Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in AGA, the gene encoding aspartylglucosaminidase/glycosylasparaginase. AGA is required for hydrolysis of the protein-oligosaccharide linkage in Asn-linked glycoproteins during lysosomal turnover; loss of enzyme activity causes storage of glycoasparagines, including GlcNAc-Asn/aspartylglucosamine, in tissues and body fluids (PMID:10571008; PMID:27906067; https://pubmed.ncbi.nlm.nih.gov/27906067/).
The most direct molecular mechanism is loss of mature active AGA. Structural and cell-biologic work shows that disease-causing AGA variants can disrupt folding, dimerization in the endoplasmic reticulum, intracellular maturation/processing, or active-site function, converging on reduced lysosomal enzyme activity (PMID:11309371). The Finnish founder allele causes a C163S amino acid substitution and is a common cause in Finland, while broader clinical reviews describe more than 30 pathogenic AGA variants worldwide (PMID:27906067; PMID:33439067).
The immediate biochemical consequence is accumulation and urinary excretion of glycoasparagine substrate. Reviews describe accumulation of undegraded glycoasparagines in tissues and body fluids, and translational studies identify large amounts of urinary GlcNAc-Asn as a diagnostic biomarker for AGU (PMID:27906067; PMID:33186692).
The nervous system is the most clinically important target. Biochemical reviews emphasize severe effects on neuronal cells, and the AGU mouse model shows absent AGA activity, urinary aspartylglucosamine excretion, lysosomal storage vacuoles in neurons and glia, brain atrophy, and deep-gray-matter MRI abnormalities that parallel human disease (PMID:10571008; PMID:9425233). This cellular storage mechanism accounts for childhood onset with delayed speech and learning, progressive intellectual disability, psychomotor decline, gait/motor abnormalities, dyskinesia, and seizures (PMID:27906067; PMID:33439067).
AGU is also systemic. Clinical reviews describe coarse facial features, skeletal abnormalities, connective-tissue overgrowth, hernias, recurrent respiratory and ear infections, and progressive physical disability (PMID:27906067; PMID:33439067). These features are consistent with non-neuronal lysosomal storage and connective-tissue involvement, though the strongest mechanistic evidence is for substrate accumulation and lysosomal storage rather than a single downstream structural pathway.
There is no approved curative or disease-modifying therapy. Current management is supportive and anticipatory. Reviews report that human enzyme replacement trials have not been reported and allogeneic stem-cell transplantation has not proved effective. Preclinical enzyme and gene-transfer studies show biological correctability: adenovirus-mediated AGA reduced lysosomal storage in liver and partly in periventricular brain, while systemic AAV9/AGA in Aga-deficient mice produced sustained AGA activity, dose-dependent substrate clearance, reduced gliosis, and preservation of cerebellar Purkinje neurons (PMID:27906067; PMID:9930336; PMID:33186692).