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A 30-minute educational webinar with Dr Nathalie Guffon (Reference Centre for Inherited Metabolic Disease, Lyon) on diagnosing alpha-mannosidosis in everyday practice. Drawing on 20 patients and four detailed cases, she shows the common signs, the wide phenotype variability, and how to use diagnostic algorithms for early identification. For paediatricians and metabolic teams.
Alpha-mannosidosis is an ultra-rare lysosomal storage disease caused by MAN2B1 variants and alpha-mannosidase deficiency, leading to accumulation of mannose-rich oligosaccharides and multisystem dysfunction. Dr Nathalie Guffon details the early symptoms — hearing loss (nearly universal), speech delay, cognitive deficits, and recurrent infections from immunoglobulin G deficiency — with additional features of macrocephaly, subtle dysmorphia, motor incoordination and skeletal problems such as genu valgum and osteoporosis, and psychiatric manifestations after age 10. She stresses that phenotypic variability is high, even between siblings with identical genotypes, so the mild/moderate/severe classification often fails in practice. Through four cases diagnosed at different ages — including one at 34 misdiagnosed as Crouzon disease — she shows how the diagnosis is missed or delayed, and that children suspected of a mucopolysaccharidosis (MPS) with normal glycosaminoglycans often turn out to have alpha-mannosidosis. Her central message is to order urinary oligosaccharide screening when MPS is suspected but the GAGs are normal, confirmed by enzyme-activity assay and genetic analysis. She reviews the age-based diagnostic algorithms (hearing loss or speech delay in children under 10; cognitive decline, psychiatric symptoms and motor regression in older patients), and a study in which 1.5% of MPS-suspected samples proved to be alpha-mannosidosis — so an MPS-like patient who tests negative should be tested for a broader set of lysosomal disorders including alpha-mannosidosis.
After viewing this webinar, participants will be able to:
Hearing loss (present in nearly all patients) and speech delay are the most consistent early signs, with cognitive deficits and recurrent infections from immunoglobulin G deficiency. Additional features include macrocephaly, subtle dysmorphia, motor incoordination and skeletal problems such as genu valgum; psychiatric manifestations — hallucinations, psychosis, depression — often appear after age 10.
No — alpha-mannosidosis is an oligosaccharidosis, not a mucopolysaccharidosis, so urinary GAGs are always normal, at any age. This is exactly why, when MPS is suspected but the GAGs come back normal, urinary oligosaccharides should be ordered — they will show the alpha-mannosidosis profile.
Because the phenotype is highly variable — even siblings with identical genotypes can differ — and many patients fit neither the mild nor the moderate type (for example, ataxia without bone abnormalities, or vice versa). Predicting an individual patient's clinical course from the classification is therefore very challenging.
In any child with unexplained hearing loss, developmental or speech delay, recurrent ENT infections, or behavioural symptoms — and in older patients with cognitive decline, psychiatric symptoms or motor regression. It should be considered even when initial metabolic screens such as urinary GAGs are negative, with confirmation by oligosaccharides, enzyme assay and genetic analysis at an expert centre.
This content is intended for healthcare professionals only. The views expressed are those of the presenters and do not necessarily reflect those of Excellence in Pediatrics; their inclusion does not imply endorsement. The content is provided for educational purposes only and does not constitute medical advice or replace independent clinical judgement.