dolichols and Neuronal-Ceroid-Lipofuscinoses

The search for biochemical abnormalities in the neuronal ceroid-lipofuscinoses (NCL) or Batten disease was initiated with the discovery of normal levels of gangliosides in juvenile amaurotic idiocy. The primary goal of most biochemical studies has been to discover the unique biochemical marker for carriers and at-risk individual. Ceroid, the singular pathomorphologic trait of NCL, was isolated and shown to differ from a similar but normal product of aged cells, lipofuscin. In spite of the availability of stored product, the chemical analysis of ceroid has not elucidated the unique biochemical defect in the NCL, as has been the case for other lysosomal storage disorders. The NCL were thought to be a result of lipid peroxidation because ceroid is also found in disorders of impaired vitamin E metabolism or results from a diet deficient in the antioxidant, vitamin E. In addition, tissue analysis indicated losses of polyunsaturated fatty acids in affecteds and carriers, as well as the presence of a secondary product of lipid peroxidation, 4-hydroxynonenal, in affected and carrier NCL dogs. With the exception of a fluorescent compound isolated from retinal ceroid, studies aimed at discovering the disease-specific fluorophores of ceroid have been largely inconclusive. The discovery of elevated dolichols in urine and brain tissue of NCL patients led to another hypothesis, that the basic biochemical defect in NCL involved the metabolism of dolichols and retinoids. However, the more recent view is that dolichol metabolism is secondary to the unknown NCL lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomarkers; Dolichols; Endopeptidases; Heterozygote; Humans; Lipid Peroxidation; Methylation; Neuronal Ceroid-Lipofuscinoses; Proteins

Adult neuronal ceroid lipofuscinosis (NCL), also called Kufs' disease, is clinically distinct from the other NCLs. It is a rare condition which is difficult to diagnose. More than 50% of the reported cases of Kufs' disease are not adult NCL and correspond very likely to a heterogeneous spectrum of lipidoses. Various clinical and genetic phenotypes of adult NCL may be recognized, one featuring a progressive myoclonus epilepsy. It is important to stress that in contradistinction with the juvenile and protracted juvenile NCL, there is no pigmentary degeneration of the retina. Adult NCL is an autosomal recessive condition but two families have an autosomal dominant inheritance. The diagnosis of adult NCL may be suggested by a careful evaluation of skin, rectal or brain biopsies with the electron microscope but the diagnosis is fraught with many hazards. The pathogenetic defect lies probably in the intracellular processing of lysosomal and perhaps of Golgi membranes. The recent discovery of subunit c of mitochondrial adenosine triphosphate synthase in the stored cytosomes represents certainly an interesting prospect for future developments.

Topics: Adolescent; Adult; Animals; Biopsy; Brain; Diagnosis, Differential; Disease Models, Animal; Dog Diseases; Dogs; Dolichols; Epilepsies, Myoclonic; Humans; Infant; Intracellular Membranes; Lipidoses; Lipids; Neuronal Ceroid-Lipofuscinoses; Neurons; Pigments, Biological; Retina; Skin

Highly elevated serum total dolichol (free dolichol + dolichyl ester) concentrations have recently been found in two lysosomal storage diseases, aspartylglucosaminuria (AGU) and mannosidosis. The present study demonstrates that the increase of serum dolichol in AGU patients is caused by an increase of serum free dolichol. In 15 patients the mean serum level of free dolichol (227 +/- 16 ng/mL) was 1.9 times higher (p < 0.001) than that in healthy controls (120 +/- 6 ng/mL), while the amounts of dolichol fatty acid esters were similar in the patients and controls (110 +/- 9 vs. 118 +/- 6 ng/mL). In contrast, 10 patients with neuronal ceroid-lipofuscinosis (NCL) (three with infantile, four with juvenile, and three with variant late infantile NCL) had significantly (p < 0.01) lower mean serum levels of both free (79 +/- 5 ng/mL) and total (159 +/- 6 ng/mL) dolichol than age-adjusted healthy controls (free, 100 +/- 6 ng/mL; total, 206 +/- 14 ng/mL). Decreased blood dolichol has not been reported earlier for any other disease. We conclude that the increased serum free dolichol in AGU reflects disturbed lysosomal function and that the decreased free and esterified dolichols in NCLs speak against their presumed primary lysosomal nature.

