisomal functions measured were found to be normal. Previously described in one other case report, this confirms the existence of another distinct form of peroxisomal disorder characterised biochemically by a deficiency in de novo plasmalogen biosynthesis only.

Acyltransferases↗

PubMed1972

Lipid changes in Duchenne muscular dystrophy.

Thin layer chromatographic analysis of lipid extracts of rectus abdominis and gastrocnemius muscles from controls and patients with severe sex-linked Duchenne muscular dystrophy shows the dystrophic tissue to contain more sphingomyelin, less lecithin plus choline plasmalogen, and more total cholesterol than normal. Comparison of normal, dystrophic, and immature muscle suggests that these observations can be interpreted as showing a similarity between dystrophic and immature muscle and in this respect human Duchenne dystrophy resembles hereditary muscular dystrophy in the mouse. Although sphingomyelin was present in apparently normal amount in muscle biopsies from patients with various other neuromuscular disorders, it was raised in two cases showing evidence of peripheral neuropathy.

Adolescent↗

PubMed1975

Cold resistance of the brain during hibernation. III. Evidence of a lipid adaptation.

The composition of membrane-bound lipids of brain from both warm-adapted and hibernating hamsters were different in the complex lipid fraction as well as their fatty acyl chains. During hibernation the content of cholesterol was less, but there were greater amounts of both the phosphatidylcholines and phosphatidylethanolamines. There were small but significant increases in monounsaturated fatty acids as well as arachidonic acid in all the glycerophosphatides of the hibernating hamster, whereas a decrease in isomyristic acid was o0served in the sphingomyelins. The most significant changes observed occurred in the fatty aldehyde composition of ethanolamine plasmalogen. A dramatic increase in oleyaldehyde was observed during hibernation. These changes in membrane-bound lipids may account for the cold-resistant properties of the brain during hibernation by retaining the fluid nature of the cell membrane.

Acclimatization↗

PubMed2002

Role of an endoplasmic reticulum Ca(2+)-independent phospholipase A(2) in oxidant-induced renal cell death.

Phospholipase A(2) (PLA(2)) hydrolyzes the sn-2 ester bond in phospholipids, releasing a fatty acid and a lysophospholipid. Recently, a novel 85-kDa membrane-bound-Ca(2+)-independent PLA(2) (iPLA(2)) was identified in insect and bacterial cells transfected with candidate PLA(2) sequences. However, few data exist demonstrating a membrane-bound-iPLA(2) in mammalian cells, its subcellular localization, or its physiological role. Herein, we demonstrate the expression of an 85-kDa endoplasmic reticulum (ER)-Ca(2+)-iPLA(2) (ER-iPLA(2)) in rabbit renal proximal tubule cells (RPTC) that is plasmalogen selective and is inhibited by the specific Ca(2+)-iPLA(2) inhibitor bromoenol lactone (BEL). RPTC exposed to tert-butylhydroperoxide for 24 h exhibited 20% oncosis compared with 2% in controls. Inhibition of ER-iPLA(2) with BEL before tert-butylhydroperoxide exposure resulted in 50% oncosis. To determine whether this effect was common to oxidants, we tested the ability of BEL to potentiate oncosis induced by cumene hydroperoxide, menadione, duraquinone, cisplatin, and the nonoxidant antimycin A. All oxidants tested produced oncosis after 24 h, and prior inhibition of ER-iPLA(2) potentiated oncosis at least twofold. In contrast, inhibition of ER-iPLA(2) did not alter antimycin A-induced oncosis. Lipid peroxidation increased from 1.4- to 5.2-fold in RPTC treated with BEL before oxidant exposure, whereas no change was seen in antimycin A-treated RPTC. These results are the first to demonstrate the expression and subcellular localization of an ER-iPLA(2). These results also suggest that ER-iPLA(2) functions to protect against oxidant-induced lipid peroxidation and oncosis.

Animals↗

PubMed1999

Sjögren-Larsson syndrome: early diagnosis, dietary management and biochemical studies in two cases.

