Aspartylglucosaminuria, often referred to as AGU, is a rare genetic, autosomal recessive disease that results in an inability of the body to breakdown fats, proteins and sugars.  This process is necessary for appropriate mental and physical development.

AGU kids are born healthy and happy.  They develop and learn skills normally.  As the disease progresses and waste builds up in their body, between the ages of 2 and 5 years, the first signs of the disease start to appear.

Life expectancy is from 25 to 35 years of age. Young adults typically die from infections.  Prior to death, AGU causes intellectual disability which progressively worsens in adolescence. Most people with this disorder lose much of the speech they have learned and affected adults usually have only a few words in their vocabulary. Adults with AGU may develop seizures or problems with movement.  There is currently no approved treatment for AGU.

Most of the reported AGU cases are found in Finland. As of 2012, there were about 260 reported cases of AGU in Finland, where the total population is about five million. One in 18,500 babies is born with AGU in Finland and 1 in 81 people in Finland are carriers of AGU.

The incidence of AGU outside Finland is unknown. The reports of the documented cases came from different countries around the world and currently account for about 50 described cases.

Science facts

Aspartylglucosaminuria, often referred to as AGU, is a rare genetic, autosomal recessive disease belonging to a group of lysosomal storage disorders. Lysosomes are cellular compartments that contain enzymes responsible for the final (cellular) breakdown of fats, proteins and sugars. This process is necessary for appropriate mental and physical development.

The basis for the disease presentation is the lack of a cellular enzyme that breaks down long sugars attached to proteins (glucoproteins). These proteins are most abundant in the body tissues and in major organs, such as the liver, spleen, thyroid and brain. When the enzyme is not working or not working properly, the sugars are not broken down in cells, leading to their excess accumulation in the body tissues and increased excretion in urine. The process is gradual, damaging the tissues and organs, progressively destroying cells and leading to eventual death. As the disorder progresses, patients typically become severely mentally and physically handicapped before dying in the third or fourth decade of their lives.

AGU is caused by mutations on the Aspartylglucosamidase (AGA) gene. Most of the reported medical information on AGU is derived from the observation of Finnish patients, which represent one genetic mutation. More than 30 different mutations of the AGA gene have been reported in patients of non-Finnish ancestry with more being discovered every year. Patients with different mutations might have different or milder/more profound signs.

AGA: Enzyme

Aspartylglucosaminidase (AGA) enzyme normal function:
Its function is proteolytic, degrading glycoprotein via hydrolytic deglycosylation. Formally classed as a hydrolase (EC, it is a member of a family called the Ntn (N-terminal nucleophilic) hydrolases. These enzymes are characterized by coding as a large pre-protein and are post-translationally cleaved by autoproteolysis to create α- and β-subunits and a new N-terminal amino acid. The heterotetrameric AGA enzyme has two active sites, consisting of an essential conserved β-chain N-terminal threonine within an active site of deep conical profile. The enzyme is novel in that it requires both the α-amino and the α-carboxyl group of the substituted amino acid residue to be free. Additionally, the same Thr residue is involved both in genesis of the active enzyme, and in catalytic function of the active site.

AGA Gene mutation:
Over 30 mutations in AGA gene have been found to cause aspartylglucosaminuria.

Most of these mutations change one amino acid in aspartylglucosaminidase. One mutation, found in 98% of people with this condition in Finland, replaces the amino acid cysteine with the amino acid serine at position 163 in the enzyme (written as Cys163Ser or C163S). Many mutations, including C163S, disrupt the proper folding of the enzyme, resulting in an AGA enzyme that cannot effectively break down glycoproteins. A buildup of glycoproteins seems to particularly affect nerve cells in the brain; loss of these cells causes a progressive decline in mental functioning and the other signs and symptoms of the disease.

Clinical Signs