Glycoprotein Storage Diseases

Glycoprotein & Related Storage Diseases are very rare, progressive, largely untreatable metabolic enzymatic defects inherited by children from both parents. The worldwide incidence for these diseases as a group has not yet been determined accurately, though they can certainly be classified as ultra-rare. The course of these disorders affects multiple systems of the body and clinical symptoms may vary patient-to-patient, and even among siblings. For most children the implications are eventual loss of mental and physical functions, and a premature death.

As the name implies, Glycoproteins are complex compounds composed of a protein and a carbohydrate. There are many different types of glycoproteins and they are found in abundance in all kinds of cells, including those of the brain. Glycoproteins play many roles in cells; some of these are well known, but others have yet to be discovered. Known roles include acting as an agent for communication between cells and assisting in maintaining the cell’s structure. The carbohydrate portion of glycoproteins is usually made of combinations of sugar molecules such as glucose, galactose, mannose and fucose, which are collectively known as oligosaccharides.

Normal functioning of the cell is characterized by the continual degradation of glycoproteins by enzymes within the lysosomes, which are membrane-bound compartments in the cell and essentially the cell’s recycling center. Specific enzymes are needed along each “step” of the recycling process in order that the continual, complete breakdown of these chains of glycoproteins is carried out. Any malfunction along the way results in the premature termination of the process with a resulting accumulation of the undegraded material within the lysosome. Today we recognize six different types of diseases caused by a defect in glycoprotein degradation: Alpha-Mannosidosis, Aspartylglucosaminuria, Beta-Mannosidosis, Fucosidosis, Galactosialidosis, Schindler Disease and Sialidosis. Two other related Glycoprotein Storage Diseases are I-Cell Disease (Mucolipidosis II) and Pseudo-Hurler Polydystrophy (Mucolipidosis III). These disorders are caused by trafficking errors that limit normal targeting of digestive enzymes, which are themselves glycoproteins, to the lysosomes and prevent the lysosome from functioning normally.

These diseases are a subset of a larger group of disorders known as Lysosomal Storage Diseases, which consist of over 40 autosomal recessive inherited metabolic diseases.

Inheritance
Glycoprotein & Related Storage Diseases are autosomal recessive conditions, meaning that a defective trait or mutation passed on from both parents is required for the disease to be expressed. Every person carries two copies of a gene, one of which they pass on to their offspring (the other provided by the second parent). In many cases, we all have a mutation or defect in some of our genes, but do not show signs of the defect because the other gene is able to allow us to function “normally.” In autosomal recessive diseases, the condition occurs when both copies of a gene are defective.

Since each parent donates a single gene copy to each offspring, there are four possible inheritance patterns for diseases to occur.


Since most people can live apparently normal lives with one healthy half of a gene pair, recessive gene disorders are relatively rare. However, as shown above, 50 % of people inheriting an unexpressed, or recessive, gene defect are known as carriers. Carriers have the ability to continue a family’s mutation to the next generation. Over time, though, the mutation will become diluted unless a carrier mates with another carrier.

Two carrier parents have a 25% chance of giving birth to a child with an autosomal recessive disease. Because these odds occur for each pregnancy, it is possible, though not likely, that a family may have more than one child with a genetic disease. There is a greater likelihood, 50%, that offspring of two such parents will be a carrier and continue to pass on the defect to future generations. Lastly, a 25% chance exists that a child born to two carrier parents will be completely healthy. Such a child inherits two good gene copies and, thus, will not pass the gene defect to its heirs.

For couples who have a known history of the same recessive genetic disease in their families, carrier testing is a possibility to assist with family planning. However, testing for a genetic defect without such prior knowledge or history is not possible or recommended for most autosomal recessive diseases.