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PubMed1976

Inborn errors of metabolism: clues to understanding human behavioral disorders.

Detailed behavioral and biochemical investigation of patients with inborn errors of metabolism, especially those intrinsic to the nervous system, may provide many clues to the genetic predisposition underlying human behavioral traits. Relatives of such patients and other individuals with homologous enzymatic lesions due to alleles specifying intermediate activity need to be studied as well. Among the metabolic disorders discussed selectively here, some masquerade as schizophrenia, manic-depressive illness, or hyperactivity syndrome of childhood, providing examples of the striking heterogeneity to be found for these common behavioral disorders.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Characterization by lectin binding of the sugar moiety of glycocompounds stored in inherited diseases.

Kidney and liver samples from two cases of Fabry's disease and spleen and liver samples from Gaucher and Niemann-Pick diseases were tested for binding to lectins such as peanut agglutinin (PNA), Bandeiraea simplicifolia, (BSA), canavalia ensiformis (Con A), soybean agglutinin (SBA) and wheat germ agglutinin (WGA) labelled with horseradish peroxidase using histochemical techniques. These techniques allowed the localization of compounds with alpha-galactosyl residues in tissues from Fabry's disease. In tissues from the Gaucher and Niemann-Pick cases, the storage material was found to be more complex than expected, and some problems regarding the significance of lectin binding are discussed.

Adult↗
PubMed2003

[Pigmented form of orthochromatic leukodystrophy].

The pigmentary type of orthochromatic leukodystrophy (van Bogaert-Nyssen disease) is a hardly known neurological disorder usually with late onset that is very difficult to diagnose in vivo. Neuropathologically, the disorder features noninflammatory demyelination and the presence of pigmented macrophages and astrocytes that may contain iron. Clinically, van Bogaert-Nyssen disease can lead to death within a few years and is characterized by dementia, psychiatric abnormalities, epileptic seizures, spastic pareses, and occasionally extrapyramidal motor symptoms. This report presents a typical case and an overview of the literature. Furthermore, galactocerebroside could be documented in remaining macrophages and astrocytes by immunohistochemistry. This possibly indicates a dysfunction in sphingolipid breakdown and could relate the pigmented form of orthochromatic leukodystrophy to the genetically defined globoid cell leukodystrophy (Krabbe's disease). Thus, the rather heterogeneous pool of orthochromatic leukodystrophies could be further narrowed.

Adult↗
PubMed1999

Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant.

Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein C (sap-C). Here we present the detailed neurological manifestations, neuropathological findings and brain lipid composition in one sap-C-deficient patient. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.

Cerebellum↗
PubMed2000

Adult-onset leukodystrophies.

Leukodystrophies are genetic metabolic diseases which generally occur in early childhood at the time of myelination. Surprisingly, these diseases can also occur during adulthood. Adult forms have various clinical presentations which reflect degenerative diseases of the nervous system. The course may last for decades. This contribution describes the main features of adult leukodystrophies and indicates those for which a biochemical and molecular diagnosis are possible. Other articles deal with their differential diagnosis of leukoencephalopathies and with the diagnostic strategy.

Adult↗
PubMed2001

The SOX10 transcription factor: evaluation as a candidate gene for central and peripheral hereditary myelin disorders.

The SOX10 transcription factor is involved in development of neural crest derivatives and fate determination in glial cells. SOX10 mutations have been found in patients with intestinal aganglionosis and depigmentation with deafness (Waardenburg-Hirschsprung). Associated neurological signs have been reported in some cases, including a patient exhibiting a central and peripheral myelin deficiency. Therefore, we screened for SOX10 mutations in a large cohort of patients with peripheral and central myelin disorders. 56 were affected by classical demyelinating Charcot-Marie-Tooth disease without identified mutations in the genes encoding PNS myelin proteins (PMP22, P0), connexin 32 and the zinc-finger transcription factor, EGR2. 88 patients with undetermined leukodystrophy were selected from a large European prospective study. Associated clinical, magnetic resonance imaging and electrophysiological signs were consistent with a defect in CNS myelination in 83 and with an active degeneration of the CNS myelin in 5. No abnormalities in the proteolipid protein gene (PLP) were found. The absence of SOX100 mutation in this large cohort of patients suggests that this gene is not frequently involved in peripheral or central inherited myelin disorders.

Charcot-Marie-Tooth Disease↗
PubMed1988

Direct analysis of glycolipids on thin-layer plates by matrix-assisted secondary ion mass spectrometry: application for glycolipid storage disorders.