Topics: Adolescent; Adult; Aspartylglucosaminuria; Child; Child, Preschool; Dolichols; Esters; Female; Humans; Lysosomal Storage Diseases; Male; Middle Aged; Neuronal Ceroid-Lipofuscinoses

The kinetics of the oligosaccharide transfer from oligosaccharyl pyrophosphoryldolichol to endogenous protein acceptors in human fibroblasts were studied. No alterations in the transferase activity and enzyme characteristics could be observed in fibroblasts from neuronal ceroid-lipofuscinosis (NCL) patients. Analysis of urinary dolichol of two NCL patients also did not reveal substantial differences with respect to controls.

Topics: Adolescent; Adult; Cations, Divalent; Cells, Cultured; Dolichols; Female; Fibroblasts; Hexosyltransferases; Humans; Male; Membrane Proteins; Middle Aged; Neuronal Ceroid-Lipofuscinoses; Polyisoprenyl Phosphate Oligosaccharides; Transferases

Topics: Child, Preschool; Diagnosis, Differential; Dolichols; Female; Humans; Neuronal Ceroid-Lipofuscinoses; Rett Syndrome

Urine from patients with classical and atypical forms of juvenile ceroid-lipofuscinosis (CL) was analyzed for the presence of disease-specific peptides. Two distinct peptide patterns were recognized on lithium dodecyl sulfate polyacrylamide gel electrophoresis in classical juvenile CL patients. Pattern 1 consisted of a single, intensely staining peptide of apparent Mr 2,000, and up to 4 heterogeneous, weakly staining peptides between 2,500 and 6,300 Mr. This peptide pattern was not seen in over 30 samples from patients with other neurodegenerative disorders, nor in normal control individuals. Reduced amounts of the 2,000 Mr peptide were seen in 2 of 3 female heterozygotes whose children had the peptide pattern 1. The presence of large amounts of the 2,000 Mr peptide in urine extracts made patient identification unequivocal. Pattern 2 had 2 to 3 intensely staining peptides of 3,800, 5,000 and 7,000 Mr, a variable number of minor bands, and diffuse staining above 7,000 and below 3,800 Mr. Parents had 2 to 3 weakly staining peptides with molecular weights similar to the major bands seen in the patients. No consistent peptide pattern was seen in 8 patients with atypical CL. Late infantile CL patients had no or very small amounts of low Mr urinary peptides. The urinary components stained well with silver, poorly with Coomassie Blue, and were digested by a nuclease-free protease, as expected for protein. They were distinctly different from the peptides isolated from ovine CL tissues. Amino acid composition analysis showed a predominantly normal spectrum of amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Child; Child, Preschool; Dolichols; Electrophoresis, Polyacrylamide Gel; Humans; Molecular Weight; Neuronal Ceroid-Lipofuscinoses; Peptides; Staining and Labeling

Ovine ceroid-lipofuscinosis is an inherited neurodegenerative disorder characterised by the accumulation of storage cytosomes in brain and visceral organs. Phosphorylated dolichol-containing compounds, largely in the form of dolichyl pyrophosphoryl oligosaccharides, have been shown to constitute 1-2% of the dry weight of storage cytosomes isolated from brain and pancreas, and 0.5 and 0.1% respectively of storage cytosomes isolated from liver and kidney. The carbohydrate portion of these glyconjugates in storage cytosomes isolated from brain, pancreas and liver consisted of a series of oligosaccharides of composition Man2-9GlcNAc2, with Man5-8GlcNAc2 predominating. The concentrations of dolichyl pyrophosphoryl oligosaccharides in storage cytosomes from ovine ceroid-lipofuscinosis are much higher than has been reported for endoplasmic reticulum, their normal functional location.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Dolichols; Kidney; Liver; Lysosomes; Microscopy, Electron; Neuronal Ceroid-Lipofuscinoses; Oligosaccharides; Pancreas; Phosphorylation; Polyisoprenyl Phosphate Oligosaccharides; Polyisoprenyl Phosphate Sugars; Sheep

Topics: Brain; Dolichols; Humans; Infant; Mannose; Neuronal Ceroid-Lipofuscinoses; Oligosaccharides

