Diagnosing Alpha-mannosidosis (AM) In Practice

Alpha-mannosidosis is an ultra-rare lysosomal storage disorder caused by mutations in the MAN2B1 gene, leading to a deficiency of alpha-mannosidase. This results in the accumulation of mannose-rich oligosaccharides in tissues and fluids, causing multisystem dysfunction. Although classically considered rare (1 in 500,000 to 1 million births), it is likely underdiagnosed due to its broad clinical presentation and overlap with more common disorders.

Dr. Guffon details key early symptoms: hearing loss (nearly universal), speech delay, cognitive deficits, and recurrent infections (due to immunoglobulin J deficiency). Additional features include macrocephaly, subtle dysmorphia, motor incoordination, and skeletal issues like genu valgum and osteoporosis. Psychiatric manifestations—hallucinations, psychosis, depression—often appear after age 10. She emphasizes that phenotypic variability is high, even among siblings, and classification into mild, moderate, and severe types often fails in clinical practice.

Using four detailed case studies, Dr. Guffon demonstrates how diagnosis is often delayed or missed. In multiple cases, children initially suspected of having mucopolysaccharidosis (MPS) had normal glycosaminoglycan (GAG) results, but further testing revealed alpha-mannosidosis. She strongly urges clinicians to order urinary oligosaccharide screening when MPS is suspected but tests return normal. Enzyme activity assays and confirmatory genetic analysis are also essential.

A major focus is placed on practical diagnostic algorithms developed using a Delphi-like methodology. For children under 10, key entry symptoms include hearing loss or speech delay, often accompanied by subtle motor or skeletal abnormalities. For older children and adults, indicators shift toward cognitive decline, psychiatric symptoms, and motor regression.

Dr. Guffon closes with recommendations for routine screening protocols: in any child with unexplained hearing loss, developmental delay, recurrent ENT infections, or behavioral symptoms, alpha-mannosidosis should be considered—even if initial metabolic screens (like GAGs) are negative.

This session underscores the value of vigilance, structured evaluation, and early referral to expert metabolic centers to enable timely diagnosis and treatment, including enzyme replacement therapy where appropriate.