Genet Med Open. 2025 Oct 13;3:103465. doi: 10.1016/j.gimo.2025.103465. eCollection 2025.
ABSTRACT
PURPOSE: Alpha-mannosidosis is an ultrarare lysosomal storage disorder characterized by considerable diagnostic delays due to symptom heterogeneity and disease rarity. This study evaluated disease manifestation and clinical course between patients with varying disease severity to identify factors causing delayed diagnosis.
METHODS: Retrospective chart data were collected from 25 patients diagnosed at age ≥ 16 years categorized as having mild (n = 14) or moderate-severe disease (n = 11) across 11 centers in 7 countries.
RESULTS: Diagnostic delays were longer in patients with mild versus moderate-severe disease (mean [range]: 26.8 [10-46] vs 19.7 [14-30] years). Hearing impairment and learning/communication disability were common first signs in patients with mild and moderate-severe disease, respectively. Learning/communication disability was the most common key diagnostic sign for both groups. Symptoms appeared later in those with mild disease, although disease presentation was similar. Genetic testing confirmed diagnosis in 90% of patients; 64% of patients with mild disease had compound heterozygous variants vs 9% of those with moderate-severe disease. Patients on enzyme replacement therapy had improved or stabilized clinical conditions, indicating treatment importance regardless of age.
CONCLUSION: This study underscores the need for improved diagnostic algorithms to facilitate timely diagnosis and treatment of patients with alpha-mannosidosis. Early suspicion and testing for alpha-mannosidosis in patients with hearing, motor, and learning impairments, along with continued reassessment of adults awaiting confirmed diagnosis are crucial.
PMID:41334501 | PMC:PMC12666804 | DOI:10.1016/j.gimo.2025.103465
