Aspartylglucosaminuria

Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder due to biallelic variants in AGA, with deficiency of aspartylglucosaminidase. It causes slowly progressive intellectual disability, coarse features and recurrent infections, and is particularly common in Finland through a founder variant (p.Cys163Ser).

Pathophysiology. Aspartylglucosaminidase cleaves the linkage between asparagine and N-acetylglucosamine in glycoproteins. Deficiency leads to storage of glycoasparagines in lysosomes of neurons and other cells.

Children appear normal in infancy.

Skills are acquired, then lost, in adolescence and adult life.

• Recurrent respiratory and ear infections in early childhood
• Diarrhoea, hernias (inguinal and umbilical)
• Speech delay, slowed development noted at 2 to 4 years
• Mild coarsening of face, macrocephaly, and a thick skin
• Behavioural problems: hyperactivity, aggression and later apathy
• Intellectual disability that progresses into adult life, with regression after 20 years
• Joint laxity, scoliosis and osteopenia
• Seizures in some
• Dental problems and caries
• Cataracts and hearing loss in some
• Psychiatric features and motor decline in the third and fourth decades

• Urine aspartylglucosamine: raised on chromatography or mass spectrometry.
• Aspartylglucosaminidase activity in leukocytes or fibroblasts: markedly reduced.
• AGA sequencing with deletion and duplication analysis. In Finland the founder variant is tested first.
• Brain MRI: delayed myelination and cerebellar changes in later disease.
• Skeletal survey, hearing and eye assessment.
• Newborn screening is not available for this condition in most countries.

• Infections: early antibiotics, vaccination, and ENT care for recurrent otitis media with grommets for persistent effusion.
• Hernias: surgical repair.
• Development and education: early intervention, speech therapy, special education, and vocational support.
• Behaviour and psychiatric care: structured behavioural support, with risperidone 0.25 mg daily increasing to 1 to 2 mg daily for severe irritability, and sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for depression or anxiety.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily in children (adults 500 mg twice daily increasing to 1500 mg twice daily).
• Bone health: vitamin D 400 to 800 international units daily in children (1000 to 2000 international units in adults), and scoliosis review yearly.
• Dental care: dental review every 6 months.
• Disease modifying therapy: haematopoietic stem cell transplantation may stabilise disease if done early, but outcomes in neurological disease are limited. Enzyme and gene therapies are under study.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Adults: monitor for regression of self-care skills, and plan supported living.

Monitoring. Development and behaviour every 6 months in childhood and yearly in adults. Hearing and eye review yearly, and skeletal review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine and developmental paediatrics. Urgent for severe infection or rapid regression.