Aspartylglycosaminuria

Aspartylglycosaminuria is a lysosomal storage disease. Lysosomes are cell particles containing enzymes that break down large molecules. A deficiency of the lysosomal enzyme, aspartylglycosamidase, causes the accumulation of a substance known as aspartylglucosamine in the body, resulting in disorders in the various body systems.

This disorder is inherited as an autosomal recessive trait. The gene responsible for this disorder is located on the long arm of the fourth chromosome at 4q32-q33. Those affected by this disorder are most often of Finnish ancestry. However, aspartylglycosaminuria can occur in people of all heritages.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. For example, “chromosome 4q32-q33” refers to a region between bands 32 and 33 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Variants (also known as mutations) in the AGA gene cause aspartylglucosaminuria. The AGA gene provides instructions for producing an enzyme called aspartylglucosaminidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Within lysosomes, the enzyme helps break down complex chains of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). AGA gene variants result in a lack (deficiency) of the aspartylglucosaminidase enzyme in lysosomes, preventing the normal breakdown of glycoproteins. As a result, glycoproteins can build up within the lysosomes. Excess glycoproteins disrupt the normal functions of the cell and can result in cell death. A buildup of glycoproteins seems to particularly affect nerve cells in the brain; loss of these cells causes many of the signs and symptoms of aspartylglucosaminuria.