Excellence in Pediatrics is a non-profit
global network dedicated to advancing
pediatric healthcare.
Rue des Vignerons 18, 1110 Morges 1 (VD), Switzerland
In this detailed webinar, Dr. Martin Magner explores the central nervous system (CNS) manifestations of alpha-mannosidosis (AM) and the critical importance of recognizing cognitive impairment as an early diagnostic clue. Drawing on patient data from the Czech Republic, Slovakia, and the United States, Dr. Magner outlines the natural history of AM and emphasizes its frequent misdiagnosis due to symptom overlap with mucopolysaccharidoses (MPS), especially types I and II.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by mutations in the MAN2B1 gene, leading to reduced alpha-mannosidase enzyme activity and the accumulation of oligosaccharides. This accumulation disrupts cellular functions and results in multisystemic disease. Dr. Magner notes that while AM was historically estimated to occur in 1 in 500,000 to 1 million births, increased awareness suggests a higher incidence, possibly 1 in 100,000.
Dr. Magner explains that early signs—including cognitive delay, coarse facial features, hearing impairment, and recurrent ENT infections—closely resemble those of MPS. However, AM is typically milder and progresses more slowly. He encourages clinicians to consider AM in any child with this triad of symptoms and highlights that even subtle dysmorphia or developmental delay should prompt further investigation.
A comparative analysis with MPS types I and II shows that AM patients often maintain borderline or mild cognitive impairment during the first decade of life. Regression typically becomes more evident during adolescence or adulthood. MRI findings such as white matter changes and cerebral atrophy, especially with a thin corpus callosum, are characteristic but less severe than in MPS.
The webinar also covers differential diagnosis with Tay-Sachs and other neurodegenerative conditions and discusses psychiatric symptoms like anxiety, depression, and psychosis, which often emerge in the second decade of life. Dr. Magner stresses that AM can remain underdiagnosed, especially in females, due to its subtle and slowly evolving phenotype.
Diagnostic approaches include urinary oligosaccharide screening, dry blood spot enzyme assays, and genetic testing. Importantly, he warns that not all NGS panels include the MAN2B1 gene, urging clinicians to confirm test coverage.
Dr. Magner concludes by reiterating the need for heightened clinical suspicion and earlier diagnosis to improve outcomes, emphasizing that subtle cognitive delay paired with hearing loss and mild dysmorphia should always raise the possibility of alpha-mannosidosis.