RARE DISEASE
Beta-mannosidosis
Beta-mannosidosis
Beta-mannosidosis
Synonyms: Beta-mannosidase deficiency
Synonyms: Beta-mannosidase deficiency
Synonyms: Beta-mannosidase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Beta-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the MANBA gene, leading to β-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Clinical features include intellectual disability, sensorineural hearing loss, recurrent infections, behavioral disturbances (e.g., hyperactivity, aggression), peripheral neuropathy, and angiokeratomas. Phenotypic heterogeneity ranges from mild adult-onset cases to severe infantile neurodegeneration. Diagnosis involves urinary oligosaccharide analysis, enzymatic assays, and genetic testing. No disease-modifying therapies exist; management focuses on symptomatic care.
Burden
Progressive neurologic/cognitive decline, developmental delays, and multisystem complications (respiratory, renal, motor) [1][6].
High caregiving demands due to behavioral issues, communication deficits, and recurrent hospitalizations [4][16].
Lifelong disability with reduced quality of life and socioeconomic strain [6][8].
Therapies
Supportive care: Antibiotics for infections, hearing aids, neuropsychiatric support, and physical/occupational therapy [2][8][16].
Experimental Hematopoietic stem cell transplantation (limited evidence) [12].
Enzyme replacement therapy: Not yet developed for beta-mannosidosis, unlike alpha-mannosidosis [3][8].
Categories: rare bone diseases, rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
17 drug discovery papers about Beta-mannosidosis, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
17 drug discovery papers about Beta-mannosidosis, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2023-02-24 | A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution
Currently available enzyme replacement therapies for lysosomal storage diseases are limited in their effectiveness due in part to short circulation times and suboptimal biodistribution of the therapeutic enzymes. We previously engineered Chinese hamster ovary (CHO) cells to produce α-galactosidase A (GLA) with various N-glycan structures and demonstrated that elimination of mannose-6-phosphate (M6P) and conversion to homogeneous sialylated N-glycans prolonged circulation time and improved biodistribution of the enzyme following a single-dose infusion into Fabry mice. Here, we confirmed these findings using repeated infusions of the glycoengineered GLA into Fabry mice and further tested whether this glycoengineering approach, Long-Acting-GlycoDesign (LAGD), could be implemented on other lysosomal enzymes. LAGD-engineered CHO cells stably expressing a panel of lysosomal enzymes [aspartylglucosamine (AGA), beta-glucuronidase (GUSB), cathepsin D (CTSD), tripeptidyl peptidase (TPP1), alpha-glucosidase (GAA) or iduronate 2-sulfatase (IDS)] successfully converted all M6P-containing N-glycans to complex sialylated N-glycans. The resulting homogenous glycodesigns enabled glycoprotein profiling by native mass spectrometry. Notably, LAGD extended the plasma half-life of all three enzymes tested (GLA, GUSB, AGA) in wildtype mice. LAGD may be widely applicable to lysosomal replacement enzymes to improve their circulatory stability and therapeutic efficacy.
2020-04-27 | The structure of mammalian β-mannosidase provides insight into β-mannosidosis and nystagmus.
β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-mannosidase, can lead to the lysosomal storage disease β-mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-mannosidase in both the apo- and mannose-bound forms. The structure is similar to previously determined β-mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand-bound β-mannosidases from bacterial and fungal sources where bound sugars were in a boat-like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β-mannosidase deficiency. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6DDT and 6DDU.
1980-04-17 | The nature of mannose-containing material which accumulates in cultured fibroblasts from patients with mannosidosis.
Fibroblasts from a patient with mannosidosis were grown in a medium containing a radioactive monosaccharide (D-[U-14C]mannose or N-acetyl-D-[1-14C]-glucosamine). An accumulation of radioactive material was observed. It was possible to prevent the accumulation to a certain degree by the addition of human liver alpha-D-mannosidase to the fibroblast medium. After six days of fibroblast culture the majority of the accumulated material had a molecular weight in the oligosaccharide range and was stationary during high-voltage electrophoresis. Paper chromatography of the stationary material separated three radioactive compounds with the same chromatographic mobilities as the oligosaccharides alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-D-GlcNAc (I), alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-GlcNAc (II), and alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-GlcNAc (III) previously isolated from the urine of patients with mannosidosis. Degradation of the three radioactive compounds with jack bean alpha-mannosidase gave D-mannose and a disaccharide (containing D-mannose and N-acetyl-D-glucosamine). Thus the three main compounts observed in the fibroblasts from patients with mannosidosis are most probably identical to the oligosaccharides I--III.
