Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpCeramide TrihexosideRelated terms:KeratoconusCorneaFabry DiseaseDescemet s MembraneAlpha-GalactosidaseCorneal DystrophyDystrophyEndothelial DystrophyStromaView all TopicsDownload as PDFSet alertAbout this pagePeripheral Neuropathy in Inherited Metabolic DiseaseMarc C. Patterson, Alan K. Percy, in Neuromuscular Disorders of Infancy, Childhood, and Adolescence (Second Edition), 2015BiochemistryDeficient α-galactosidase (trihexosylceramide α-galactosidase) activity is the basis for Fabry disease.50 Trihexosylceramide is an important membrane sphingolipid in kidney and the first intermediate in the degradation of globoside, the prominent sphingolipid of red cell membranes. In Fabry disease, trihexosylceramide accumulates in kidney, liver, and lung from 30 to 300 times normal levels. A lesser degree of digalactosylceramide accumulation is also seen, primarily in the kidney. Diagnosis can be made in leukocytes and cultured skin fibroblasts, and numerous mutations are described.51–53View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780124170445000196Whipple DiseaseIn Diagnostic Pathology: Lymph Nodes and Extranodal Lymphomas (Second Edition), 2018DIFFERENTIAL DIAGNOSISMycobacter i um avium-intracellulare Infection•Granulomas often ill defined, irregular, or serpiginous with variable plasma cells and neutrophils•PAS(+), acid-fast (+)Mycobacterium tuberculosis Infection•Caseating granulomas with Langhans-type giant cells•PAS(-), acid-fast (+)Lysosomal Storage Disorders, PAS(+)•Fabry disease○Intracellular accumulation of galabiosylceramide (ceramide trihexoside) and digalactosyl ceramide○Involves skin, renal glomeruli, and tubular epithelium, blood vessels, corneal epithelium, myocardium, and ganglion cells•Gaucher disease○Histiocytes with abundant, finely fibrillar, pale blue-gray cytoplasm that is crinkled or wrinkled paper-like○Confirm diagnosis with absence of glucocerebrosidase in peripheral blood monocytesDiseases Related to GI Tract Malabsorption•Abetalipoproteinemia○Marked fat vacuoles in apical villous cytoplasm○Fat stains highlight lipid vacuoles•Agammaglobulinemic sprue○No plasma cells in lamina propria•Disaccharidase (lactase) deficiency○Serum enzyme measurement•Intestinal lymphangiectasia○Dilated lymphatic channels cause protein-rich fluid in lamina propria and intestinal lumen, cause protein-losing enteropathyView chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780323477796500181Carbohydrates and Their Derivatives Including Tannins, Cellulose, and Related LigningsGerhild van Echten-Deckert, Konrad Sandhoff, in Comprehensive Natural Products Chemistry, 19993.05.2.3.1 Substrate specificity and topology of glycosyltransferasesTransfer of subsequent sugars to LacCer to form various trihexosylceramides, thus defining the core structure and diversity of the respective GSL series (Figure 1), as well as the sequential addition of further monosaccharide or sialic acid residues to the growing oligosaccharide chain, is catalyzed by membrane bound glycosyltransferases, which have been shown to be restricted to the lumenal leaflet of the Golgi apparatus.57–60 In other words, higher GSLs are synthesized in the Golgi lumen and they cannot translocate towards the cytosolic leaflet.55 Their transport follows the kinetics of vesicular traffic.61,62 As demonstrated for rat liver Golgi, sequential glycosylation of analogous precursors, which differ only in the number of neuraminic acid residues bound to the inner galactose residue of the oligosaccharide chain, is catalyzed by a set of rather unspecific glycosyltransferases (Figure 7).50 As illustrated by Figure 7, the number of sialic acid residues bound to the inner galactose of the carbohydrate chain (0, 1, 2 or 3) determines to which series (asialo, a, b or c, respectively) a certain ganlioside belongs. It has been shown, in rat liver Golgi, that only one GalNAc-transferase catalyzes the reaction from LacCer, GM3, GD3, and GT3 to GA2, GM2, GD2, and GT2, respectively,64,65 and accordingly, only one galactosyltransferase is responsible for the