Aspartylglucosaminuria (AGU) is an autosomal recessive glycoprotein degradation defect in which glycoasparagines, mainly aspartylglucosamine, accumulate in the lysosomes of several tissues, leading to slowly progressive developmental delay. The disease has worldwide distribution, with a strong enrichment in the Finnish population due to a founder effect. The basic biochemical abnormality is the lack of activity of the lysosomal enzyme aspartylglucosaminidase, glycoasparaginase (AGA), normally present at low quantities in all tissues. The corresponding cDNA and the gene on chromosome 4q have been cloned, and multiple mutations in AGU patients have been identified. Characteristically, the mutations interfere with normal folding and intracellular processing of the enzyme, resulting in a misfolded and inactive enzyme molecule. AGA has been crystallized, and its three-dimensional structure is solved. Currently it is one of the best characterized lysosomal enzymes defective in lysosomal storage diseases.

The phenotypic manifestation of aspartylglucosaminuria is characterized by global delay of psychomotor development with onset between 2 and 4 years of age. Delayed speech and motor clumsiness are often preceded by repeated upper respiratory infections. Patients reach the developmental capacities of a 5- to 6-year-old child around puberty and thereafter slowly deteriorate to the level of severe mental retardation at adulthood. Mild connective tissue changes causing coarse facial features, thick calvarium, and osteoporosis are associated with the developmental delay. A fifth of patients have epileptic seizures during the later course of the disease. Brain magnetic resonance imaging (MRI) shows abnormalities in the differentiation between gray and white matter and signs of delayed myelination.

The primary metabolic abnormality in aspartylglucosaminuria is deficient cleavage of the bond between asparagine and N-acetylglucosamine as the final step in lysosomal breakdown of glycoproteins and oligosaccharides due to defective or absent activity of the lysosomal enzyme aspartylglucosaminidase (also called glycosylasparaginase). The main abnormal degradation product is aspartylglucosamine (N-acetylglucosaminyl-asparagine), which is accumulated in large amounts in the lysosomes in neurons and glial cells in the central nervous system but also in all visceral organs and skin. Small amounts of other glycoasparagines containing additional monosaccharide units linked to the aspartylglucosamine core are also stored in the lysosomes. The same glycosasparagines and a number of other derivative structures are excreted in the urine of patients, providing an easy way to detect and screen for aspartylglucosaminuria.

Based on its three-dimensional structure, AGA was recently shown to be the only known mammalian representative so far of N-terminal hydrolases with a structure consisting of a central four-layer sandwich of α-helices and β-sheets and a catalytic N-terminal nucleophile (threonine). AGA is synthesized as a 346-amino-acid-long enzymatically inactive precursor polypeptide that during intracellular processing in endoplasmic reticulum (ER) is dimerized and cleaved into alpha- and beta-subunits of 27 kDa and 17 kDa, respectively. The structure of the catalytic center as well as the crucial amino acids for catalysis are well characterized. The heterotetrameric mature enzyme has an unusually high pH optimum of 7–9. Complete proteolytic cleavage of the N-glycosylated polypeptides precedes asparagine-N-acetylglucosamine bond hydrolysis by AGA and this activity is independent of the length of the sugar chain. AGU patients have absent or minimal activity of the AGA enzyme in cells from various sources, including brain, liver, leukocytes, and skin fibroblasts. Heterozygotes have reduced activity, to 40–60 percent of that of controls.

The gene coding for AGA is located at 4q34-35, has a total length of approximately 13 kb, and consists of nine exons. The 2.2-kb cDNA contains a 1041-bp coding region and a long 3′ untranslated region. A missense mutation (C163S) causing disruption of a disulfide bridge in the polypeptide structure is the predominant founder mutation in the Finnish population, representing 98 percent of the disease mutations. Several other “private” mutations have been detected in families with different ethnic backgrounds.

The laboratory diagnosis of AGU can be based on (a) demonstration of urinary excretion of glycoasparagines by chromatographic techniques; (b) assays of AGA activity in leukocytes, cultured fibroblasts, or, in the case of fetal diagnosis, in cultured amniotic fluid cells or in a chorionic villus sample; or (c) identification of the disease-causing mutation in the AGA gene if the mutation in the population (Finland) or in the family is known.

Two knockout mouse models of AGU have been produced, enabling new therapeutic approaches to be evaluated. No effective treatment is presently available. Bone marrow transplantation (BMT) with successful engraftment has been performed in at least three children, in whom follow-up has demonstrated biochemical normalization and disappearance of storage lysosomes. Brain MRI has shown less abnormalities post BMT, but evidence for an effect on the course of the disease will require longer follow-up.