Understanding alpha-mannosidosis
Alpha-mannosidosis is a rare, autosomal genetic lysosomal storage disorder (LSD) caused by mutations affecting the α-mannosidase lysosomal enzyme. If the α-mannosidase enzyme is impaired, degradation of glycoproteins is blocked and a progressive accumulation of mannose-rich oligosaccharides occurs in all tissues, leading to impaired cellular function and apoptosis.1,2
The exact prevalence of alpha-mannosidosis is not known. Reports from different countries estimate that it occurs in approximately 1 in every 500,000 to 1 in every 1,000,000 babies born worldwide.3
The condition is often diagnosed and treated using a multidisciplinary approach, involving pediatricians, orthopedists, ophthalmologists, otolaryngologists, neurologists, immunologists, neurosurgeons, and physiotherapists.4
Alpha-mannosidosis is a progressive disorder and its presence should be suspected in patients with cognitive disabilities, skeletal changes (eg, swollen joints, curved spine), hearing loss, and recurrent infections.4 Alpha-mannosidosis can impact a patient’s quality of life in many ways, including their ability to live independently, socialize, or find employment.4
Genetic features of alpha-mannosidosis
Alpha-mannosidosis is caused by mutations in the MAN2B1 gene, which encodes lysosomal α-mannosidase.4 The MAN2B1 gene includes 24 exons. It encodes a 1011 amino acid polypeptide, which is post-translationally modified in the endoplasmic reticulum of the cell.2
MAN2B1 expression appears to be highest in4:
Lung
Kidney
Pancreas
Peripheral Blood
Leukocytes
In the central nervous system, expression appears to be highest in4:
Corpus Callosum
Spinal Cord
Significantly lower levels are observed in the cerebellum, cerebral cortex, and the frontal and temporal lobes. It is not clear at present if these variations can indicate meaningful changes in disease presentation.4
Mutations in MAN2B1
When the MAN2B1 gene is not functioning correctly, as in alpha-mannosidosis, there is a loss in lysosomal α-mannosidase activity. Mutant MAN2B1 proteins can be found in different parts of the cell, including the endoplasmic reticulum and lysosomes, depending on the causative MAN2B1 mutation.2
Endoplasmic reticulum
MAN2B1 protein is folded incorrectly and is stopped in the endoplasmic reticulum.
Lysosomes
MAN2B1 protein is folded correctly, but is transported to the lysosomes in an inactive form.
There are many possible variants of the MAN2B1 mutation—127 pathogenic mutations (also termed pathogenic variants) in the MAN2B1 gene have been identified to date.2
Location of non-splicing mutations on the MAN2B1 gene sequence.5
Adapted from Khan JM et al. 2019.5
If the α-mannosidase enzyme is impaired, there is a reduction in the degradation of glycoproteins and a progressive accumulation of mannose-rich oligosaccharides in all tissues, leading to impaired cellular function and apoptosis.2
Phenotypic variability is high, even between siblings with identical genotypes. In addition to genetic factors, environmental factors may influence the disease. For instance, exposure to pathogens may cause recurrent infections and a worsening of disease symptoms.4