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:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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