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The Journal of Biological Chemistry May 1981A rapidly fatal neurovisceral storage disease was discovered in both male and female offspring of clinically normal Nubian goats. Microscopic examination of fixed...
A rapidly fatal neurovisceral storage disease was discovered in both male and female offspring of clinically normal Nubian goats. Microscopic examination of fixed tissues revealed extensive demyelination and ubiquitous distribution of lysosomal storage vacuoles containing dispersed floccular material and membranous fragments. Urine was found to contain elevated levels of both mannose and N-acetylglucosamine, suggestive of an oligosaccharide storage disease. Brain was found to contain 2.2 mumol/g of a trisaccharide Man(beta 1-4)GlcNAc(beta 1-4)GlcNAc; (Jones, M. Z., and Laine, R. A. (1980) Fed. Proc. 39, 2521 and Jones, M. Z., and Laine, R. A. (1981) J. Biol. Chem. 256, 5181-5184). A profound deficiency of beta-D-mannosidase activity was found in a number of tissues from affected goats; obligate heterozygotes showed a partial enzyme deficiency. Other lysosomal hydrolase activities were normal or elevated over normal, including alpha-D-mannosidase, confirming that this was a hitherto undescribed inborn error of glycoprotein catabolism.
Topics: Animals; Carbohydrate Metabolism, Inborn Errors; Female; Goats; Kidney; Kinetics; Male; Mannosidases; Monosaccharides; Nervous System Diseases; beta-Mannosidase
PubMed: 7228876
DOI: No ID Found -
Molecular Genetics & Genomic Medicine Jul 2019Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency...
BACKGROUND
Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available.
METHODS
We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease.
RESULTS
We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers.
CONCLUSION
Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.
Topics: Brain; Child, Preschool; Chromatography, High Pressure Liquid; Cord Blood Stem Cell Transplantation; Dried Blood Spot Testing; Humans; Intellectual Disability; Leukocytes; Magnetic Resonance Imaging; Male; Tandem Mass Spectrometry; beta-Mannosidase; beta-Mannosidosis
PubMed: 31115173
DOI: 10.1002/mgg3.712 -
The Journal of Biological Chemistry Mar 1992Goat beta-mannosidase was purified 120,000-fold in 26% yield from kidney using concanavalin A-Sepharose chromatography followed by immunoaffinity and cation-exchange...
Goat beta-mannosidase was purified 120,000-fold in 26% yield from kidney using concanavalin A-Sepharose chromatography followed by immunoaffinity and cation-exchange chromatography. When analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by Coomassie Blue staining, the purified enzyme preparation consists of 90- and 100-kDa peptides. Both these peptides react with anti-beta-mannosidase monoclonal antibodies and produce similar electrophoretic peptide patterns when subjected to limited proteolysis. Deglycosylation reduces the size of the 90- and 100-kDa peptides to 86 and 91 kDa, respectively. Goat kidney tissues lacking beta-mannosidase activity, acquired from animals affected with beta-mannosidosis, do not contain detectable quantities of the 90- and 100-kDa peptides as judged by monoclonal antibody reactivity. We postulate that the 90- and 100-kDa peptides represent two related forms of beta-mannosidase.
Topics: Animals; Antibodies; Antibodies, Monoclonal; Chromatography, Affinity; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Electrophoresis, Polyacrylamide Gel; Glycosylation; Goats; Kidney; Kinetics; Lysosomes; Mannosidases; Molecular Weight; Peptide Mapping; beta-Mannosidase
PubMed: 1556126
DOI: No ID Found -
Orphanet Journal of Rare Diseases Jan 2021Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause...
BACKGROUND
Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders.
METHODS
The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation.
RESULTS
The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/β-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS.
CONCLUSION
This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.
