Aspartylglucosaminuria

Aspartylglucosaminuria (AGU) is an inherited lysosomal storage disorder (LSD) due to defective degradation of asparagine-linked glycoproteins with multisystemic involvement. AGU is caused by biallelic pathogenic variants of the AGA gene on chromosome 4q34.3 coding for AGA [N(4)-(beta-N-acetylglucosaminyl)-l-asparaginase. Primary manifestations of AGU include progressive deterioration of psychomotor functions with skeletal and connective tissue abnormalities leading to premature death. Largely non-specific clinical symptoms and overlapping with other well-established clinical syndromes, such as autism spectrum disorders (ASD), further contribute to delays in the AGU diagnosis. Individuals with AGU are healthy at birth and typically present with mild to moderate developmental delay, including delayed speech and walking, at around 12–15 months of age. Clinical manifestations include coarse facies, macrocephaly, inguinal and abdominal hernias, recurrent upper respiratory and ear infections, clumsiness, hyperactivity, and sleep abnormalities. Deteriorating cognitive abilities, loss of independence and socialization, and sleep abnormalities, with increasing behavioral problems with age, cause a large burden on AGU patients and their caregivers, adversely affecting their quality of life.