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. Associated genes include MAN2B1.