BACKGROUND: Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder with worldwide distribution. It consists of ichthyosis, spastic diplegia and mental retardation caused by an enzymatic defect in fatty alcohol oxidation. OBJECTIVE: To study the effects of dietary management on clinical outcome and plasma/red blood cell fatty alcohol and plasmalogen concentrations. METHODS: To reduce fatty alcohol production, we reduced total fat intake to 30% of total intake of calories. To correct d 6 desaturase deficiency, we supplemented the diet with both n-3 and n-6 fatty acids to obtain a linoleic/linolenic acid ratio of 6 with low erucic acid rapeseed oil, plus high unsaturated fatty acids. We used gas liquid chromatography to assay blood cell membranes and plasma fatty alcohols/plasmalogens. RESULTS: Two SLS infants with proven fatty alcohol/NAD+ oxidoreductase deficiency were studied. Good clinical results were obtained in one of the patients when dietary intervention was started in early infancy and correlated well with plasma fatty alcohol decrease. However, no clinical improvement was seen in the other patient who started later with low compliance. Acitretin therapy was necessary to control skin symptoms in this second patient. CONCLUSION: Dietary intervention using the combined approach described here may improve fatty alcohol metabolism in SLS. However, only very early intervention seems clinically beneficial.

Alcohol Oxidoreductases↗

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↗

PubMed1988

Neonatal seizures and retardation in a girl with biochemical features of X-linked adrenoleukodystrophy: a possible new peroxisomal disease entity.

Neonatal hypotonia, seizures beginning at 5 days, and severe retardation were noted in a girl with normal karyotype and biochemical evidence of impaired adrenal function. Postmortem examination at 14 months revealed malformative and destructive lesions of central gray and white matter, atrophy of adrenal cortex with striated adrenocortical cells, hepatic fibrosis, and PAS-positive macrophages in several organs. Pathologically and clinically, this patient most closely approximated neonatal adrenoleukodystrophy (ALD) and differed strikingly from X-linked childhood ALD. In contrast, biochemical changes resembled the abnormalities observed in X-linked ALD and differed from those in the neonatal form. The very-long-chain fatty acid accumulation characteristic of both disorders was demonstrated, but unlike neonatal ALD, the levels or metabolism of plasmalogens, pipecolic acid, phytanic acid, and bile acid intermediates were normal, and peroxisomes in a liver biopsy specimen were present in normal number and appeared enlarged. While the case resembles the recently reported entity of peroxisomal acyl-CoA oxidase deficiency, assignment to this category was excluded by immunoblot studies on postmortem liver, which revealed normal amounts of this enzyme. Correlation of clinical, morphologic, and biochemical data suggests that this case is an example of a so-far undescribed entity, and reinforces the concept that the phenotypic spectrum of peroxisomal disorders is wider than realized.

Adrenoleukodystrophy↗

PubMedDate not supplied

The peroxisome deficient PEX2 Zellweger mouse: pathologic and biochemical correlates of lipid dysfunction.

Zellweger syndrome is the prototypic human peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. A murine model for this disorder was previously developed by targeted deletion of the PEX2 peroxisomal gene. By labeling neuronal precursor cells in vivo with a mitotic marker, we can demonstrate a delay in neuronal migration in the cerebral cortex of homozygous PEX2 mutant mice. Postnatal PEX2 Zellweger mice develop severe cerebellar defects with abnormal Purkinje cell development and an altered folial pattern. When the PEX2 mutation is placed on an inbred murine genetic background, there is significant embryonic lethality and widespread neuronal lipidosis throughout the brain. Biochemical analysis of PEX2 mutant mice shows the characteristic accumulation of very long chain fatty acids and deficient plasmalogens in a wide variety of tissues. Docosahexaenoic acid levels (DHA; 22:6n-3) were found to be reduced in the brain of mutant mice but were normal in visceral organs at birth. All tissues examined in postnatal mutant mice had reduced DHA. The combined use of morphologic and biochemical analyses in these mice will be essential to elucidate the pathogenesis of this complex peroxisomal disease.

Animals↗

PubMedDate not supplied

Restoring the DHA levels in the brains of Zellweger patients.

Patients with the Zellweger syndrome and its variants have very low levels of docosahexaenoic acid (DHA) in the brain, retina, and other tissues. Such a marked DHA deficiency could be related to the pathogenesis of peroxisomal disorders. Therefore, restoring the DHA levels in these patients can probably improve the clinical course of the disease. With this rationale, 20 patients with generalized peroxisomal disorders have been treated to date with DHA ethyl ester, at daily doses of 100-500 mg, for variable periods of time. Treatment has been always accompanied by a nutritious diet, normal for the age, in order to provide all the necessary nutrients and avoid a polyunsaturated fatty acid (PUFA) imbalance. The most constant improvement has been normalization of the DHA levels and liver function. Vision has improved in about half the patients and muscle tone has generally increased. Magnetic resonance imaging (MRI) examination revealed improvement of myelination in 9 patients. Significantly, the clinical improvement has been most marked in those patients who started the treatment before 6 mo of age. Biochemically, the plasma very long-chain fatty acids (VLCFA) 26:0 and 26:1n-9 decreased markedly despite the complete diet provided. In erythrocytes, the plasmalogen ratio 18: ODMA/18:0 increased in most cases, and sometimes even normalized. All these beneficial effects suggest that DHA deficiency plays a fundamental role in the pathogenesis of peroxisomal disease. Because DHA accretion is maximal during early brain development, it is essential to initiate the treatment as soon as possible. Otherwise, restoration of brain DHA levels and prevention of further damage will not be possible.