Topics: Chromatography, High Pressure Liquid; Fucosidosis; Glycogen Storage Disease Type II; Humans; Lysosomal Storage Diseases; Oligosaccharides; Tandem Mass Spectrometry
PubMed: 33422100
DOI: 10.1186/s13023-020-01662-8 -
The Journal of Biological Chemistry Dec 1985Four oligosaccharide fractions were isolated and purified from the kidney of goats affected with beta-mannosidosis by repeating Bio-Gel P-2 column chromatography. The...
Structural characterization of novel complex oligosaccharides accumulated in the caprine beta-mannosidosis kidney. Occurrence of tetra- and pentasaccharides containing a beta-linked mannose residue at the nonreducing terminus.
Four oligosaccharide fractions were isolated and purified from the kidney of goats affected with beta-mannosidosis by repeating Bio-Gel P-2 column chromatography. The structural characterization of the purified oligosaccharide fractions (oligosaccharides A, B, C1,2, and D) included sugar composition analysis by gas chromatography, sugar sequence analysis by mass spectrometry of their permethylated alditols, and by methylation analysis as well as anomeric configuration studies by exoglycosidase digestions. Oligosaccharides A and B were the major oligosaccharides accumulating in the kidney and were elucidated as Man beta 1-4GlcNAc and Man beta 1-4GlcNAc beta 1-4GlcNAc, respectively (Matsuura, F., Laine, R. A., and Jones, M. Z. (1981) Arch. Biochem. Biophys. 211, 485-493). Oligosaccharide C1,2 was a mixture of two tetrasaccharides and oligosaccharide D was a pentasaccharide. The proposed structures are: oligosaccharide C1, Man beta 1-4GlcNAc beta 1-4Man beta 1-4GlcNAc; oligosaccharide C2, Man alpha 1-6Man beta 1-4GlcNAc beta 1-4GlcNAc; oligosaccharide D, Man beta 1-4GlcNAc beta 1-4Man beta 1-4GlcNAc beta 1-4GlcNAc. Tetrasaccharide C1 and pentasaccharide D are heretofore undiscovered oligosaccharides. There is no precedent for these structures in glycoproteins or other glycoconjugates. One possibility which accounts for the presence of oligosaccharide C1 and D is that a bisecting N-acetylglucosamine (the beta-N-acetylglucosamine residue linked at the C-4 position of the beta-mannosyl residue of the trimannosyl core of the asparagine-linked sugar chains) is linked by a beta-mannosyl residue. Moreover, the detection of oligosaccharides containing two N-acetylglucosamine residues at the reducing terminus, together with those containing a single N-acetylglucosamine residue, is further corroboration of species-specific differences in glycoprotein catabolic pathways (Hancock, L. W., and Dawson, G. (1984) Fed. Proc. 43, 1552) or in glycoprotein structures.
Topics: Animal Diseases; Animals; Chromatography, Thin Layer; Glycoside Hydrolases; Goats; Kidney; Mannose; Mannosidases; Mass Spectrometry; Oligosaccharides; alpha-Mannosidosis; beta-Mannosidase
PubMed: 4066670
DOI: No ID Found -
The Biochemical Journal Jan 1993Lysosomal beta-mannosidase was purified 160,000-fold in 24% yield from bovine kidney by a four-step purification procedure, which included concanavalin A-Sepharose,... (Comparative Study)
Comparative Study
Lysosomal beta-mannosidase was purified 160,000-fold in 24% yield from bovine kidney by a four-step purification procedure, which included concanavalin A-Sepharose, immunoaffinity, TSK-butyl and h.p.l.c. cation-exchange chromatography. When analysed by SDS/PAGE and detected by Coomassie Blue or silver staining, the purified enzyme preparation consists of two prominent peptides (100 and 110 kDa) and a third minor peptide (84 kDa). These three peptides are immunologically related and are consistently associated with beta-mannosidase activity in all chromatographic steps. Removal of N-linked carbohydrate from the 84, 100 and 110 kDa peptides decreases their molecular sizes to 75, 86 and 91 kDa respectively. Bovine kidneys lacking beta-mannosidase, activity, acquired from calves affected with beta-mannosidosis, do not contain detectable quantities of the three beta-mannosidase peptides, as judged by monoclonal- and polyclonal-antibody reactivity.
