alpha-mannosidosis

Alpha-mannosidosis is an inherited lysosomal storage disorder that primarily affects multiple organ systems, including the immune system, skeletal structure, and central nervous system. It is caused by pathogenic variants in the MAN2B1 gene, which lead to deficient enzyme activity and the accumulation of mannose-rich compounds. The condition is inherited in an autosomal recessive manner and is very rare, affecting approximately 1 to 9 individuals per million. Symptoms typically become apparent in early childhood, although the age of onset and specific manifestations can vary widely.

Individuals with alpha-mannosidosis often present with a constellation of clinical features. Most affected individuals exhibit decreased circulating alpha-mannosidase activity, and characteristic findings include intellectual disability and global developmental delay, indicating significant central nervous system involvement. Other common features include coarse facial features, a depressed nasal bridge, craniofacial hyperostosis, and skeletal dysplasia with delayed skeletal maturation. In addition, many experience hepatomegaly, splenomegaly, macroglossia, hearing impairment, and ocular abnormalities such as corneal opacity and cataract. That not all individuals experience all features, and severity varies considerably.

Alpha-mannosidosis results from pathogenic variants in the MAN2B1 gene. This gene encodes the enzyme alpha-mannosidase, which is essential for breaking down complex sugars in the lysosome. A deficiency in this enzyme leads to the accumulation of mannose-rich oligosaccharides, contributing to the multi-system manifestations observed in affected individuals. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual must inherit two copies of the altered gene—one from each parent. This condition is more common when parents share a common ancestor, as both are more likely to carry the same rare genetic variant; genetic counseling can help families understand these implications.

Currently, management of alpha-mannosidosis focuses on supportive care and symptom management, as there are no approved treatments directly targeting the underlying enzyme deficiency. Treatment is tailored to the individual and typically involves a multidisciplinary team to address the diverse clinical features. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Genetic counseling is recommended for families to understand the inheritance pattern and plan accordingly, while supportive therapies such as physical and occupational therapy can help improve quality of life.

Alpha-mannosidosis is a lifelong condition with a variable course. With current standards of care, many individuals live into adulthood; however, outcomes vary depending on symptom severity, age of diagnosis, and access to specialized care. The condition may progress, stabilize, or show a variable course in different individuals, and outcomes described in medical literature continue to evolve as standards of care improve. Patients and families are encouraged to consult with genetic counselors and specialized care teams to determine the best approach for ongoing management and support.

There are several clinical trials currently investigating new treatment approaches for alpha-mannosidosis. Active research efforts aim to improve our understanding of the disease and develop potential therapies. Individuals interested in clinical trials are encouraged to search ClinicalTrials.gov or consult their care team about eligibility for emerging studies.