Adrenoleukodystrophy↗

PubMed2003

Structural characterization of plasmenylcholine photooxidation products.

Oxidative damage to plasmenyl-type lipids contributes to decreased membrane barrier function, loss of membrane structure and formation of nonlamellar defects in membrane bilayers. Previous results from this laboratory have shown that membrane-soluble sensitizers (e.g. zinc phthalocyanine and bacteriochlorophyll a) mediate the photooxidation of palmitoyl plasmenylcholine (1-O-alk-1'-Z-enyl-2-palmitoyl-sn-glycero-3-phosphocholine; PPlsC) vesicles with the subsequent creation of lamellar defect structures, vesicle contents leakage and membrane-membrane fusion. Because plasmalogen lipids are significant components of sarcoplasma and myelin membranes, we sought to characterize the products of their photooxidation. This study focuses on the photooxidation of PPlsC vesicles in the presence of the water-soluble sensitizer, aluminum phthalocyanine tetrasulfonate (AlPcS4(4-)). Attack of photogenerated singlet oxygen on the 1-O-alkenyl ether linkage of PPlsC lipids was expected to generate dioxetane- and ene-type photoproducts. The products formed during continuous aerobic irradiation (28 mW/cm2, (610 nm) of PPlsC vesicles in the presence of AlPcS4(4-) were separated via reverse-phase high-performance liquid chromatography (HPLC) with electrochemical detection (ECD) or evaporative light-scattering detection (ELSD). Photooxidized dipalmitoyl-phosphatidylcholine-cholesterol vesicles (control) were used to optimize the HPLC-ECD conditions, using 7 alpha-hydroperoxy-cholesterol as standard. HPLC-ECD was found to be most sensitive for PPlsC hydroperoxides, whereas HPLC-ELSD was more sensitive for nonhydroperoxide photoproducts. The three major photoproducts formed during vesicle irradiation were isolated via preparative HPLC and then characterized by 1H-nuclear magnetic resonance and mass spectrometry. 1-Formyl-2-palmitoyl-sn-glycero-3-phosphocholine and 1-hydroxy-2-palmitoyl-sn-glycero-3-phosphocholine were identified as dioxetane cleavage products that coeluted at approximately 3 min. The second fraction (retention time [RT] = 48 min) was identified as a PPlsC allylic hydroperoxide. The third photoproduct, eluting at RT = 64 min, is tentatively identified as an oxidation product arising from allylic hydroperoxide degradation via Hock rearrangement or free radical decomposition.

Chromatography, High Pressure Liquid↗

PubMed2005

Lipid alterations in the earliest clinically recognizable stage of Alzheimer's disease: implication of the role of lipids in the pathogenesis of Alzheimer's disease.

Lipids have many important yet distinct functions in cellular homeostasis such as forming an impermeable barrier separating intracellular and extracellular compartments, providing a matrix for the appropriate interactions of membrane-associated proteins, and serving as storage reservoirs for biologically active second messengers. Alterations in cellular lipids may therefore result in abnormal cellular functions. This review summarizes the results from the examination of lipid alterations in Alzheimer's disease (AD). In addition to the effects of cholesterol on AD, substantial depletions of plasmalogen and sulfatide as well as dramatic increases in ceramide are specifically manifested at the earliest clinically recognizable stage of AD. The potential mechanism(s) underlying these changes and the potential consequences of these changes in neuronal function and in AD development are also discussed. Collectively, this review will provide an overview of the lipid alterations in Alzheimer's disease and the relationship of these lipid alterations with the development of AD pathogenesis.

Alzheimer Disease↗

PubMed2002

MR imaging and MR spectroscopy in rhizomelic chondrodysplasia punctata.

A case of rhizomelic chondrodysplasia punctata was investigated with MR imaging of the brain and hydrogen-1 MR spectroscopy of the brain and blood. Areas with abnormal signal hyperintensity on T2-weighted images or hypointensity on T1-weighted images were detected in the subcortical white matter. MR spectroscopy of the brain showed that normal-appearing white matter was characterized by increased levels of mobile lipids and myo-inositol, reduced levels of choline, and the presence of acetate. The importance of these metabolic anomalies is correlated to the deficiency in plasmalogen biosynthesis.

Acyltransferases↗