Topics: Animals; Carbohydrates; Cattle; Cattle Diseases; Chromatography, Affinity; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Electrophoresis, Polyacrylamide Gel; Kidney; Kinetics; Lysosomes; Mannosidases; Molecular Weight; Reference Values; alpha-Mannosidosis; beta-Mannosidase
PubMed: 8424779
DOI: 10.1042/bj2890343 -
Genetics Nov 1993beta-Mannosidosis is a lethal lysosomal storage disease inherited as an autosomal recessive in man, cattle and goats. Laboratory assay data of plasma beta-mannosidase...
beta-Mannosidosis is a lethal lysosomal storage disease inherited as an autosomal recessive in man, cattle and goats. Laboratory assay data of plasma beta-mannosidase activity represent a mixture of homozygous normal and carrier genotype distributions in a proportion determined by genotype frequency. A maximum likelihood approach employing data transformations for each genotype distribution and assuming a diallelic model of inheritance is described. Estimates of the transformation and genotype distribution parameters, gene frequency, genotype fitness and carrier probability were obtained simultaneously from a sample of 2,812 observations on U.S. purebred Salers cattle with enzyme activity, age, gender, month of pregnancy, month of testing, and parents identified. Transformations to normality were not required, estimated gene and carrier genotype frequencies of 0.074 and 0.148 were high, and the estimated relative fitness of heterozygotes was 1.36. The apparent overdominance in fitness may be due to a nonrandom sampling of progeny genotypes within families. The mean of plasma enzyme activity was higher for males than females, higher in winter months, lower in summer months and decreased with increased age. Estimates of carrier probabilities indicate that the test is most effective when animals are sampled as calves, although effectiveness of the plasma assay was less for males than females. Test effectiveness was enhanced through averaging repeated assays of enzyme activity on each animal. Our approach contributes to medical diagnostics in several ways. Rather than assume underlying normality for the distributions comprising the mixture, we estimate transformations to normality for each genotype distribution simultaneously with all other model parameters. This process also excludes potential biases due to data preadjustment for systematic effects. We also provide a method for partitioning phenotypic variation within each genotypic distribution which allows an assessment of the value of repeat measurements of the predictive variable for genotype assignment.
Topics: Animals; Cattle; Cattle Diseases; Female; Gene Frequency; Genotype; Humans; Male; Mannosidases; Models, Genetic; Models, Statistical; Probability; Seasons; United States; alpha-Mannosidosis; beta-Mannosidase
PubMed: 8293984
DOI: 10.1093/genetics/135.3.855 -
The Biochemical Journal Feb 1986Cultured skin fibroblasts established from goats affected with beta-mannosidosis, an inherited neurovisceral storage disorder, showed an absence of lysosomal...
Cultured skin fibroblasts established from goats affected with beta-mannosidosis, an inherited neurovisceral storage disorder, showed an absence of lysosomal beta-mannosidase activity and the corresponding accumulation of a trisaccharide (TS) with the structure Man beta (1----4)GlcNAc beta (1----4)GlcNAc (0.4 mumol/g) and lesser amounts (0.15 mumol/g) of a Man beta (1----4)GlcNAc disaccharide (DS). By using purified storage TS isolated from fibroblasts metabolically labelled with [3H]GlcN, no conversion of TS into DS could be demonstrated in homogenates of affected cells at either lysosomal pH (4.4) or cytosolic pH (6.1), or in the culture medium (pH 7.0) of affected cells. Both TS and DS were secreted into the culture medium by affected fibroblasts. When affected fibroblasts were treated with tunicamycin before labelling with [3H]GlcN, the accumulation of both labelled TS and DS was completely inhibited. Treatment of both affected and normal goat fibroblasts with swainsonine resulted in the inhibition of lysosomal alpha-mannosidase activity and in the accumulation of the same labelled oligosaccharides in both. The major storage pentasaccharide from both normal and affected swainsonine-treated fibroblasts was sensitive to digestion with alpha-mannosidase and endo-beta-N-acetylhexosaminidase D, suggesting a branched mannose structure and a chitobiose core. In the absence of evidence for the existence of unusual N-linked glycoprotein-associated chitotriose oligosaccharide structures in affected goat fibroblasts, it must be concluded that degradative pathways for N-linked oligosaccharides are similar in both normal and affected goat fibroblasts, and that these pathways differ from catabolic pathways in human fibroblasts.