formation of GA1, GM1a, and GD1b from GA2, GM2 and GD2, respectively. Similar results were obtained for sialyltransferase IV64 and sialyltransferase V.66 Kinetic studies in rat liver Golgi came to the conclusion that sialyltransferases I and II which catalyze the initial sialylation steps are more specific for their substrate.67 On the other hand, Nara et al.68 reported that cloned sialyltransferase II (GD3 synthase) isolated from human melanoma cells69 also has sialyltransferase V activity, catalyzing the formation of GD3 and of GD1c, GT1a and GQ1b in vitro. Furthermore, by transfection of the cloned human α 2,8-sialyltransferase cDNA, transient and stable expression of GT1a and GQ1b was also observed in COS-7 cells as well as in Swiss 3T3 cells, both of which originally lacked sialyltransferase II and sialyltransferase V activities.Several other sialyltransferases have been cloned and analyzed.70 The overlapping substrate specificities of different sialyltransferase families observed in vitro must not necessarily be relevant for the much more complex in vivo situation.70 A species-specific substrate specificity of different sialyltransferases, as well as the existence of isoenzymes in different cell types can also not be excluded. Thus, a ganglioside-specific sialyltransferase, catalyzing the formation of both GD3 and GT3 is specifically expressed in neural tissues.71 Among human tissues the expression of its mRNA is highly restricted to fetal and adult brain.71View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780080912837001016Non-Neoplastic KidneySHARDA G. SABNIS, ... ZDENA PAVLOVA, in Modern Surgical Pathology (Second Edition), 2009Clinical PresentationAs a consequence of the deficiency, neutral glycosphingolipids, predominantly ceramide trihexoside and cerebroside dihexoside, accumulate in many organs, including the kidney. These substances cause a clinical syndrome with punctate skin lesions, renal disease, and shooting pain in the lower extremities. Systemic manifestations result from accumulation of glycosphingolipids in blood vessels, heart, kidney, and other organs. Renal manifestations occur in approximately 50% of patients. Renal involvement is manifested by polyuria and polydipsia, which are caused by decreased concentrating ability, hematuria, and proteinuria, usually developing in the second decade with gradual decrease in renal function by the third or fourth decade.400 Death occurs around the fifth decade of life as a result of renal, cardiac, and cerebrovascular involvement. It was initially thought that kidney transplantation would provide the missing enzyme, but this procedure produces no significant release of the enzyme, and the disease continues to progress.401 One potential treatment is recombinant a-Gal A, which is available and should be considered for eligible individuals.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9781416039662000291Lysosomal storage disordersC. Yu, in Biomarkers in Inborn Errors of Metabolism, 201710.4.4 Plasma (or Urine) Globotriaosylsphingosine (Lyso-Gb3)Similarly to Gaucher disease, globotriaosylceramide (Gb3), also named ceramidetrihexoside (CTH), is the primary lipid storage in Fabry disease. However, recently, the deacylated substrate lyso-Gb3 has proven to be the hallmark biochemical marker for Fabry disease manifestation. In vitro exposure with lyso-Gb3, not Gb3, resulted in marked proliferation of smooth muscle cells in culture, which indicates the vasoactive effects of this metabolite.20 Plasma lyso-Gb3 concentration is elevated 250-fold in classic male Fabry patients, in contrast to the 3-fold increase of Gb3. Plasma lyso-Gb3 level is also unequivocally highly elevated in classic female patients, in contrast to the normal Gb3 level in female carriers. Therefore the plasma lyso-Gb3 can be used as a diagnostic test for Fabry disease in both males and females.20,56 Additional analogs of lyso-Gb3 have been reported in urine and can be quite abundant in Fabry patients. The diagnostic and monitoring values of these analogs for Fabry disease have yet to be