Aspartylglucosaminuria is inherited as an autosomal recessive disorder that belongs to a family of disorders identified as lysosomal storage diseases. This disorder is characterized by the lysosomal accumulation of glycoasparagines, primarily aspartylglucosamine. These glycoasparagines accumulate in the lysosomes as a consequence of defects in the lysosomal hydrolase, N-aspartyl-β-glucosaminidase (also called aspartylglucosaminidase or glycoasparaginase). Aspartylglucosaminidase cleaves the asparagine from the residual N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. As such this is a key enzyme in the catabolism of N-linked oligosaccharides of glycoproteins.
The N-aspartyl-β-glucosaminidase gene (AGA) is located on chromosome 4q34.3 spanning 13kbp and composed of 9 exons that generate two alternatively spliced mRNAs. These mRNAs encode a 346 amino acid protein (isoform 1) and a 336 amino acid protein (isoform 2). The 346 amino acid protein exhibits an approximate mass of 35kDa. Following synthesis the protein is cleaved to generate two subunits. The α-subunit is 27kDa and the β-subunit is 17kDa and these subunits form a heterotetrameric enzyme. The predominant mutation resulting in AGU is a missense mutation which changes the cysteine residue at position 163 to a serine (C163S). This mutation is found in 98% of all AGU cases.
The hallmark symptom of aspartylglucosaminuria is a global delay in psychomotor development that begins between 2 and 4 years of age. There is a period of frequent upper respiratory infections followed by delayed speech and physical clumsiness. The disorder in speech development is a cardinal sign of mental retardation and is usually the first indication to parents that there is something amiss with their child in the 2nd or 3rd year. Almost all patients will only reach the mental and developmental age of a 5–6 year old by the time of puberty. Thereafter, there will be a slow deterioration such that in adulthood patients suffer severe mental retardation. The progression of the mental retardation is highly age-related. Patients under 10 years will be subnormal or only mildly retarded, patients in the second decade of life will be moderately to severely retarded and all adults will be severely affected.