The lipids accumulated in organs of patients with Gaucher's, Tay-Sachs, and Fabry's disease were identified by means of the combination of thin-layer chromatography and matrix-assisted secondary ion mass spectrometry. The total lipid extract of each lipidosis tissue was chromatographed on a TLC plate and then analyzed directly by mass spectrometry without elution of the sample from the TLC plate. The amount of material needed to obtain an adequate spectrum is in the order of a few micrograms of lipids per band for both positive and negative ion detection. By scanning the plates, mass spectral and chromatographic information can be obtained simultaneously, which was shown to be useful for the qualitative identification of the components on the plates.

Chromatography, Thin Layer↗
PubMed1984

Lysosomal involvement in cellular turnover of plasma membrane sphingomyelin.

At least two isoenzymes of sphingomyelinase (sphingomyelin cholinephosphohydrolase, EC 3.1.4.12), including lysosomal acid sphingomyelinase and nonlysosomal magnesium-dependent neutral sphingomyelinase, catalyse the degradation of sphingomyelin in cultured human skin fibroblasts. A genetically determined disorder of sphingomyelin metabolism, type A Niemann-Pick disease, is characterized by a deficiency of lysosomal acid sphingomyelinase. To investigate the involvement of lysosomes in the degradation of cellular membrane sphingomyelin, we have undertaken studies to compare the turnover of plasma membrane sphingomyelin in fibroblasts from a patient with type A Niemann-Pick disease, which completely lack acid sphingomyelinase activity but retain nonlysosomal neutral sphingomyelinase activity, with turnover in fibroblasts from normal individuals. Plasma membrane sphingomyelin was labeled by incubating cells at low temperature with phosphatidylcholine vesicles containing radioactive sphingomyelin. A fluorescent analog of sphingomyelin, N-4-nitrobenzo-2-oxa-1,3-diazoleaminocaproyl sphingosylphosphorylcholine (NBD-sphingomyelin) is seen to be readily transferred at low temperature from phosphatidylcholine liposomes to the plasma membranes of cultured human fibroblasts. Moreover, when kinetic studies were done in parallel, a constant ratio of [14C]oleoylsphingosylphosphorylcholine ( [14C]sphingomyelin) to NBD-sphingomyelin was taken up at low temperature by the fibroblast cells, suggesting that [14C]sphingomyelin undergoes a similar transfer. The comparison of sphingomyelin turnover at 37 degrees C in normal fibroblasts compared to Niemann-Pick diseased fibroblasts shows that a rapid turnover of plasma membrane-associated sphingomyelin within the first 30 min appears to be similar in both normal and Niemann-Pick diseased cells. This rapid turnover appears to be primarily due to rapid removal of the [14C]sphingomyelin from the cell surface into the incubation medium. During long-term incubation, an increase in the formation of [14C]ceramide correlating with the degradation of [14C]sphingomyelin is observed in normal fibroblasts. In contrast, the level of [14C]ceramide remains constant in Niemann-Pick diseased cells, which correlates with a higher level of intact [14C]sphingomyelin remaining in these cells compared to normal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Chloro-7-nitrobenzofurazan↗
PubMed1986

Varied citrus treatment of ruminant gagging in a teenager with Batten's disease.

Chronic ruminant gagging was substantially reduced in a severely retarded 13-year-old girl with Batten's disease through the use of contingent citrus juice in an ABAB design. Previous literature suggests that citrus juice may not be effective for treatment of rumination in older and/or handicapped children due to habituation. In this study, habituation may have been prevented by alternating lime juice and lemon juice when ruminative gagging reached a predetermined rate. The lemon/lime variation offers an effective, practical, and acceptable alternative to other response suppression procedures for rumination.

Adolescent↗
PubMed1976

Isolation of acidic glycopeptides from urine by means of anion-exchange resins. Application to some cases of glycosphingolipidosis or mucolipidosis.

An acidic fraction containing aminosugar was isolated by means of Dowex 1 from normal human urine which had previously been filtered through Ecteolacellulose. After purification, the fraction was shown to be composed of peptides and carbohydrates in comparable amounts. Threonine, serine and dicarboxylic acids were the principal amino acids. The carbohydrate moiety was mainly composed of galactose and glucosamine in the approximate ratio 3 : 1, together with smaller amounts of fucose, sialic acid, galactosamine and mannose. The presence of an O-glycosidic bond to threonine was shown by alkali treatment in reducing conditions. The fraction is probably a mixture of acidic glycopeptides. Fractions showing similar characteristics were isolated from urine of patients with Niemann-Pick disease, Gaucher's disease, I-cell disease, Ehlers-Danlos syndrome. Slight differences from the normal were found in the composition of the fraction isolated from GM1-gangliosidosis type 1.

Amino Acids↗
PubMed1977

GM1-ganglioside beta-galactosidase in leukocytes and cultured fibroblasts.

