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Delayed diagnosis and clinical course of alpha-mannosidosis: A retrospective study of 25 patients with varying
James H Nurse1, Julia B Hennermann2, Marco A Curiati3
1University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
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.
Insights
Alpha-mannosidosis diagnosis is often delayed, especially in milder cases. Early identification of hearing and learning impairments is crucial for timely intervention in this rare lysosomal storage disorder.
Area of Science:
- Biochemistry
- Genetics
- Rare Diseases
Background:
- Alpha-mannosidosis is an ultrarare lysosomal storage disorder.
- Significant diagnostic delays occur due to symptom variability and disease rarity.
Purpose of the Study:
- Evaluate disease manifestation and clinical course in alpha-mannosidosis patients with different disease severities.
- Identify factors contributing to diagnostic delays in alpha-mannosidosis.
Main Methods:
- Retrospective chart review of 25 patients diagnosed at age ≥16 years.
- Patients categorized into mild (n=14) or moderate-severe (n=11) disease groups.
- Data collected from 11 centers across 7 countries.
Main Results:
- Longer diagnostic delays observed in mild (26.8 years) vs. moderate-severe (19.7 years) disease.
- Common initial signs: hearing impairment (mild) and learning/communication disability (moderate-severe).
- Learning/communication disability was the most frequent key diagnostic sign for both groups; genetic testing confirmed diagnosis in 90%.
Conclusions:
- Improved diagnostic algorithms are needed for timely alpha-mannosidosis diagnosis and treatment.
- Early suspicion and testing in patients with hearing, motor, or learning impairments are vital.
- Continued reassessment of adults awaiting diagnosis is recommended.
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