determined.57–59View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128028964000171Fabry DiseaseIn Diagnostic Imaging: Brain (Third Edition), 2016PATHOLOGYGeneral Features•Etiology○Disorder of glycosphingolipid metabolism○α-galactosidase A deficient activity□Causes progressive accumulation of glycosphingolipids (ceramide trihexoside)–Vascular endothelium and smooth muscle cells affected–Endothelial accumulation causes ↓ vessel lumen–Parenchymal cells in kidney, heart, and brain affected□Leads to myocardial ischemia and stroke•Genetics○X-linked inheritance, abnormality in GLA gene•Associated abnormalities○Left ventricular hypertrophy, short PR interval, AV block○Renal cysts (subcapsular predilection)○Lung (bronchial thickening)○LymphedemaGross Pathologic Surgical Features•Characteristic lateral pulvinar Ca++Microscopic Features•Glycosphingolipid deposits○Form lamellate membrane-like structure (myeloid or \"Zebra bodies”)○Neurons (basal ganglia, brainstem, amygdala, hypothalamus)View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780323377546502414Anti-Gal in Humans and Its Antigen the α-Gal EpitopeUri Galili PhD, in The Natural Anti-Gal Antibody As Foe Turned Friend In Medicine, 2018Antigenic specificity of anti-GalRabbit RBC were reported to contain in their membrane two major glycolipids with terminal α-galactosyl units. These were ceramide trihexoside (CTH, with a 3-carbohydrate chain, Galα1-4Galβ1-4Glc-Cer) and ceramide pentahexoside (CPH, with a 5-carbohydrate chain, Galα1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc-Cer) (Eto et al., 1968; Stellner et al., 1973). To determine whether anti-Gal binds to any of these glycolipids, rabbit RBC glycolipids were chromatographed on thin layer chromatography (TLC) plates and immunostained with anti-Gal. As shown in Fig. 1, anti-Gal bound to CPH and not to CTH (Galili et al., 1985). The presence in human serum of antibodies that bind to rabbit CPH was also reported by other investigators (Suzuki and Naiki, 1984). The carbohydrate trisaccharide Galα1-3Galβ1-4GlcNAc was called \"Galα1-3Gal epitope” (Galili et al., 1985, 1987a,b), or \"α-galactosyl epitope” (Galili et al., 1988a) and ultimately shortened to \"α-gal epitope” (Galili et al., 1998).Analysis of the various neutral glycolipids (i.e., glycolipids-lacking sialic acid) in rabbit RBC membranes further demonstrated that glycolipids with carbohydrate chains longer than the five carbohydrates of CPH, increase in size in increments of five carbohydrates and that each increase is as a new branch (also called antenna), up to eight branches, all having the α-gal epitope (Dabrowski et al., 1984; Egge et al., 1985; Hanfland et al., 1988; Honma et al., 1981). The one exception is a glycolipid with seven carbohydrates called ceramide heptahexoside that also has one α-gal epitope at its nonreducing end (Egge et al., 1985). All these glycolipids (referred to as α-gal glycolipids) readily bind the human anti-Gal antibody (Galili et al., 1987b, 2007) (see Fig. 3 in Chapter 10 for glycolipids structure and anti-Gal binding). An α-gal glycolipid with 10 carbohydrates (ceramide decahexoside) is illustrated in Fig. 2B. Anti-Gal was also found to bind to α-gal epitopes on carbohydrate chains of glycoproteins (Towbin et al., 1987; Galili, 1993; Thall and Galili, 1990), and to synthetic α-gal epitopes on glycoproteins (Stone et al., 2007a), or to synthetic α-gal epitopes linked to silica beads (Galili et al., 1985). The carbohydrate chains carrying α-gal epitopes on glycoproteins are mostly Asn (N)-linked carbohydrate chains of the complex type, as that in Fig. 2A.Figure 2. Glycoproteins (A) and glycolipids (B) with α-gal epitopes on their carbohydrate chains (marked by dashed line rectangles). (A) α-Gal epitopes are synthesized by α1,3galactosyltransferase (α1,3GT) within the Golgi apparatus. N (asparagine)-linked carbohydrate chains of glycoproteins (left structure) are synthesized when the amino acid sequence within a protein is: asparagine–any amino acid–serine or threonine (N–X–S/T). Galactose (Gal) provided by the high-energy sugar donor uridine diphosphate galactose (UDP-Gal) is