RARE DISEASE
Alpha-mannosidosis
Alpha-mannosidosis
Alpha-mannosidosis
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Drug discovery
4
drugs
With orphan designations
Overview
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by MAN2B1 gene mutations, leading to deficient alpha-mannosidase enzyme activity. This results in toxic accumulation of mannose-rich oligosaccharides, causing multisystem manifestations such as intellectual disability, hearing loss, skeletal abnormalities, recurrent infections, and psychiatric symptoms. Disease severity ranges from mild (delayed onset) to severe (infantile forms with early mortality). Management focuses on symptom alleviation, enzyme replacement therapy (ERT), and hematopoietic stem cell transplantation (HSCT) in select cases [1][3][9][20].
Burden
Progressive disability: Mobility loss, cognitive decline, and skeletal deformities impair independence [4][5][17].
High caregiver strain: Up to 24 hours/day care required for severe cases, impacting employment and mental health [4][12].
Economic impact: Frequent hospitalizations, specialized care, and therapies contribute to lifelong healthcare costs [4][5][12].
Therapies
Enzyme replacement therapy: Weekly intravenous velmanase alfa (Lamzede®) improves non-neurological symptoms (e.g., mobility, respiratory function) [3][13][17].
HSCT: Stabilizes neurocognitive decline in early-stage patients but carries significant risks [13][18].
Supportive care: Includes antibiotics for infections, hearing aids, physical therapy, and psychiatric support [4][16][18].
Categories: rare bone diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
126 drug discovery papers about Alpha-mannosidosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
126 drug discovery papers about Alpha-mannosidosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-01-22 | Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children. This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017-2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records. A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)]. Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.
2025-09-02 | Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.
The lysosomal storage disease alpha-mannosidosis (AMD) is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Animal models of lysosomal diseases have demonstrated the benefit of early treatment; however, many human diagnoses occur after patients are symptomatic. We demonstrate here partial correction of the globally distributed storage lesions by infusion of a high dose of adeno-associated virus 1-feline alpha-mannosidase into the cerebrospinal fluid via the cisterna magna in the gyrencephalic AMD cat brain at different ages, corresponding with different stages of disease progression. Significant improvements in clinical parameters were observed, and partial correction was documented pre mortem by non-invasive magnetic resonance spectroscopy and diffusion tensor imaging. Post mortem analysis demonstrated that higher levels of lysosomal alpha-mannosidase activity in animals treated at 12 weeks of age did not translate into increased correction of lysosomal storage lesions throughout the brain when compared with animals treated at earlier time points. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes.
2025-08-08 | A Review on the Structure-function Relationship of Class II α-Mannsoidases
Of fundamental importance to every function an enzyme or a protein performs is its three-dimensional structure. The structure plays a crucial, though often subtle, role in catalysis. The conformational changes in enzymes are often small, and even these small changes could be significant. Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSD), immune interactions, congenital disorders, and tumour progression. Alpha-Mannosidases Class 2B is a lysosomal hydrolase. Dysfunction of this has been implicated as a causative factor in mannosidosis, a lysosomal storage disorder characterized by cognitive impairment, hearing loss, and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers, and neurodegenerative pathologies is highly ambiguous. Although many Class II α-mannosidases have been reported from various sources but not many of them have been characterized structurally. Through the combined efforts of various types of spectroscopies and protein crystallography, structure-function relationship studies in some Class II α-mannosidases from various sources have been carried out, and the same has been reported. The structure of Class II α-mannosidases from different sources has revealed the involvement of various types of folding of the protein, the presence of metal ions such as Zn+ in the active site, and their role in substrate specificity and catalytic mechanism is reviewed here.
2025-06-24 | Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis.
The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.
2024-07-01 | Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.
Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.
2026-01-22 | Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children. This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017-2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records. A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)]. Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.
2025-09-02 | Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.
The lysosomal storage disease alpha-mannosidosis (AMD) is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Animal models of lysosomal diseases have demonstrated the benefit of early treatment; however, many human diagnoses occur after patients are symptomatic. We demonstrate here partial correction of the globally distributed storage lesions by infusion of a high dose of adeno-associated virus 1-feline alpha-mannosidase into the cerebrospinal fluid via the cisterna magna in the gyrencephalic AMD cat brain at different ages, corresponding with different stages of disease progression. Significant improvements in clinical parameters were observed, and partial correction was documented pre mortem by non-invasive magnetic resonance spectroscopy and diffusion tensor imaging. Post mortem analysis demonstrated that higher levels of lysosomal alpha-mannosidase activity in animals treated at 12 weeks of age did not translate into increased correction of lysosomal storage lesions throughout the brain when compared with animals treated at earlier time points. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes.
2025-08-08 | A Review on the Structure-function Relationship of Class II α-Mannsoidases
Of fundamental importance to every function an enzyme or a protein performs is its three-dimensional structure. The structure plays a crucial, though often subtle, role in catalysis. The conformational changes in enzymes are often small, and even these small changes could be significant. Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSD), immune interactions, congenital disorders, and tumour progression. Alpha-Mannosidases Class 2B is a lysosomal hydrolase. Dysfunction of this has been implicated as a causative factor in mannosidosis, a lysosomal storage disorder characterized by cognitive impairment, hearing loss, and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers, and neurodegenerative pathologies is highly ambiguous. Although many Class II α-mannosidases have been reported from various sources but not many of them have been characterized structurally. Through the combined efforts of various types of spectroscopies and protein crystallography, structure-function relationship studies in some Class II α-mannosidases from various sources have been carried out, and the same has been reported. The structure of Class II α-mannosidases from different sources has revealed the involvement of various types of folding of the protein, the presence of metal ions such as Zn+ in the active site, and their role in substrate specificity and catalytic mechanism is reviewed here.
2025-06-24 | Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis.
The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.
2024-07-01 | Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.
Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.
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Drug Discovery Landscape
4 orphan drug designations for Alpha-mannosidosis, including 2 approved therapies.
4 orphan drug designations for Alpha-mannosidosis, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous peripheral blood-derived CD34+ haematopoietic stem and progenitor cells transduced with a lentiviral vector containing the human MAN2B1 gene | gene therapies | EMA | 2025-12-09 | — | Fondazione Telethon Ets |
adeno-associated virus serotype 6 containing human LAMAN cDNA | gene therapies | FDA | 2018-02-15 | — | Stephen G. Kaler, MD |
velmanase alfa-tycv [Lamzede] | proteins | FDA | 2006-02-02 | 2023-02-16 | Chiesi USA, Inc. |
Recombinant human α-Mannosidase [Lamzede] | proteins | EMA | 2005-01-26 | 2018-03-27 | Chiesi Farmaceutici S.p.A. |
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