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.

Suggestive Findings

Aspartylglucosaminuria should be suspected in probands with the following clinical, laboratory, imaging, and family history findings.

Clinical findings

• Mild-to-moderate developmental delay
• Mild-to-moderate intellectual disability
• Other neurologic manifestations (seizures, poor balance, and coordination)
• Behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood; disruptive sleep patterns)
• Recurrent infections (typically respiratory tract, ear, or skin infections)
• Characteristic craniofacial features (macrocephaly; coarsening of the facial features through childhood and adolescence progressing to characteristic facial features in adults, including prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, and macroglossia) (See Figures 1 and 2.)
• Skin manifestations (facial seborrhea, rosacea, and angiofibromas)
• Musculoskeletal manifestations (lordosis, scoliosis, and arthritis in adolescents and young adults; progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood)
• Gastrointestinal manifestations (chronic diarrhea or constipation, abdominal or inguinal hernias)
• Neutropenia and thrombocytopenia in some individuals

Figure 1.

Two brothers with aspartylglucosaminuria demonstrate progression of facial features with age. One sib at age two years (A), three years (B), four years (C), six years (D), and ten years (E). Second sib at age four months (F), one year (G), two years (H), (more...)

Figure 2.

Two unrelated individuals with aspartylglucosaminuria demonstrate progression of facial features with age, notably periorbital fullness, short nose, thick vermilion of the upper and lower lips, and obesity. First individual at age two years (A), four (more...)

Laboratory findings

• Elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis
• Vacuoles and large lysosomes in analysis of leukocytes or fibroblasts [Goodspeed et al 2021]

Imaging findings

• Brain MRI. Increased signal intensity of subcortical and periventricular white matter and decreased T₂ and SWI signal intensity in the thalami (especially pulvinar nucleus), poor grey-white differentiation, thinning of the corpus callosum, cerebral/cerebellar atrophy on T₂-weighted images, and progressive iron accumulation [Tokola et al 2015, Anna et al 2017, Tokola et al 2019, Sairanen et al 2020]. Progressive cerebral atrophy in adulthood.
• Radiographs of the chest and spine. Broad and misshapen ribs, vertebral dysplasia (flattened vertebral bodies with anterior wedging), spondylolisthesis, lordosis, scoliosis, and kyphosis [Arvio & Mononen 2016]

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of aspartylglucosaminuria can be established in a proband with suggestive findings including elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis by identification of either:

• Reduced aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts [Banning et al 2023];
  AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in AGA by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic AGA variants of uncertain significance (or of one known AGA pathogenic variant and one AGA variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Aspartylglucosaminuria is a lysosomal storage disorder characterized by developmental delay, intellectual disability, behavioral manifestations, recurrent infections, growth deficiency, musculoskeletal features, and characteristic craniofacial features that become more prominent with age. Adults have progressive psychomotor decline and eventually lose the ability to communicate verbally and remain completely dependent as adults. To date, approximately 500 individuals have been identified with biallelic pathogenic variants in AGA [Arvio & Mononen 2016, Goodspeed et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay. Individuals with aspartylglucosaminuria tend to have mild-to-moderate delays in early developmental milestones. The delay in acquisition of new developmental skills becomes more prominent over time, with a widening gap between chronologic age and developmental age equivalent as children get older. There is typically a plateau in new skill acquisition in late childhood to early adolescence that persists for the remainder of the individual's life. Periods of significant developmental regression in childhood are not typically seen [Arvio & Mononen 2016, Goodspeed et al 2021].

Intellectual disability. Individuals with aspartylglucosaminuria typically have mild-to-moderate intellectual disability. Earlier studies suggested that cognitive ability peaks in early adolescence; however, more recent studies suggest that the peak cognitive ability may be reached earlier (by ages seven to ten years) and remain stable throughout adolescence [Harjunen et al 2020]. There is typically a slow cognitive decline beginning in early adulthood [Arvio & Mononen 2016].

Other neurologic features. Some individuals with aspartylglucosaminuria will develop epilepsy, typically in adolescence or early adulthood [Goodspeed et al 2021]. Additionally, individuals with aspartylglucosaminuria are described as being clumsier than peers, with poor balance and coordination [Arvio & Mononen 2016, Goodspeed et al 2021].

Neurobehavioral/psychiatric manifestations. Children with aspartylglucosaminuria are typically described as hyperactive and may meet criteria for attention-deficit/hyperactivity disorder [Arvio & Mononen 2016, Goodspeed et al 2021]. Many individuals will also have disruptive sleep patterns. Beginning in adolescence, symptoms of restlessness or anxiety may emerge, and during adulthood, some individuals may experience psychotic episodes or develop apathy, withdrawing from social activities [Arvio & Mononen 2016]. Some individuals may also meet criteria for autism spectrum disorder.

