A Cross-sectional Quantitative Analysis of the Natural History of Alpha-mannosidosis

Purpose: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha-mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha-mannosidosis, but evaluation regarding long-term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival.

Methods: We performed a quantitative analysis of published cases (n = 111) with alpha-mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha-mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected.

Results: Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (n = 111). Residual alpha-mannosidase activity (n = 34) predicted survival: Patients with a residual alpha-mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha-mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the USA and Germany.

Conclusion: By retrospective quantitative natural history modeling, important long-term outcome measures could be defined and expand the quantitative understanding of the clinical phenotype of alpha-mannosidosis.

Reference

1. Komatsuzaki S, Zielonka M, Mountford WK, et al. Clinical characteristics of 248 patients with Krabbe disease: quantitative natural history modeling based on published cases. Genet Med 2019;•••: 10.1038/s41436-0

No conflict of interest has been declared by the author(s).