cell therapies
2025-06-01 | Lysosomal storage diseases. Glycoproteinoses — oligosaccharidoses
The epidemiology, clinical, biochemical and molecular genetic characteristics of oligosaccharidoses are presented — a group of rare autosomal recessive lysosomal diseases, includes sialidosis, mannosidosis, fucosidosis, aspartylglucosaminuria and α-N-acetylgalactosaminidase deficiency. All these diseases are caused by impaired catabolism of glycoproteins and excessive accumulation of various types of oligosaccharides in lysosomes. Clinically, they are characterized by progressive neuropsychiatric disorders combined with a mild gurler-like phenotype. Two genetically heterogeneous variants of alpha- and beta-mannosidosis are caused by mutations in the MAN2B1 and MANBA genes, respectively, and hereditary deficiency of two related α- and β-mannosidases. The cause of the development of fucosidosis is inactivating mutations in the FUCA1 gene, leading to deficiency of lysosomal α-L-fucosidase and accumulation of fucoglycoproteins and fucoglycolipids. The pathogenesis of aspartylglucosaminuria is associated with impaired catabolism of aspartylglucosamine and its accumulation in the lysosomes of liver, spleen, thyroid, kidney and brain cells. The cause of α-N-acetylgalactosaminidase deficiency is mutations in the NAGA gene and the accumulation of uncleaved glycoconjugants in lysosomes. A description of existing experimental models is presented and their role in studying the pathogenesis of these severe lysosomal diseases and the development of various therapeutic approaches is discussed. The most successful treatment for alpha-mannosidosis has been enzyme replacement therapy using a recombinant enzyme — velmanase alfa, which has already passed phase III clinical trials and is used in clinical practice. Pathogenetic treatments for the other oligosaccharidoses discussed here have not been described, although preclinical trials have shown promise for hematopoietic stem cell transplantation and gene therapy for the treatment of β-mannosidosis and aspartyl glucosaminuria, respectively.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2019-05-21 | Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood‐onset beta‐mannosidosis
Abstract 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.
1997-08-21 | Biochemical and morphological expression of early prenatal caprine beta-mannosidosis.
Lysosomal storage diseases associated with early-onset pathological changes may require prenatal therapy to avert the profound effects of the metabolic error on organs, especially the central nervous system. The present investigation determined the extent of expression of beta-mannosidase deficiency in the caprine fetus at 62 days of gestation, near the end of the period of immunotolerance when donor cells can engraft in various organs without immune rejection and supply missing enzyme. Three pairs of obligate carrier goats from the beta-mannosidosis colony were mated. Out of six fetuses delivered at 62 days of gestation, one (V385) was identified by measurement of beta-mannosidase activity as the only fetus affected with beta-mannosidosis. Thin-layer chromatography and quantitation of oligosaccharides revealed the presence of tri- and disaccharides, typical of beta-mannosidosis, only in V385. Morphological analysis revealed cytoplasmic vacuolation typical of beta-mannosidosis in V385; in thyroid, spinal cord, and kidney, the pattern of vacuolation was similar to, but less severe than, that observed previously in newborn affected goats. On the basis of these results, it will be possible to determine the effects of prenatal cell transplantation therapeutic strategies performed during the period of immunotolerance by monitoring phenotypic characteristics after treatment.
1994-04-11 | Possible beta-mannosidosis chimera. Altered expression of metabolic perturbations.
