Last Updated: October 28, 2025
Introduction to α-Mannosidosis
Alpha-mannosidosis (α-mannosidosis) is an autosomal recessive inherited disease that belongs to the family of disorders identified as lysosomal storage diseases. This disorder is characterized by the lysosomal accumulation of small mannose-rich oligosaccharides. These glycoconjugates accumulate in the lysosomes as a consequence of defects in the lysosomal hydrolase, α-mannosidase, class 2B, member 1. The major oligosaccharide excreted by α-mannosidosis patients is the trisaccharide Man(α1,3)Man(β1,4)GlcNAc (represents mannose linked to mannose via a α-1,3 glycosidic bond and then linked to N-acetylglucosamine via a β-1,4 glycosidic bond).
Molecular Biology of α-Mannosidosis
Humans express several genes encoding mannosidase enzymes and these genes are divided into two families called mannosidases type alpha and mannosidases type beta. The mannosidase type alpha family is further divided into three subfamilies identified as alpha class 1, alpha class 2, and endo-alpha. The alpha class 1 subfamily contains seven genes. The alpha class 2 subfamily contains five genes, and the endo-alpha subfamily contains two genes. The mannosidase type beta family is composed of two gene.
The α-mannosidase, class 2B, member 1 enzyme is encoded by the MAN2B1 (mannosidase, alpha, class 2B, member 1) gene. The MAN2B1 gene is located on chromosome 19p13.13 spanning 21.5 kb and comprising 24 exons that generate two alternatively spliced mRNAs. These two mRNAs encode proteins of 1011 amino acids (isoform 1) and 1010 amino acids (isoform 2). The only difference in these two proteins is that isoform 2 lacks an internal glutamine (Q) residue.
Biochemical characterization of the protein products of the MAN2B1 gene reveal that α-mannosidase undergoes a complex series of processing events. The precursor protein is processed into three distinct glycoproteins of 70 kDa, 42 kDa, and 13/15 kDa. In addition, the 70 kDa species is further processed into three additional peptides linked by disulfide bonds. These three 70 kDa-derived peptides are identified as the A, B, and C peptides of the MAN2B1 gene. The 42 kDa peptide is referred to as the D peptide and the 13/15 kDa peptide is referred to as the E peptide.
As of 2025 there have been a total of 162 pathogenic mutations identified in the MAN2B1 that result in α-mannosidosis.
Clinical Features of α-Mannosidosis
Although the clinical spectrum of α-mannosidosis is broad, the disease has been divided into three general categories defined by age of onset of pathology and the overall symptoms.
Type I disease is referred to as the mild form with symptoms typically being recognizable after 10 years of age. The typical symptoms of the type I disease are mild skeletal deformities and cognitive impairment.
Type II disease is referred to as the moderate form with typical symptoms appearing before 10 years of age. The typical symptoms of type II disease, which exhibit a slow rate of progression, include myopathy, dysmorphic facial features, immune
deficiency, dysostosis multiplex, ataxia and progressive cognitive impairment.
Type III disease is the most severe and is associated rapid progression of symptoms that include severe skeletal abnormalities in early infancy and progressive psychomotor deterioration leading to early death from primary central nervous system involvement or infection.
Overall, patients with α-mannosidosis will exhibit varying levels of intellectual impairment, coarse facial features, corneal opacities, and a constellation of skeletal abnormalities referred to dystosis multiplex.
Dystosis multiplex is characterized by an enlarged skull, thickened calvarium, premature closure of lamboid and sagittal sutures, shallow orbits, enlarged J-shaped sella turcica (a saddle-shaped skull structure into which sits the bottom of the pituitary gland), and abnormal spacing of the teeth with dentigerous cysts. There is anterior hypoplasia of the lumbar vertebrae, the long bone diaphyses are enlarged and an irregular appearance of the metaphyses. The epiphyseal centers not well developed, the pelvis is poorly formed with small femoral heads and coxa valga. The clavicles are short, thick and irregular and the ribs are oar shaped. Phalanges are shortened and trapezoidal in shape.
Patients with the type III form of the disease suffer from rapid mental deterioration, have pronounced hepatosplenomegaly and much more severe dystosis multiplex than type II patients. Type I and type II patients have a more normal early developmental period. Intellectual impairment only becomes apparent in type II patients during childhood or adolescence. Analysis for the presence of vacuolated lymphocytes is a useful diagnostic finding in α-mannosidosis patients.