Aspartylglucosaminuria: Clinical Presentation and Potential Therapies

Abstract

Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures followed by premature death. AGU is caused by pathogenic variants in the aspartylglucosaminidase ( AGA) gene, leading to glycoasparagine accumulation and cellular dysfunction. Although more prevalent in the Finnish population, more than 30 AGA variants have been identified worldwide. Owing to its rarity, AGU may be largely underdiagnosed. Recognition of the following early clinical features may aid in AGU diagnosis: developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias, clumsiness, characteristic facial features, recurring upper respiratory and ear infections, tonsillectomy, multiple sets of tympanostomy tube placement, and sleep problems. Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance, management of expectations, early interventions, and prophylaxis; it will also be crucial for increased clinical benefits of future AGU disease-modifying therapies.

The Finnish genetic heritage in 2022 – from diagnosis to translational research

“…AGU [Online Mendelian Inheritance in Man (OMIM) ] is a neuropediatric lysosomal storage disease that results from pathogenic variants in the AGA gene ( Box 1 ). AGA deficiency leads to the accumulation of glycoasparagine conjugates in the cells and body fluids of AGU patients, causing a slow but progressive developmental delay that manifests early in childhood, with intellectual disability only becoming evident by the age of 7-10 years ( Arvio and Mononen, 2016 ; Goodspeed et al, 2021 ; Harjunen et al, 2020 ). In addition to developmental delay, AGU patients present with motor clumsiness, recurrent infections, behavioral problems and mild to moderate skeletal problems, as well as coarse facial features, increased risk of epilepsy and severe retardation later in life.…”

Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage

“…AGU (OMIM 208400) represents one of the rare FDH diseases that has been subjected to some treatment strategies and preclinical development (see below). AGU is a recessive neurodegenerative disease which is characterized by progressive intellectual disability, skeletal and connective tissue abnormalities, behavioral changes (e.g., hyperactivity, tantrums and violence) and disruptive sleep patterns followed by premature death, usually before the age of 50 [95][96][97][98]. Developmental delay is the first typical sign of neurological defects, which become evident at 15-18 months of age.…”

“…Although being enriched in Finland, AGU affects all ethnicities, and approximately 40 different AGA variants have been identified worldwide (A. Banning and R. Tikkanen, personal communication). Roughly half of the variants are missense mutations, while the rest represent many different aberrations without proper understanding of the genotype-phenotype causalities [98]. Notably, recent findings have demonstrated several patients with high residual AGA activity and a milder phenotype [108].…”

A cross‐sectional natural history study of aspartylglucosaminuria

“… 3 , 4 , 5 Treatment for AGU is limited to supportive care, but the slow progression creates a large therapeutic window for disease‐modifying therapy. 6 Early studies of bone marrow transplantation for AGU demonstrated slow biochemical rescue, however, long‐term follow‐up showed severe post‐transplant complications and worse developmental outcomes in comparison to untreated AGU patients, although transplantation during infancy shows more promise. 7 , 8 , 9 Alternatively, a chaperone therapy to improve AGA enzymatic activity and gene transfer therapy remain promising options for future treatments.…”