An aberrant beta-mannosidosis phenotype in a 5-month-old triplet goat kid was characterized by a late postnatal onset of mild neurological symptoms. Necropsy examination revealed relatively normal myelination; however, the distribution of cytoplasmic vacuolation in the kidney and brain was similar to that observed in neonatal beta-mannosidosis. Variable engraftment of donor stem cells, resulting from transplacental transfusion of stem cells from a normal sibling during the immunotolerant period, may have modified the expected severe beta-mannosidosis phenotype. This investigation was designed to determine the effects of a possible chimeric state on organ-specific metabolic perturbations. Residual beta-mannosidase enzyme activity was found in plasma, kidney, liver and spleen but not in brain. Other lysosomal enzyme activities were comparable to normal values. Immunoreactive beta-mannosidase was estimated to be less than 10% of normal levels. Kidney, brain grey matter and brain white matter contained 33%, 12% and 4%, respectively, of the oligosaccharides expected in the organs of beta-mannosidosis animals. There were no detectable oligosaccharides or cytoplasmic vacuolation in the liver or spleen. Studies of this possible chimera provided preliminary evidence for the efficacy of prenatal treatment of early-onset neurodegenerative disorders.
gene therapies
2026-04-16 | An Essential Parameters of Beta-D Mannosidosis Include Signs as well as Symptoms, Brain Image, Causes, Disorders with Similar Symptoms, Diagnosis, Treatment, Clinical Trails as well as Studies
Within the broader category of lysosomal storage disorders, beta-mannosidosis (β-mannosidosis) is a very uncommon hereditary condition. Metabolic problems that lead to an accumulation of different hazardous chemicals, particularly in the lysosomal compartment of cells throughout the body, are indicative of lysosomal storage diseases. The intensity and age at which beta-mannosidosis manifests itself vary. Nearly all affected people experience some kind of intellectual handicap, and some have shown signs of delayed motor development. Other signs and symptoms can include muscle abnormalities, seizures, speech and hearing difficulties, decreased sensations in extremities, repeat ear and respiratory infections, unique facial features, and behavioral and psychiatric challenges. Beta-mannosidosis occurred by changes (variants or mutations) in the MANBA gene and is typically inherited in an autosomal recessive pattern.
2020-03-05 | Large animal models contribute to the development of therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are a group of 70 monogenic disorders characterized by the lysosomal accumulation of a substrate. As a group, LSDs affect ~1 in 5000 live births; however, each individual storage disease is rare, limiting the ability to perform natural history studies or to perform clinical trials. Perhaps in no other biomedical field have naturally occurring large animal (canine, feline, ovine, caprine, and bovine) models been so essential for understanding the fundamentals of disease pathogenesis and for developing safe and effective therapies. These models were critical for the development of hematopoietic stem cell transplantation in α- and β- mannosidosis, fucosidosis, and the mucopolysaccharidoses; enzyme replacement therapy for fucosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis; and small molecule therapy in Niemann-Pick type C disease. However, their most notable contributions to the biomedical field are in the development of gene therapy for LSDs. Adeno-associated viral vectors to treat nervous system disease have been evaluated in the large animal models of α-mannosidosis, globoid cell leukodystrophy, GM1 and GM2 gangliosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis. This review article will summarize the large animal models available for study as well as their contributions to the development of central and peripheral nervous system dysfunction in LSDs.
proteins
2023-02-24 | A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution
Currently available enzyme replacement therapies for lysosomal storage diseases are limited in their effectiveness due in part to short circulation times and suboptimal biodistribution of the therapeutic enzymes. We previously engineered Chinese hamster ovary (CHO) cells to produce α-galactosidase A (GLA) with various N-glycan structures and demonstrated that elimination of mannose-6-phosphate (M6P) and conversion to homogeneous sialylated N-glycans prolonged circulation time and improved biodistribution of the enzyme following a single-dose infusion into Fabry mice. Here, we confirmed these findings using repeated infusions of the glycoengineered GLA into Fabry mice and further tested whether this glycoengineering approach, Long-Acting-GlycoDesign (LAGD), could be implemented on other lysosomal enzymes. LAGD-engineered CHO cells stably expressing a panel of lysosomal enzymes [aspartylglucosamine (AGA), beta-glucuronidase (GUSB), cathepsin D (CTSD), tripeptidyl peptidase (TPP1), alpha-glucosidase (GAA) or iduronate 2-sulfatase (IDS)] successfully converted all M6P-containing N-glycans to complex sialylated N-glycans. The resulting homogenous glycodesigns enabled glycoprotein profiling by native mass spectrometry. Notably, LAGD extended the plasma half-life of all three enzymes tested (GLA, GUSB, AGA) in wildtype mice. LAGD may be widely applicable to lysosomal replacement enzymes to improve their circulatory stability and therapeutic efficacy.