Light and electron microscopic examinations were performed on two autopsy cases of ceroid-lipofuscinosis of the juvenile (Case 1) and late infantile (Case 2) types. Much ceroid-lipofuscin (CL) was found in nerve cells throughout the nervous system. In Case 1, CL had also accumulated in thyroid follicular cells, glomerular podocytes, and epithelial cells of the ductus epididymidis, and in the endothelium and smooth muscle of vessels. Electron microscopy showed CL in 5% of peripheral lymphocytes sampled when the patient was alive. In Case 2, an accumulation of CL was found in the vascular endothelial cells of the cerebrum, and Kupffer cells and sinusoidal endothelial cells of the liver. The CL was autofluorescent, and was seen to be composed of electron-dense granules, lipid droplets, lamellar structures, and curvilinear bodies by electron microscopy. Limiting membranes were often found surrounding CL granules. The dolichol level in the cerebral cortex was high in Case 1. Accumulation of CL was found in cells other than nerve cells, although the main signs and symptoms were caused by the involvement of nerve cells. The CL showed various ultrastructural features.

Topics: Adult; Autopsy; Brain Chemistry; Child; Dolichols; Female; Histocytochemistry; Humans; Male; Microscopy, Electron; Microscopy, Fluorescence; Neuronal Ceroid-Lipofuscinoses; Neurons; Organ Size; Staining and Labeling

Although, compared to age-matched control samples, nonphosphorylated dolichols are significantly increased in the cerebral cortex of children with the late infantile and juvenile types of neuronal ceroid-lipofuscinosis (NCL), dolichyl phosphates are increased to a much greater extent in infantile, late infantile, and juvenile forms of this disease group. Dolichyl phosphates in the cerebral cortex, expressed as a percentage of the combined nonphosphorylated and phosphorylated compounds, ranged from 59 to 85 (mean 71) in NCL, whereas in the non-NCL disease group the range is 18-36 (mean 25). This marked proportional increase in dolichyl phosphates is not unique to NCL but is also found in the brain of GM1-gangliosidosis and Tay-Sachs disease patients. In the liver from NCL patients, dolichyl phosphates are not a major proportion of the total dolichol compounds (1-9%). However, in the kidney and heart, dolichyl phosphates are again markedly increased, and this is associated with large storage of ceroid. Although to a lesser extent than in NCL, dolichols and dolichyl phosphates are significantly increased over levels in age-matched control samples in the temporal cortex in Alzheimer disease. Our interpretation of these results is that storage in secondary in secondary lysosomes in NCL and the gangliosidoses leads to a decrease in the catabolism of dolichyl phosphate compounds in the Golgi saccules or primary lysosomes.

Topics: Alzheimer Disease; Brain Chemistry; Cerebral Cortex; Child, Preschool; Dolichol Phosphates; Dolichols; Humans; Infant; Kidney; Liver; Myocardium; Neuronal Ceroid-Lipofuscinoses; Polyisoprenyl Phosphates; Tay-Sachs Disease

We studied clinical manifestations of Japanese patients with neuronal ceroid-lipofuscinosis (NCL). The onset of the disease and initial symptoms were almost identical to those reported previously in Caucasians. Japanese patients with NCL were not significantly clinically different from Caucasian cases. An atypical case NCL associated with a deficiency of diaminobenzidine peroxidase activity was also presented. Pathogenesis of NCL was studied on the basis of urine dolichol excretion, autofluorescent compounds in urine, thiol protease activities and protein analysis in tissues of NCL patients. Possible biochemical abnormalities in NCL are discussed.

Topics: Adolescent; Adult; Asian People; Brain; Child; Child, Preschool; Dolichols; Fluorescence; Humans; Japan; Neuronal Ceroid-Lipofuscinoses; Peroxidases; White People

The dolichol contents of urine sediments from a patient with infantile (Santavuori), a patient with late infantile (Jansky-Bielschowsky) and two patients with juvenile (Spielmeyer-Vogt) neuronal ceroid lipofuscinosis (Batten's disease) were not elevated when compared to those from healthy controls.

Topics: Child; Child, Preschool; Creatinine; Diterpenes; Dolichols; Female; Humans; Male; Neuronal Ceroid-Lipofuscinoses

The concentrations of phosphorylated dolichol (P-dolichol) and of non-phosphorylated dolichol were estimated in a number of different tissues from ceroid-lipofuscinosis (CL) and control cases. The P-dolichol contents of four tissues, brain, pancreas, muscle and kidney were significantly greater than control values. Liver and spleen showed little or no increase in P-dolichol content. Though non-phosphorylated dolichol levels were higher in CL tissues than in control tissues, the differences were significant only for brain and pancreas. In control muscle, a linear age-related increase in non-phosphorylated dolichol content was observed. The relative amounts of the major homologs of P-dolichol and of non-phosphorylated dolichol were estimated. Each tissue has a characteristic homolog size-distribution, and there is close similarity between the size-distribution profiles of P-dolichol and of non-phosphorylated dolichol for each tissue.

