Orphanet Journal of Rare Diseases | Evaluating Clinical Outcomes of HSCT versus ERT for Alpha-Mannosidosis

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This study systematically compares the efficacy and safety of HSCT and ERT in alpha-mannosidosis, providing critical evidence for clinical decision-making regarding intervention timing and therapeutic strategies, particularly emphasizing the importance of early diagnosis for neurocognitive function preservation.

 

Literature Overview

The article 'Clinical outcomes in alpha-mannosidosis: a systematic review of therapeutic approaches,' published in Orphanet Journal of Rare Diseases, systematically investigates the therapeutic efficacy and safety of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in alpha-mannosidosis (AM). By integrating limited yet critical clinical data through a systematic review approach, this study offers the most comprehensive evidence to date for managing this rare lysosomal storage disorder.

Background Knowledge

Alpha-mannosidosis (AM) is a rare lysosomal storage disease caused by mutations in the MAN2B1 gene, leading to alpha-mannosidase deficiency. It manifests with multisystem involvement including progressive neurocognitive decline, skeletal deformities, hearing loss, and immunodeficiency. Due to nonspecific clinical presentations, AM is often confused with other lysosomal disorders, resulting in delayed diagnosis. Current research on MAN2B1-related mechanisms is limited by the lack of effective models to predict genotype-phenotype correlations, and therapeutic options remain extremely limited. Among existing treatments, HSCT can improve neurological function but carries high transplant-related risks, whereas ERT (e.g., velmanase alfa) has favorable safety but limited impact on central nervous system (CNS) manifestations due to poor blood-brain barrier penetration. Therefore, this study focuses on comparing the clinical outcomes of these two mainstream interventions to inform personalized treatment strategies, particularly regarding early diagnosis and optimal timing of intervention.

 

Assess the pathogenicity of gene variants to provide a reference for analyzing [[MAN2B1]] mutation functions, aiding molecular diagnosis and genetic counseling for [[Alpha-mannosidosis]].

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Research Methods and Core Experiments

The authors conducted a systematic review following PRISMA guidelines, searching multiple databases including PubMed, EMBASE, and Cochrane Library, identifying 12 primary studies (involving 103 patients) with HSCT (n=28) and ERT (n=75) cohorts. Study designs included cohort studies, randomized controlled trials (RCTs), and case series, with data extraction focusing on clinical manifestations, biomarker changes, and safety events before and after treatment. Due to high heterogeneity and limited number of studies, meta-analysis was not performed; instead, a narrative synthesis was used. Key evidence came from multicenter long-term follow-up data, such as the Grewal and Mynarek cohorts, which assessed neurocognitive, skeletal, and hearing function changes post-HSCT; ERT studies relied on multicenter RCTs and open-label trials conducted by Lund and Borgwardt, monitoring pulmonary function, motor ability, and oligosaccharide levels.

Key Conclusions and Insights

• HSCT significantly delays neurocognitive decline in younger patients, with better outcomes when performed before age 6, suggesting early HSCT may protect central nervous function by reconstituting enzyme-active microenvironments
• ERT significantly improves respiratory and motor functions, with functional gains demonstrated in children via 3MSCT and 6MWT tests, supporting its central role in managing non-neurological symptoms
• Oligosaccharide levels significantly decrease in serum and urine after HSCT, indicating donor-derived cells effectively restore alpha-mannosidase activity, validating the mechanistic feasibility
• Although ERT improves immune function (e.g., increased IgG levels), it fails to reverse existing CNS lesions, highlighting blood-brain barrier limitations as a fundamental bottleneck for current ERT
• HSCT-related mortality is non-negligible, with increased risks of GVHD and infections in older patients, underscoring the need for individualized assessment of transplant timing and donor matching strategies

Research Significance and Future Perspectives

This study provides clear direction for drug development: future efforts should explore modified enzyme formulations capable of crossing the blood-brain barrier or combine ERT with gene therapy. For clinical monitoring, a comprehensive assessment system incorporating neuroimaging, biomarkers (e.g., CSF oligosaccharides), and functional scales is recommended to dynamically track treatment response. In disease modeling, animal models more closely mimicking human MAN2B1 mutation phenotypes are needed to validate therapeutic mechanisms and toxicity.

 

Input the [[MAN2B1]] gene to view its involved signaling pathways and upstream/downstream molecules, helping understand the role of alpha-mannosidase in cellular metabolic networks and supporting mechanistic research and drug target exploration.

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Conclusion

This systematic review emphasizes that early intervention is key to improving outcomes in alpha-mannosidosis, regardless of whether HSCT or ERT is used. HSCT offers unique advantages in preserving neurocognitive function, especially in younger patients, though its high-risk nature requires careful evaluation. ERT excels in improving respiratory, motor, and immune functions with high safety, making it suitable for long-term management of non-neurological symptoms. The two approaches are complementary rather than interchangeable, and future treatment strategies should move toward individualized integration. From bench to bedside, this study provides a solid evidence base for establishing newborn screening, early genetic diagnosis, and multidisciplinary management pathways, marking a significant step toward precision medicine for lysosomal storage disorders. Advancing MAN2B1 functional research and developing novel delivery systems will be essential for achieving comprehensive symptom coverage.

 

Arezki Azzi, Reem Bin Shlhoob, and Hassan Al-Shehri. Clinical outcomes in alpha-mannosidosis: a systematic review of therapeutic approaches. Orphanet Journal of Rare Diseases.