α-Mannosidosis is an autosomal recessive inherited disease that belongs to a 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 2B1. The major oligosaccharide excreted by α-mannosidosis patients is the trisaccharide Man(α1,3)Man(β1,4)GlcNAc: mannose linked to mannose via a α-1,3 glycosidic bond and then linked to N-acetylglucosamine via a β-1,4 glycosidic bond.
The α-mannosidase, class 2B1 gene (MAN2B1: mannosidase, alpha, class 2B, member 1) is located on chromosome 19p13.2 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 isofomr 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 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.
Although the clinical spectrum of α-mannosidosis is broad, the disease has been divided into two general categories. Type I disease is the more severe and is characterized as the infantile disease. Type I disease presents between 3 and 12 months of age and leads to fatality between 3 and 8 years of age. Type II disease is referred to as the juvenile form of the disease and usually manifests between 1 and 4 years of age. Patients with both types of disease exhibit mental retardation, 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 I form of the disease suffer from rapid mental deterioration, have pronounced hepatosplenomegaly and much more severe dystosis multiplex than type II patients. Type II patients have a more normal early developmental period. Mental retardation 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.