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Chromatography, High Pressure Liquid; Diterpenes; Dolichols; Female; Humans; Male; Neuronal Ceroid-Lipofuscinoses; Phosphorylation

Ceroid-lipofuscinosis is described in Australian Cattle dogs. Lesions included storage of ceroid-lipofuscin in most tissues with characteristic ultrastructural inclusion body patterns in neurons and other cells. Dolichol concentration of the affected dog's brain was similar to those in age-matched control dog brains. However, concentrations in brain, liver and kidneys were markedly higher than in a slightly younger dog. Biochemical data including lysosomal enzyme activities exclude other lysosomal storage diseases. The clinical and pathological features of this disorder resemble those of the juvenile Spielmeyer-Vogt type of Batten disease in humans.

Topics: Age Factors; Animals; Cerebral Cortex; Disease Models, Animal; Dog Diseases; Dogs; Dolichols; Genes, Recessive; Lipid Metabolism; Lysosomes; Neuronal Ceroid-Lipofuscinoses; Pedigree

Two of our 5 patients with neuronal ceroid lipofuscinosis excreted a large amount of autofluorescent lipids in their urine. These autofluorescent lipids consisted of more than 5 bands in the thin-layer-chromatography. Excitation and emission spectra of these lipids showed that they had heterogeneous components. This finding was specific to neuronal ceroid lipofuscinosis, and never found in other neurological diseases. We also measured unesterified dolichol and dolichol fatty acid ester in urine, and 4 of our patients did not excrete a large amount of such compounds compared with control groups. This finding suggest that increased excretion of dolichol in urine of patient with neuronal ceroid lipofuscinosis may be the secondary effect, but there are some possibilities that certain abnormalities in glycoprotein metabolism exist in neuronal ceroid lipofuscinosis.

Topics: Chromatography, Thin Layer; Dolichols; Fluorescence; Fluorometry; Humans; Lipids; Neuronal Ceroid-Lipofuscinoses

The ceroid lipofuscinoses are inherited lysosomal diseases of children characterized by a fluorescent lipopigment stored in a variety of tissues. Defects in lipid metabolism or the control of lipid peroxidation have been postulated to explain their pathogenesis. In the present study, lipopigment was isolated from the liver of sheep affected with ceroid lipofuscinosis. It was 70% protein, the rest being mainly lipids. These were only one-sixth as fluorescent as total liver lipids, but contained a number of fluorophors. None were major components of the lipopigment or the postulated fluorescent product of lipid peroxidation. Lipopigment lipids included the lysosomal marker bis(monoacylglycero)phosphate that contained 42.9% linoleate and 16.5% linolenate. Lipopigment neutral lipids were dolichol, dolichyl esters, ubiquinone, free fatty acids, and cholesterol, indicative of a lysosomal origin of the lipopigment. Phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine were present in proportions and with fatty acid profiles typical of lysosomes. No differences were found between the lipids of total control and affected livers, nor the fatty acid profiles of their phosphatidylcholine, phosphatidylethanolamine, or triglycerides. It is concluded that ovine ceroid lipofuscinosis is not a lipidosis, nor does the lipopigment arise from the abnormal peroxidation of lipids. Strong similarities between the lipopigment and the age pigment lipofuscin were noted.

Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Disease Models, Animal; Dolichols; Fatty Acids; Fluorescence; Liver; Lysophospholipids; Lysosomes; Magnetic Resonance Spectroscopy; Monoglycerides; Neuronal Ceroid-Lipofuscinoses; Phosphatidic Acids; Phospholipids; Pigments, Biological; Proteins; Sheep; Sheep Diseases; Ubiquinone

Previous studies on the lipopigment from the livers of sheep affected with ceroid lipofuscinosis showed that the disease does not involve a defect in lipid metabolism or abnormal lipid peroxidation and that most of the lipopigment was proteinaceous. In this study, lipopigment was isolated from liver, kidney, pancreas, and brain of affected sheep without the use of proteolytic enzymes. Lipopigment from all tissues was two-thirds protein. Modified silver staining after sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a major band of Mr = 14,800, heterogeneous material between Mr = 5,000 and 9,000, and a major band of Mr = 3,500. These compounds did not stain for RNA or carbohydrate and were digested by a nuclease-free protease as expected for protein. They are not normal lysosomal proteins. Lipopigment levels of dolichol, ubiquinone, and cholesterol were consistent with the lipopigment being protein-enriched lysosome-derived cytosomes. The presence of the Mr = 3,500 proteins in whole affected tissue homogenates distinguished them from homogenates of normal tissues. It was concluded that low Mr proteins are specifically stored in ovine ceroid lipofuscinosis and that the ceroid lipofuscinoses may result from inherited defects in lysosomal protein catabolism.