2020-04-27 | The structure of mammalian β-mannosidase provides insight into β-mannosidosis and nystagmus.
β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-mannosidase, can lead to the lysosomal storage disease β-mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-mannosidase in both the apo- and mannose-bound forms. The structure is similar to previously determined β-mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand-bound β-mannosidases from bacterial and fungal sources where bound sugars were in a boat-like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β-mannosidase deficiency. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6DDT and 6DDU.
1980-04-17 | The nature of mannose-containing material which accumulates in cultured fibroblasts from patients with mannosidosis.
Fibroblasts from a patient with mannosidosis were grown in a medium containing a radioactive monosaccharide (D-[U-14C]mannose or N-acetyl-D-[1-14C]-glucosamine). An accumulation of radioactive material was observed. It was possible to prevent the accumulation to a certain degree by the addition of human liver alpha-D-mannosidase to the fibroblast medium. After six days of fibroblast culture the majority of the accumulated material had a molecular weight in the oligosaccharide range and was stationary during high-voltage electrophoresis. Paper chromatography of the stationary material separated three radioactive compounds with the same chromatographic mobilities as the oligosaccharides alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-D-GlcNAc (I), alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-GlcNAc (II), and alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 2)-alpha-D-Man-(1 leads to 3)-beta-D-Man-(1 leads to 4)-GlcNAc (III) previously isolated from the urine of patients with mannosidosis. Degradation of the three radioactive compounds with jack bean alpha-mannosidase gave D-mannose and a disaccharide (containing D-mannose and N-acetyl-D-glucosamine). Thus the three main compounts observed in the fibroblasts from patients with mannosidosis are most probably identical to the oligosaccharides I--III.
cell therapies
2025-06-01 | Lysosomal storage diseases. Glycoproteinoses — oligosaccharidoses
The epidemiology, clinical, biochemical and molecular genetic characteristics of oligosaccharidoses are presented — a group of rare autosomal recessive lysosomal diseases, includes sialidosis, mannosidosis, fucosidosis, aspartylglucosaminuria and α-N-acetylgalactosaminidase deficiency. All these diseases are caused by impaired catabolism of glycoproteins and excessive accumulation of various types of oligosaccharides in lysosomes. Clinically, they are characterized by progressive neuropsychiatric disorders combined with a mild gurler-like phenotype. Two genetically heterogeneous variants of alpha- and beta-mannosidosis are caused by mutations in the MAN2B1 and MANBA genes, respectively, and hereditary deficiency of two related α- and β-mannosidases. The cause of the development of fucosidosis is inactivating mutations in the FUCA1 gene, leading to deficiency of lysosomal α-L-fucosidase and accumulation of fucoglycoproteins and fucoglycolipids. The pathogenesis of aspartylglucosaminuria is associated with impaired catabolism of aspartylglucosamine and its accumulation in the lysosomes of liver, spleen, thyroid, kidney and brain cells. The cause of α-N-acetylgalactosaminidase deficiency is mutations in the NAGA gene and the accumulation of uncleaved glycoconjugants in lysosomes. A description of existing experimental models is presented and their role in studying the pathogenesis of these severe lysosomal diseases and the development of various therapeutic approaches is discussed. The most successful treatment for alpha-mannosidosis has been enzyme replacement therapy using a recombinant enzyme — velmanase alfa, which has already passed phase III clinical trials and is used in clinical practice. Pathogenetic treatments for the other oligosaccharidoses discussed here have not been described, although preclinical trials have shown promise for hematopoietic stem cell transplantation and gene therapy for the treatment of β-mannosidosis and aspartyl glucosaminuria, respectively.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2019-05-21 | Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood‐onset beta‐mannosidosis
Abstract 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.
1997-08-21 | Biochemical and morphological expression of early prenatal caprine beta-mannosidosis.