linked by α1,3GT to the nascent carbohydrate chain to generate α-gal epitopes. Each carbohydrate chain may have 2–4 branches. A similar reaction results in synthesis of α-gal epitopes on glycolipids. (B) A glycolipid is comprised of a carbohydrate chain linked to ceramide that is anchored into the membrane by its fatty acid \"tails.” This representative glycolipid has 10 sugars in its carbohydrate chain and two branches (antennae). Each branch is capped by an α-gal epitope. Glycolipids may have 1–8 branches, some of which, or all may be capped with α-gal epitopes. α-Gal epitopes on both glycoproteins and glycolipids bind the natural anti-Gal antibody. Gal, galactose; Glc, glucose; GlcNAc, N-acetylglucosamine; Man, mannose; N, asparagine; S, serine; T, threonine; UDP-Gal, uridine diphosphate galactose; X, any amino acid.Reprinted from Galili, U., 2015. Significance of the evolutionary α1,3galactosyltransferase (GGTA1) gene inactivation in preventing extinction of apes and Old World monkeys. J. Mol. Evol. 80, 1–9, with permission.Immunostaining of glycolipids on TLC plates further indicated that anti-Gal does not bind to carbohydrate chains with β-galactosyl terminal units at the nonreducing end (Galili et al., 1985; Teneberg et al., 1996). Analysis of anti-Gal binding to porcine cells further confirmed this antibody specificity, by demonstrating that anti-Gal interaction with α-gal epitopes on cell membrane glycolipids and glycoproteins cannot be inhibited by Galα1-2Gal oligosaccharides, by β-galactosyls, and by blood group O (Fucα1-2Galβ1-4GlcNAc), but it is effectively inhibited by Galα1-3Gal oligosaccharides of various lengths (Neethling et al., 1996). In vivo binding of anti-Gal to α-gal epitopes could be demonstrated in patients receiving infusion of therapeutic monoclonal antibodies. Monoclonal antibodies that carry α-gal epitopes were found to display much shorter half-life in the circulation than monoclonal antibodies lacking this epitope (Borrebaeck et al., 1993). In addition, infusion of polyethylene glycol carrying multiple α-gal epitopes into monkeys was found to effectively bind anti-Gal in the circulation (Katopodis et al., 2002; Diamond et al., 2002). α-Gal epitopes on carbohydrate chains of glycolipids and glycoproteins are illustrated in Fig. 2. The α-gal epitope should not be confused with α-gal ceramide containing only the carbohydrate galactose linked to ceramide and binding to receptors on NKT cells (Barral and Brenner, 2007).The affinity between anti-Gal and radiolabeled α-gal epitope trisaccharide was measured by equilibrium dialysis. These studies demonstrated an affinity of ∼10−6 M, whereas the disaccharide Galα1-3Gal affinity to anti-Gal is approximately sevenfold lower than that of the trisaccharide (Galili and Matta, 1996). These differences in affinity may be the reason for detection of substantially less anti-Gal in normal human serum passed through columns presenting the disaccharide epitope rather than the trisaccharide epitope (Barreau et al., 2000; Bovin, 2013). The affinity of anti-Gal to α-gal epitopes is lower by at least 100-fold than affinity of human anti-proteins antibodies to corresponding protein antigens (e.g., anti-Rh antibody). This difference is the result of lack of electrostatically charged groups on the α-gal epitope (as on all neutral carbohydrate antigens). In the absence of these charges, there are no ionic bonds between anti-Gal and the α-gal epitope. Ionic bonds are major contributors to the interaction between anti-protein antibodies and the charged amino acids comprising the corresponding antigen. Anti-Gal interaction with the α-gal epitope is likely to be mediated primarily by hydrogen bonds, hydrophobic bonds, and van der Waals forces.As indicated below, humans lack α-gal epitopes. However, TLC immunostaining analysis of 34 glycolipid molecules from various mammalian species demonstrated that, in addition to binding to α-gal epitopes on glycolipids, the only other glycolipid-binding anti-Gal is a glycolipid called x2 with the structure GalNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβl-Cer, which