Topics: Animals; Brain Chemistry; Cholesterol; Disease Models, Animal; Dolichols; Electrophoresis, Polyacrylamide Gel; Fatty Acids; Fluorescence; Kidney; Lipids; Liver; Lysosomes; Molecular Weight; Neuronal Ceroid-Lipofuscinoses; Pancreas; Phospholipids; Pigments, Biological; Proteins; Sheep; Sheep Diseases; Ubiquinone

Long-chain polyisoprenol alcohol (dolichols) levels are significantly increased in the urinary sediment of patients with infantile, late-infantile, and juvenile forms of neuronal ceroid-lipofuscinosis (NCL). The values in obligate heterozygotes for these diseases are similar to those in patients with other neurological diseases and in healthy controls. Antioxidant treatment of patients with juvenile NCL has no effect on dolichol values. The rate of false-negative results is 13.9% in infantile, 7.5% in late-infantile, and 15.0% in juvenile NCL. False-positive results were found in 8.2 to 14.3% of patients with other neurological diseases and in 15.4% of healthy controls. The test is of considerable value in the diagnosis of NCL and in decisions on whether to perform a biopsy. It is not useful in the screening of random samples, however.

Topics: Adolescent; Adult; Child; Child, Preschool; Diterpenes; Dolichols; Evaluation Studies as Topic; False Negative Reactions; False Positive Reactions; Heterozygote; Humans; Infant; Middle Aged; Nervous System Diseases; Neuronal Ceroid-Lipofuscinoses

Nonesterified dolichols have been measured in the urinary sediment of 20 patients with the late infantile and juvenile forms of neuronal ceroid lipofuscinosis (Batten disease), in 15 patients with other storage and neurodegenerative disorders and in 10 control subjects. Dolichols were measured by a high performance liquid chromatographic method and were related to urinary creatinine concentration. The levels of dolichols in Batten disease were not significantly elevated when compared to the normal subjects or to patients with other neurodegenerative disorders. The highest levels seen were in two patients with mucopolysaccharidosis types II and IV, respectively. Measurement of dolichols in urinary sediment is of little value in the diagnosis of Batten disease or in furthering our understanding of the underlying primary defect.

Topics: Adolescent; Adult; Child; Creatinine; Diterpenes; Dolichols; Humans; Mucopolysaccharidoses; Nervous System Diseases; Neuronal Ceroid-Lipofuscinoses

Concentrations of free dolichol, total non-phosphorylated dolichol, and total phosphorylated dolichol were measured in autopsy specimens of brain and liver from ceroid-lipofuscinosis (CL) and control cases. Levels of non-phosphorylated dolichol, mainly as free dolichol, were increased approximately two-fold in late-infantile CL brain. No increase was observed for CL liver. In late-infantile and juvenile CL brain, the increase in phosphorylated dolichol was at least ten-fold, but no significant difference was found for CL liver. A substantial part of the increase in phosphorylated dolichol in CL brain appeared to be due to lipid-linked oligosaccharides. The results suggest that CL might involve a defect in the metabolism of dolichol-linked oligosaccharides.

Topics: Adolescent; Adult; Brain Chemistry; Child; Child, Preschool; Diterpenes; Dolichol Phosphates; Dolichols; Female; Humans; Liver; Male; Neuronal Ceroid-Lipofuscinoses; Polyisoprenyl Phosphates

Human ceroid lipofuscinosis (CL) is an inherited disease marked by cerebromacular degeneration and early death. We have utilized the canine model to investigate the possible role of dolichol and dolichyl phosphate in the developmental pathology of CL. We found that while brain levels of dolichol increase with age in both affected and unaffected dogs, the amount in the diseased animal was similar to that in controls. Brain levels of dolichyl phosphate ranged from 20 to 35 micrograms/g in control dogs at all ages examined, but increased substantially during development in the affected dogs, a value of 113 +/- 24 micrograms/g (mean +/- SD) being obtained in the end-stage animals. In addition to the results obtained in the canine model, dolichyl phosphate levels in human brain tissues from a 5-year-old with late infantile CL and from a 19-year-old with juvenile CL were found to be 153 and 382 micrograms/g, respectively, compared with a control that assayed 26 micrograms/g. The preliminary findings with human tissues provide further evidence for an association of elevated brain dolichyl phosphate levels with CL. Whether the increase is primary or secondary remains to be determined.