Lysosomal storage diseases associated with early-onset pathological changes may require prenatal therapy to avert the profound effects of the metabolic error on organs, especially the central nervous system. The present investigation determined the extent of expression of beta-mannosidase deficiency in the caprine fetus at 62 days of gestation, near the end of the period of immunotolerance when donor cells can engraft in various organs without immune rejection and supply missing enzyme. Three pairs of obligate carrier goats from the beta-mannosidosis colony were mated. Out of six fetuses delivered at 62 days of gestation, one (V385) was identified by measurement of beta-mannosidase activity as the only fetus affected with beta-mannosidosis. Thin-layer chromatography and quantitation of oligosaccharides revealed the presence of tri- and disaccharides, typical of beta-mannosidosis, only in V385. Morphological analysis revealed cytoplasmic vacuolation typical of beta-mannosidosis in V385; in thyroid, spinal cord, and kidney, the pattern of vacuolation was similar to, but less severe than, that observed previously in newborn affected goats. On the basis of these results, it will be possible to determine the effects of prenatal cell transplantation therapeutic strategies performed during the period of immunotolerance by monitoring phenotypic characteristics after treatment.
1994-04-11 | Possible beta-mannosidosis chimera. Altered expression of metabolic perturbations.
An aberrant beta-mannosidosis phenotype in a 5-month-old triplet goat kid was characterized by a late postnatal onset of mild neurological symptoms. Necropsy examination revealed relatively normal myelination; however, the distribution of cytoplasmic vacuolation in the kidney and brain was similar to that observed in neonatal beta-mannosidosis. Variable engraftment of donor stem cells, resulting from transplacental transfusion of stem cells from a normal sibling during the immunotolerant period, may have modified the expected severe beta-mannosidosis phenotype. This investigation was designed to determine the effects of a possible chimeric state on organ-specific metabolic perturbations. Residual beta-mannosidase enzyme activity was found in plasma, kidney, liver and spleen but not in brain. Other lysosomal enzyme activities were comparable to normal values. Immunoreactive beta-mannosidase was estimated to be less than 10% of normal levels. Kidney, brain grey matter and brain white matter contained 33%, 12% and 4%, respectively, of the oligosaccharides expected in the organs of beta-mannosidosis animals. There were no detectable oligosaccharides or cytoplasmic vacuolation in the liver or spleen. Studies of this possible chimera provided preliminary evidence for the efficacy of prenatal treatment of early-onset neurodegenerative disorders.
gene therapies
2026-04-16 | An Essential Parameters of Beta-D Mannosidosis Include Signs as well as Symptoms, Brain Image, Causes, Disorders with Similar Symptoms, Diagnosis, Treatment, Clinical Trails as well as Studies
Within the broader category of lysosomal storage disorders, beta-mannosidosis (β-mannosidosis) is a very uncommon hereditary condition. Metabolic problems that lead to an accumulation of different hazardous chemicals, particularly in the lysosomal compartment of cells throughout the body, are indicative of lysosomal storage diseases. The intensity and age at which beta-mannosidosis manifests itself vary. Nearly all affected people experience some kind of intellectual handicap, and some have shown signs of delayed motor development. Other signs and symptoms can include muscle abnormalities, seizures, speech and hearing difficulties, decreased sensations in extremities, repeat ear and respiratory infections, unique facial features, and behavioral and psychiatric challenges. Beta-mannosidosis occurred by changes (variants or mutations) in the MANBA gene and is typically inherited in an autosomal recessive pattern.
2020-03-05 | Large animal models contribute to the development of therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are a group of 70 monogenic disorders characterized by the lysosomal accumulation of a substrate. As a group, LSDs affect ~1 in 5000 live births; however, each individual storage disease is rare, limiting the ability to perform natural history studies or to perform clinical trials. Perhaps in no other biomedical field have naturally occurring large animal (canine, feline, ovine, caprine, and bovine) models been so essential for understanding the fundamentals of disease pathogenesis and for developing safe and effective therapies. These models were critical for the development of hematopoietic stem cell transplantation in α- and β- mannosidosis, fucosidosis, and the mucopolysaccharidoses; enzyme replacement therapy for fucosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis; and small molecule therapy in Niemann-Pick type C disease. However, their most notable contributions to the biomedical field are in the development of gene therapy for LSDs. Adeno-associated viral vectors to treat nervous system disease have been evaluated in the large animal models of α-mannosidosis, globoid cell leukodystrophy, GM1 and GM2 gangliosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis. This review article will summarize the large animal models available for study as well as their contributions to the development of central and peripheral nervous system dysfunction in LSDs.
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