displays topographical similarities to CPH (Teneberg et al., 1996) and which is found in very small amounts in human RBC membranes and in other human tissues (Kannagi et al., 1982; Thorn et al., 1992). It is possible that x2 is a cryptic glycolipid on human RBC, which is exposed because of protease activity on the surface of macrophages of the reticuloendothelial system, when normal RBC lose flexibility after 120 days in the circulation (due to water loss). The exposure of x2 may result in anti-Gal binding to RBC and opsonization of these cells. The opsonized RBC are phagocytosed by macrophages of the reticuloendothelial system (Galili et al., 1986a). It was further suggested that in pathologic RBC as in β-thalassemia and sickle cell anemia, x2 is exposed already on young RBC because of the poor flexibility of these pathologic RBC and thus, prolonged exposure to reticuloendothelial macrophages. The binding of anti-Gal to the prematurely exposed x2 glycolipids ultimately may result in phagocytosis of these anti-Gal-coated RBC within few weeks after they are released from the bone marrow (Galili et al., 1986b). As discuss in the chapter on anti-Gal and autoimmunity (Chapter 8), exposure of x2 on other tissues may account for one of the possible mechanisms mediating anti-Gal binding to various tissues that display destruction by the immune system.It is of interest to note that several peptides mimetic to the α-gal epitope have been identified in peptide libraries (Kooyman et al., 1996; Zhan et al., 2003; Lang et al., 2006). The observations that anti-Gal can interact with mimetic mucin peptides (Sandrin et al., 1997; Apostolopoulos et al., 1999) further raise the question of whether binding of anti-Gal to such peptides can occur in vivo (see Chapter 8), and whether such peptides can stimulate the immune system to produce the anti-Gal antibody.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128133620000014Sphingolipid Disorders and the Neuronal Ceroid Lipofuscinoses or Batten Disease (Wolman Disease, Cholesteryl Ester Storage Disease, and Cerebrotendinous Xanthomatosis)Rose-Mary Boustany, ... Sariah El-Haddad, in Emery and Rimoin s Principles and Practice of Medical Genetics, 2013104.13.4 BiochemistryLow activity α-galactosidase A leads to the accumulation of neutral GSLs with terminal α-galactosyl residues. There is widespread accumulation of globotriaosylceramide or ceramide trihexoside (CTH) in the lysosomes of vascular endothelial and smooth muscle cells, and in the epithelial and perithelial cells of most organs. CTH levels in hemizygote males may be 30–300 times that in normals (434,556). Galabiosylceramide also reaches high levels in FD patients, but in a tissue-specific manner. Affected tissues include kidney, pancreas, right heart, lung, dehisced renal tubule cells, and spinal and sympathetic ganglia (557). Blood groups B and B1 GSLs that inhibit blood group B agglutination accumulate in patients with blood groups B and AB. GSLs are degraded in a stepwise fashion by a family of specific exoglycosidases found predominantly in lysosomes. These exoglycosidases are glycoproteins with optimal catalytic activity at acidic pH. α-Galactosidase A deficiency causes FD, whereas α-galactosaminidase B deficiency causes a type of neuroaxonal dystrophy called Schindler disease (397,558). α-Galactosidase A is a protein of ~101 kDa. Affected males have normal plasma α-galactosidase A activities, but deficient peripheral leukocyte α-galactosidase A. Plasma GSLs are synthesized in the liver and incorporated into lipoproteins in the systemic circulation. Hepatic enlargement/dysfunction is not a feature of FD, although storage occurs in hepatocytes. Twenty-five percent of the plasma GSL pool is newly synthesized each day, and a portion is derived from the turnover of senescent red blood cells. The rate of GSL exchange between plasma and that found in cell membrane has not been determined. This has to be taken into account while measuring changes in plasma CTH and while trying to correlate it to clinical response to therapy and/or disease