GM1-ganglioside hydrolysis by leukocytes and fibroblasts, tissues easily obtainable from patients, was investigated using 3H-labeled GM1 and was found to be at least as active as that reported for any other tissue. Sodium taurocholate was required for the reaction, the crude bile salt at an optimum concentration of 0.4% producing twice as much activity as pure taurocholate at its optimum concentration of 0.8%. Leukocyte GM1-ganglioside beta-galactosidase and 4-MU-beta-gal cleaving activities were similar, 134.5 +/- 23.3 and 179.8 +/- 25.4 nmol/h/mg protein, respectively. In cultured skin fibroblasts and amniotic fluid cells these enzyme activities were 4 to 5 times higher. Homozygotes for GM1-gangliosidosis showed negligible activity while in heterozygotes the leukocyte GM1-cleaving activity was reduced to one-third of control values. In leukocytes from patients with four other sphingolipid storage diseases the activity was either normal (Krabbe's, Tay-Sachs, Metachromatic leukodystrophy) or increased (adult Gaucher's).

Adult↗
PubMed1985

Studies on a sphingolipid activator protein (SAP-2) in fibroblasts from patients with lysosomal storage diseases, including Niemann-Pick disease Type C.

Sphingolipid activator protein-2 (SAP-2) has been found to stimulate the enzymatic hydrolysis of at least three sphingolipids, glucosylceramide, galactosylceramide and sphingomyelin. Using monospecific antibodies against SAP-2 the level of SAP-2 was determined in cultured skin fibroblasts by rocket immunoelectrophoresis. Extracts from 14 controls had 1.03 +/- 0.28 micrograms cross-reactive material/mg solubilized protein and extracts from 46 patients with Niemann-Pick disease Type C had 1.12 +/- 0.26. Extracts from other lysosomal storage diseases, including Gaucher disease, Krabbe disease and Niemann-Pick disease Types A, B and D, had normal or slightly elevated SAP-2 concentrations, while extracts from patients with I-Cell disease had half normal SAP-2 concentration. When the fibroblast extracts were subjected to sodium dodecylsulfate-polyacrylamide gel electrophoresis followed by electroblotting and immunochemical staining two major SAP-2 bands with estimated molecular weights of 9000 and 10000 were found. Extracts from patients with I-Cell disease showed only a faint higher molecular weight band. Isoelectric focusing followed by electroblotting and immunochemical staining demonstrated no significant difference in the charge of SAP-2 obtained from different cell lines. In this study we could not demonstrate any change in concentration, size or charge of SAP-2 in fibroblast extracts from Niemann-Pick disease Type C, and we provided evidence that SAP-2 might be subject to post-translational processing similar to that of lysosomal enzymes.

Adolescent↗
PubMed1995

Tissue accumulation of sulfatide and GM3 ganglioside in a patient with variant Farber disease.

We analyzed the lipids in the tissues of a patient with an atypical form of Farber disease who developed several clinical symptoms not seen in patients with typical Farber disease (acid ceramidase deficiency). Lipids were extracted from formalin-fixed brain, liver and kidney and purified by ion exchange and silica gel column chromatographies and further by high-performance liquid chromatography on a silica gel column. We performed structural and quantitative analyses of three lipids named lipids X, Y and Z. Lipid X accumulated in the liver but not in the brain. Accumulation of lipids Y and Z was observed in liver and kidney. The content of lipid Y in the patients liver was more than ten times that in a control. The structures of lipids X, Y and Z were confirmed by means of 1H-nuclear magnetic resonance spectroscopy, fast atom bombardment mass spectrometry, infrared absorption spectroscopy, and component analysis involving gas liquid chromatography and gas chromatography-mass spectrometry. The structures of lipids X, Y and Z were identified as those of ceramide, sulfatide and GM3 ganglioside, respectively. These results suggest two possibilities. One is that the accumulation of glycolipids such as sulfatide and GM3 ganglioside is a secondary event produced by the accumulation of ceramide due to ceramidase deficiency. The other is that the accumulation of glycolipids other than ceramide is due to a deficiency of sphingolipid activator proteins which may affect the degradation of sulfatide and GM3 ganglioside as well as ceramide.

Acid Ceramidase↗
PubMed1977

Heritable catabolic and anabolic disorders of lipid metabolism.

The principal manifestations and metabolic defects in ten heritable disorders of lipid metabolism are discussed. Facile procedures have been developed for the diagnosis of patients with these conditions, the identification of heterozygous carriers, and the prenatal detection of any of these diseases. Enzyme replacement appears promising for patients with Fabry's disease and Gaucher's disease who do not have central nervous system damage. The clinical and biochemical abnormalities that occur in patients with a novel inherited disorder of ganglioside anabolism are described.

Adult↗