Topics: Alkaloids; Animals; Cells, Cultured; Chromatography, Gel; Fibroblasts; Glycoproteins; Goats; Mannosidases; Oligosaccharides; Skin; Swainsonine; Tunicamycin; beta-Mannosidase
PubMed: 3085658
DOI: 10.1042/bj2340175 -
JIMD Reports 2013β-Mannosidosis results from a functional deficiency of the lysosomal enzyme, β-mannosidase. While being a well recognised, naturally occurring disease in both goats...
β-Mannosidosis results from a functional deficiency of the lysosomal enzyme, β-mannosidase. While being a well recognised, naturally occurring disease in both goats and cattle, it is an extremely rare disorder in humans with the first cases only being recorded in 1986. Until now the severity of the human disease has not mirrored that of its bovine or caprine counterparts, whose presentation is typically in the neonatal period with both altered skull morphology and seizures. Human β-mannosidosis has previously appeared to be a more indolent disease, with its only consistent phenotypic feature being developmental delay of varying severity. We report a patient, homozygous for a private mutation, who presented in the immediate perinatal period with seizures and who subsequently developed communicating hydrocephalus at 2 years of age.These are two new phenotypic features for β-mannosidosis. The first being the neonatal onset of the seizures, for while seizures have been seen in 3 out of the previous 20 documented cases, they have never before manifested prior to 6 months of age. However, as in the previous documented cases, the seizures were difficult to control and were associated with severe developmental delay.The second unique feature about this case was the development of communicating hydrocephalus. We discuss the possible mechanisms of its development.In summary, β-mannosidosis must thus now be considered in the differential diagnosis of neonatal onset seizures, and the potential for the development of hydrocephalus should be monitored during subsequent clinical follow-up.
PubMed: 23588843
DOI: 10.1007/8904_2013_227 -
The Journal of Biological Chemistry Nov 1990Human beta-mannosidosis urine was fractionated by gel permeation chromatography on Bio-Gel P-2 and by high performance liquid chromatography on Partisil 10 SAX. Besides...
Human beta-mannosidosis urine was fractionated by gel permeation chromatography on Bio-Gel P-2 and by high performance liquid chromatography on Partisil 10 SAX. Besides the disaccharide Man beta 1-4GlcNAc as the major component, a sialic acid-containing compound was detected in an amount of 10% compared to that of Man beta 1-4GlcNAc. Structural characterization of the oligosaccharide and of its reduced analogue by sugar composition analysis, methylation analysis, gas-liquid chromatography-mass spectrometry, and 500-MHz 1H NMR spectroscopy gave conclusive evidence for a novel urinary constituent: NeuAc alpha 2-6Man beta 1-4GlcNAc. This linear trisaccharide can be considered as the result of an alpha 2-6-sialylation of the major accumulating compound, Man beta 1-4GlcNAc. The hitherto unknown linkage between sialic acid and mannose was shown to be susceptible to sialidase digestion.
Topics: Carbohydrate Sequence; Carbohydrates; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Gas Chromatography-Mass Spectrometry; Humans; Magnetic Resonance Spectroscopy; Male; Mannose; Mannosidases; Methylation; Molecular Sequence Data; N-Acetylneuraminic Acid; Sialic Acids; Trisaccharides; beta-Mannosidase
PubMed: 2246252
DOI: No ID Found