progression. It has been suggested that the changes in urinary CTH may be a more sensitive and specific measure of tissue and body CTH burden (559).The mechanism by which accumulating GSLs cause multiorgan disease is not completely understood. It cannot be explained by pure substrate storage (560). The mechanical deposition of storage material in blood vessels was believed to lead to decreased blood supply with consequent organ dysfunction. Many secondary biochemical processes may be involved in the pathogenesis of FD. Compromised energy metabolism occurs in vitro and in vivo, and altered lipid composition of membranes can lead to abnormalities in the trafficking and sorting of raft-associated proteins, leading to cellular and organ dysfunctions (561). In the brain, the pathogenesis of FD vasculopathy may be associated with endothelial dysfunction, cerebral hyper-perfusion, and a prothrombotic state with increased production of ROS. These abnormalities are further modified by genetic and possibly other vascular risk factors.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123838346001099Pathology and Quantitation of Cutaneous InnervationWILLIAM R. KENNEDY, ... JUSTIN C. McARTHUR, in Peripheral Neuropathy (Fourth Edition), 2005Fabry s DiseaseFabry s disease is an X-linked recessive disorder caused by deficiency of α-galactosidase A activity. Hemizygotes develop deposits of neutral glycosphingolipids, principally ceramide trihexoside, throughout the nervous system but predominantly in vascular endothelial cells. A painful small fiber neuropathy develops that is difficult to detect and quantitate by conventional methods. The neuropathy can develop in children as young as 5 years of age, with characteristic episodes of acral burning pain. Twenty Fabry s disease patients (hemizygotes, ages 19 to 56 years) with preserved renal function were found to have normal nerve conduction studies and large fiber quantitation by sural nerve biopsy. By contrast, involvement of small cutaneous fibers in these patients was easily demonstrated and quantified by punch skin biopsy. All patients showed severe loss of intraepidermal innervation at the distal part of the leg, with a density of 0 to 2.4 fibers/mm versus a density for control subjects at this site of 4.7 to 6.5 fibers/mm. Fiber loss at the distal thigh was proportionately less severe. Fabry s disease patients underwent biopsy at 6-month intervals for periods ranging from 1 to 3 years with no significant longitudinal changes in density except in two patients who demonstrated a rapid decrement in innervation density following an increase in spontaneous pain.92View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780721694917500375FABRY DISEASE 272.7 (Angiokeratoma Corporis Diffusum Universale, Anderson–Fabry Disease, Glycolipid Lipidosis)Koji Hirano MD, PhD, in Roy and Fraunfelder s Current Ocular Therapy (Sixth Edition), 2008Laboratory findingsAffected males have the following:•A reduced a-galactosidase A level in plasma, serum, leukocytes, tears, and skin fibroblasts;•Elevated trihexosyl ceramide level in urine, plasma and skin fibroblasts;•Abnormal intracytoplasmic and intracellular lipid deposits.Ultrastructural examination of these inclusions in epithelial cells of the cornea, conjunctiva, and lens reveals that they consist of a single membrane surrounding concentrically arranged membranous lamellae; however; the myelin-like structures are not pathognomonic of Fabry disease.The histopathologic basis for the whorl-like corneal pattern has been the subject of debate; increasing evidence indicates that the pattern is due to a combination of:•Lysosomal granules in the epithelium (which have been detected even in fetal eyes);•Duplication of the basal lamina of the corneal epithelium.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9781416024477500839Recommended publicationsInfo iconHuman PathologyJournalMultiple Sclerosis and Related DisordersJournalPediatric NeurologyJournalHeart, Lung and CirculationJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. 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