Clinical outcomes in alpha-mannosidosis: a systematic review of therapeutic approaches

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Not quantifiable; narrative synthesis only. HSCT associated with neurocognitive preservation and skeletal stabilisation, particularly when performed at young age. ERT associated with improved respiratory function, reduced skeletal abnormalities, improved QoL, and favourable safety profile but limited neurocognitive benefit.

• Primary Outcome: Comparison of neurocognitive preservation, skeletal stabilisation, infection rates, respiratory function, and quality of life between HSCT (n=28) and ERT (n=75) in alpha-mannosidosis

• Nnt Or Sensitivity: Not calculable from available data; no control group, no event rates, and no quantitative outcome data provided to derive NNT or hazard ratios

• Confidence Interval: Not reported; no quantitative synthesis performed

Clinical Application

HSCT requires specialist haematology/transplant infrastructure, HLA-matched donor availability, and carries substantial procedural risk including graft-versus-host disease and transplant-related mortality — feasibility is limited to tertiary centres. ERT (velmanase alfa) requires regular intravenous infusions and lifelong administration, with feasibility dependent on healthcare system support, infusion centre access, and drug availability. Both therapies require multidisciplinary specialist teams with lysosomal storage disorder expertise. Alpha-mannosidosis is an ultra-rare condition in Australia. Velmanase alfa (Lamzede, Chiesi) received EMA approval in 2018 but does not currently have TGA registration or PBS listing in Australia as of the knowledge cutoff, meaning access would require Special Access Scheme (SAS) Category B application or participation in clinical trials. HSCT for lysosomal storage disorders is performed at a small number of Australian centres (e.g., Sydney Children's Hospital Network, Royal Children's Hospital Melbourne) under specialist metabolic disease and bone marrow transplant teams. RACGP guidelines do not specifically address alpha-mannosidosis management; referral to a metabolic disease specialist or clinical geneticist is the appropriate primary care pathway. The Australian Inherited Metabolic Diseases network and Rare Voices Australia may provide additional support resources. Newborn screening for alpha-mannosidosis is not currently part of the Australian national screening programme. Patients with confirmed alpha-mannosidosis (MAN2B1 mutation, α-mannosidase enzyme deficiency), particularly paediatric patients in whom early therapeutic intervention may modify disease trajectory. Results are most applicable to patients with mild-to-moderate disease severity prior to significant cognitive deterioration.

Abstract

BACKGROUND: Alpha mannosidosis (AM) is a rare lysosomal storage disorder caused by a deficiency in the α-mannosidase enzyme, resulting in impaired glycoprotein metabolism within lysosomes. Enzyme dysfunction is attributed to an autosomal recessive mutation in the MAN2B1 gene. Affected individuals present with a broad spectrum of manifestations, including developmental delays, cognitive decline, musculoskeletal abnormalities, hearing difficulties, and recurrent infections. Current therapeutic options are limited to hematopoietic stem cell transplantation and the more recently developed enzyme replacement therapy. OBJECTIVE: The aim of this review was to evaluate and compare the therapeutic outcomes, benefits and challenges associated with Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in the treatment of AM. METHODS: A systematic search across PubMed, MEDLINE, EMBASE, the Cochrane Library, OMIM, and ScienceDirect identified 12 original studies from 307 records. The data are presented narratively due to the scarcity of literature and the heterogeneity of study designs and interventions. RESULTS: A total of 28 patients who received hematopoietic stem cell transplantation showed improvements in preserving neurocognitive function and skeletal stabilization and reduced infection rates, especially when performed at relatively young ages. However, this treatment carries significant risks, including infections, graft-versus-host disease, and increased morbidity and mortality, particularly in older patients. Conversely, enzyme replacement therapy was administered to 75 patients, who demonstrated a favorable safety profile, enhanced respiratory function, reduced skeletal abnormalities, and improved overall quality of life. However, enzyme replacement therapy has limited efficacy in preventing neurocognitive decline and requires lifelong administration. CONCLUSION: Both interventions yield better outcomes when initiated early, particularly before cognitive deterioration becomes significant. This review emphasizes the importance of a timely diagnosis to optimize treatment outcomes and prevent severe complications.

References

1. 1.Azzi, A., Bin Shlhoob, R., & Al-Shehri, H. (2026). Clinical outcomes in alpha-mannosidosis: a systematic review of therapeutic approaches. Orphanet Journal of Rare Diseases. https://doi.org/10.1016/j.ymgme.2024.108444