Aspartylglucosaminuria

Clinical characteristics: Aspartylglucosaminuria is a lysosomal storage disorder characterized by developmental delay, intellectual disability, behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood), recurrent infections, musculoskeletal features, and characteristic craniofacial features (prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, thick vermilion of the upper and lower lips, and macroglossia) that become more prominent with age. Additional neurologic manifestations can include seizures, poor balance and coordination, and progressive cerebral atrophy in adulthood. Macrocephaly is common. Musculoskeletal features include lordosis, scoliosis, and arthritis in adolescents and young adults; vertebral dysplasia and/or rib cage abnormalities; and progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood. Skin manifestations (facial seborrhea, rosacea, and angiofibromas), gastrointestinal manifestations, neutropenia, and thrombocytopenia occur in some individuals. The clinical manifestations of aspartylglucosaminuria worsen with age, and adults have progressive psychomotor decline.

Diagnosis/testing: The diagnosis of aspartylglucosaminuria can be established in a proband with characteristic clinical and laboratory findings by identification of decreased aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts and/or biallelic pathogenic variants in AGA by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational services; standardized treatments for seizures, behavioral manifestations, sleep issues, dental manifestations, recurrent infections, scoliosis, joint swelling and mobility problems, osteoporosis, and gastrointestinal manifestations; social work support and care coordination as needed.

Surveillance: At each visit, assess for developmental progress, educational needs, seizures, balance and coordination issues, recurrent infections, spine issues, muscle wasting, joint manifestations, chronic diarrhea or constipation, and family needs. Assess behavioral and sleep issues annually or as needed. Dental examination every six months. Assess bone density every five years, or every two years in those treated for osteoporosis. Complete blood count with differential to assess for neutropenia and thrombocytopenia in those with any clinical manifestations of cytopenia.

Evaluations of relatives at where risk: It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of supportive treatments.

Genetic counseling: Aspartylglucosaminuria is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AGA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.