Alpha-Mannosidosis

Impaired language:

A consequence of hearing loss and the cerebral dysfunction is a delayed ability of speech, with incomplete sentences, restricted vocabulary, and the understanding of abstracts. This handicap can be reduced with special training by a professional, both in the kindergarten as well as in the school. Sometimes sign language might be of help.

The existence of so-called Hurler-like diseases had been known for many years when in 1967 Oeckermann in Lund, Sweden, described a boy who represented an isolated case of an apparently new disorder. Mental retardation, susceptibility to infection, coarse features, and skeletal abnormalities were seen. Abnormal white blood cells containing so-called vacuoles were found. The child died of an infection, and in the tissues total mannose, a particular sugar, was strikingly increased and alpha-mannosidase activity, the enzyme which normally should take care of these sugars, showed to be only a few per cent of expected. Since then, the disease has also been found in a number of other species, like in cattle and in cats.

The following facts summarize much of what is known about Alpha-Mannosidosis. For a more complete explanation of the disease, its causes, effects and possible treatments please read Dr. Dag Malm’s review on the GeneReviews website.

In the cells of the body, proteins are synthesized in the endoplasmic reticulum and further processed in the Golgi apparatus. These are small compartments or organs inside the cell with specialized functions. Many of these proteins are coupled with sugars, forming so-called glycoproteins. In the end, these molecules have to be degraded. This takes place in the lysosomes, which are the principal sites of intracellular digestion. Glycoproteins, which are proteins containing sugar groups, serve to stabilize the membranes in lysosomes. Lysosomal alpha-mannosidase (LAMAN), in the following called mannosidase, is an enzyme that cleaves alpha-mannosidic linkages during the ordered degradation of oligosaccharides. Only after degradation, the sugars can leave the lysosomes, the cell and later the body. Defective mannosidase activity causes a block in the degradation of glycoprotein. This results in lysosomal accumulation of mannose-rich oligosaccharides chains. Consequently, these sugars are accumulated in the lysosomes because they are too big to leave. Consequently, the lysosomes increase in size, producing huge vacuoles and impaired cell function is induced. However, exactly how these sugars impair cell function is unknown.

Mannose-rich glycoproteins accumulate in all cells of the body and cause the symptoms of mannosidase. In the brain, at least in cats, mannosidosis causes abnormal shape in special nerve cells in the gray matter and the cerebellum, inducing the diffuse malfunction of the brain. In bone producing cells, architecture of the bone tissue is disturbed. In white blood cells the same vacuoles with undigested material are found with possible negative effects to the function of the white blood cells.

Mannosidosis is found in all ethnic groups in Europe, America, Africa and also Asia. So far, a diagnosis are made by measuring enzyme activity in white blood cells and eventually by measuring certain substances in urine. Diagnosis is often made late, symptoms are often mild, biochemical diagnosis difficult, and therefore the condition might be under diagnosed. There are no certain data on the prevalence of the disease. The incidence for Alpha-Mannosidosis is believed to be, with a degree of uncertainty, to be about 1:500,000.

Human mannosidosis is heterogeneous both clinically and biochemically, meaning that there is a huge variation in degree of the disease and in the residual activity of the enzyme. Symptoms of the most severe form may begin within the first months of life with rapid progression of mental retardation, liver and spleen enlargement, skeletal abnormalities, and coarse facial features. A milder form of this disorder involves normal early although mild to moderate mental retardation may develop during childhood or adolescence. Studies on diseased human fibroblasts show that whereas some secret excessive amounts of a larger, inactive mannosidase precursor, synthesis in other fibroblasts is absent. This confirms heterogeneity in mannosidosis at the level of the gene product.