Stem Cell Transplants Show Clinical Benefit for Rare Childhood Metabolic Disease
A 21-patient multicenter study finds HSCT improves key symptoms of alpha-mannosidosis with zero mortality, though neurodevelopmental gains need longer follow-up.
Summary
Alpha-mannosidosis is a rare inherited lysosomal storage disorder causing progressive intellectual disability, recurrent infections, and organ involvement. This retrospective multicenter study examined outcomes in 21 children who underwent hematopoietic stem cell transplantation (HSCT) after 2010. With a median follow-up of 2.3 years, no patients died. Improvements were documented in hepatomegaly, recurrent infections, and hearing disorders. Primary engraftment succeeded in 17 of 21 patients, with four requiring a second transplant. Complications included severe infections in nine patients and acute graft-versus-host disease in five. Neurodevelopmental delays persisted in most children post-HSCT, though earlier treatment showed trends toward better outcomes. The findings support HSCT as a safer, clinically beneficial option for alpha-mannosidosis management.
Detailed Summary
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme alpha-mannosidase, leading to accumulation of mannose-rich oligosaccharides. It causes progressive intellectual disability, frequent infections, hearing loss, and organ involvement, with few curative treatment options available. Understanding the real-world outcomes of hematopoietic stem cell transplantation (HSCT) in this population is critical for guiding clinical decisions.
This retrospective multicenter study enrolled 21 children (11 female) with enzymatically and/or genetically confirmed alpha-mannosidosis from centers across Europe, the United States, and the Middle East. Patients were diagnosed at a mean age of 14 months and underwent HSCT at a median age of 3.9 years, with follow-up extending up to 14.1 years.
The results were encouraging on several fronts. Notably, no patient died during the follow-up period, representing a meaningful improvement in transplant safety compared to older historical cohorts. Hepatomegaly prevalence dropped from 40% to 10% post-HSCT, recurrent infections fell from 62% to 30%, and hearing disorder rates decreased from 85% to 65%. Seventy-four percent of patients received unrelated grafts, and four required a second HSCT after initial engraftment failure — all subsequently achieving successful engraftment.
Neurodevelopmental outcomes were more complex: mild-to-significant delays persisted in 85% of children with developmental data post-HSCT, though trends suggested that earlier transplantation may correlate with higher functioning. Seven of ten patients also received enzyme replacement therapy around the time of HSCT.
The study underscores HSCT as a viable and increasingly safe intervention for alpha-mannosidosis, particularly for somatic symptoms. However, its impact on cognitive and neurodevelopmental trajectories remains uncertain and requires longer-term, larger-scale investigation to fully characterize outcomes across the phenotypic spectrum.
Key Findings
- Zero patient deaths occurred across the entire follow-up period of up to 14.1 years post-HSCT.
- Hepatomegaly prevalence dropped from 40% to 10% and recurrent infections from 62% to 30% after transplant.
- Hearing disorder rates improved modestly, decreasing from 85% to 65% of affected patients post-HSCT.
- 85% of children with developmental data still showed at least mild neurodevelopmental delays after transplant.
- Earlier HSCT showed trends toward better neurodevelopmental functioning, supporting timely intervention.
Methodology
This was a retrospective multicenter study including 21 pediatric patients transplanted after 2010 across centers in Europe, the US, and the Middle East. Outcomes were assessed at a median follow-up of 2.3 years (range 0.3–14.1 years). Clinical, developmental, and transplant-related endpoints were evaluated using pre- and post-HSCT comparisons.
Study Limitations
The study is retrospective and limited to 21 patients, restricting statistical power and generalizability. Median follow-up of only 2.3 years is insufficient to fully characterize long-term neurodevelopmental trajectories. Phenotypic heterogeneity across patients complicates outcome interpretation and comparison.
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