Topics: Adult; Animals; Brain Chemistry; Child, Preschool; Diterpenes; Dog Diseases; Dogs; Dolichol Phosphates; Dolichols; Heterozygote; Homozygote; Humans; Male; Microscopy, Fluorescence; Neuronal Ceroid-Lipofuscinoses; Phosphoric Monoester Hydrolases; Polyisoprenyl Phosphates

Dolichol metabolism was investigated in skin fibroblast cultures from normal individuals and patients with Batten's disease. Incorporation of [3H]mevalonolactone and [14C]acetate into the dolichol fraction of total lipid extracts was similar in cells from normal individuals and patients with Batten's disease. [14C]Acetate incorporation into dolichol in non-saponifiable lipid extracts was compared with incorporation into dolichol in total lipid extracts, and no difference in the proportion of dolichol esterified to fatty acids was found in Batten's cells as compared to normal cells. The rate of loss of radioactivity from the dolichol pool after prelabelling with [14C]acetate was also similar in cells from Batten's and normal individuals. Thus, in the fibroblast system used, no evidence was found to support the hypothesis that Batten's disease is due to a defect in dolichol metabolism.

Topics: Acetates; Acetic Acid; Carbon Radioisotopes; Cells, Cultured; Diterpenes; Dolichols; Fibroblasts; Humans; Mevalonic Acid; Neuronal Ceroid-Lipofuscinoses; Reference Values; Skin; Tritium

Long-chain polyisoprenoid alcohols (dolichols) increase more than tenfold from age 5 to 80 years in human cerebral cortex. The dolichol content of brain from infantile, late infantile, and juvenile forms of neuronal ceroid lipofuscinosis (NCL) was significantly higher than in age-matched patients with other neurologic diseases. Significant increase of dolichols was also found in the urinary sediment in all three types of NCL patients, and this test is useful in making the diagnosis. Dolichol accumulation is the first biochemical marker of NCL and seems to parallel storage of ceroid lipofuscin.

Topics: Adolescent; Adult; Aged; Cerebral Cortex; Child; Diterpenes; Dolichols; Humans; Middle Aged; Neuronal Ceroid-Lipofuscinoses

Dolichols as unesterified alcohols were identified as significant components of lipid extracts from storage cytosomes isolated post-mortem from the brains of patients with the infantile, late infantile, and juvenile types of neuronal ceroid-lipofuscinosis (NCL). Very small amounts of dolichols were present in the corresponding subcellular fractions of non-NCL brains. The nuclear fraction from NCL cerebral cortex contained the highest dolichol content expressed per milligram protein or lipid, whereas the crude mitochondrial fraction was the richest in normal brain. Highly significant elevations of dolichol levels were found in human cerebral cortex of patients with NCL and Alzheimer's disease compared with age-matched controls, but the levels were normal in Pick's disease. In human non-NCL cerebral cortex, dolichols increased from 16 micrograms/g at age 5 to over 200 at age 81. Rat cerebral cortex showed a similar progressive increase in dolichol content with age. The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain. This is the first time a uniform biochemical abnormality has been found in all childhood forms of NCL, but the enzyme defect is still unidentified. It may lie on pathways where dolichols and retinyl compounds are recycled in Golgi membranes and derived organelles during the biosynthesis of glycoproteins.

Topics: Adolescent; Adult; Aged; Aging; Alzheimer Disease; Animals; Cerebral Cortex; Child; Child, Preschool; Cytoplasmic Granules; Dementia; Diterpenes; Dolichols; Humans; Microscopy, Electron; Middle Aged; Neuronal Ceroid-Lipofuscinoses; Rats; Reference Values; Subcellular Fractions

Topics: Adolescent; Adult; Aged; Cerebral Cortex; Child; Child, Preschool; Chromatography, High Pressure Liquid; Diterpenes; Dolichols; Humans; Middle Aged; Neuronal Ceroid-Lipofuscinoses