Craniofacial features. Infants with aspartylglucosaminuria may not demonstrate any abnormal facial features until they are older. Characteristic facial features include hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, macroglossia, and poor dentition in adulthood [Arvio & Mononen 2016, Goodspeed et al 2021]. All facial features tend to coarsen with age and are more noticeable in older individuals (see Figures 1 and 2).

Recurrent infections. Children tend to have recurrent ear and upper respiratory tract infections. Skin infections are also reported. Life span is reduced, as individuals often succumb to a respiratory tract infection in middle adulthood.

Growth. Individuals with aspartylglucosaminuria may have typical growth patterns through infancy and early childhood, but many will experience a stagnation in growth in puberty and have reduced adult height [Arvio & Mononen 2016]. Obesity is common in older individuals.

Musculoskeletal features. Individuals with aspartylglucosaminuria commonly have vertebral dysplasia (flattened vertebral bodies with anterior wedging) and rib cage abnormalities such as broad and misshapen ribs. They may develop lordosis, scoliosis, and/or kyphosis that progresses with age. Scoliosis can be severe and require bracing or surgical intervention, and may interfere with procedures such as lumbar puncture. Some individuals will also develop progressive muscle wasting, arthritis, bursitis, joint contractures, and osteoporosis with age [Arvio & Mononen 2016, Goodspeed et al 2021].

Skin manifestations. Some individuals have seborrhea, rosacea, and/or angiofibromas that become more apparent with age [Arvio & Mononen 2016, Goodspeed et al 2021].

Gastrointestinal manifestations include chronic diarrhea or constipation and abdominal or inguinal hernias.

Hematologic manifestations. Neutropenia and thrombocytopenia are most common, tend to be mild to moderate even in older individuals with aspartylglucosaminuria, and rarely require intervention.

Prognosis. Aspartylglucosaminuria is a slowly progressive neurodegenerative disorder with systemic manifestations. All clinical manifestations of aspartylglucosaminuria worsen with age, typically over the course of years to decades. Life expectancy is well into middle adulthood with proper care and preventive medicine. Most individuals are dependent upon caregivers throughout their entire life due to significant cognitive impairment that continues to worsen in adulthood [Arvio & Mononen 2016, Goodspeed et al 2021].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified. In a small study including both Finnish and non-Finnish individuals with aspartylglucosaminuria, there were no clear genotype-phenotype correlations identified [Goodspeed et al 2022].

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], aspartylglucosaminuria is referred to as AGA-related aspartylglucosaminuria and included in the lysosomal storage diseases with skeletal involvement group.

Prevalence

The vast majority of identified individuals with aspartylglucosaminuria are of Finnish descent, with a prevalence rate of 1.5-5:100,000 live births in Finland [Arvio & Mononen 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aspartylglucosaminuria, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for aspartylglucosaminuria. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at 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. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Biochemical testing, including urinary oligosaccharide analysis to identify elevated aspartylglucosamine and other glycoasparagines, if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Early studies of bone marrow transplantation demonstrated no benefit in individuals with aspartylglucosaminuria. However, a case series of four children treated with hematopoietic stem cell transplant at an early age (age five months to nine years) demonstrated reduction in aspartylglucosamine and favorable neurodevelopmental outcomes [Arvio & Mononen 2016, Selvanathan et al 2021].

There are also many small molecules that show promise as chaperone therapies to increase aspartylglucosaminidase activity [Banning et al 2016, Banning et al 2018]. For certain missense variants, glycine, asparagine, and betaine can increase aspartylglucosaminidase activity in cell culture, while amlexanox appears to rescue nonsense-mediated decay of nonsense variants [Banning et al 2018]. For splice site variants, methylxanthine derivatives and food-derived flavonoid luteolin enhance correct splicing to facilitate translation of a full-length, functional aspartylglucosaminidase [Banning & Tikkanen 2021]. Additionally, there is an ongoing clinical trial to assess the safety and efficacy of Cystadane^® (betaine) for the treatment of aspartylglucosaminuria (EudraCT 2017-000645-48).

Furthermore, early initiation of enzyme replacement therapy (ERT) in mice with aspartylglucosaminuria has been shown to reduce accumulation of aspartylglucosamine, but clinical development of ERT is complicated by the need to deliver high doses of recombinant aspartylglucosaminidase at an early age to improve penetration of the blood-brain barrier in individuals with aspartylglucosaminuria [Dunder et al 2010].

Finally, gene transfer therapy using an adeno-associated viral type 9 (AAV9) vector carrying codon-optimized human AGA has shown promise in preclinical studies. Aga knockout mice treated with AAV9/AGA demonstrated favorable toxicity profiles, restoration of aspartylglucosaminidase enzyme activity, reduction of aspartylglucosamine accumulation, and rescue of the behavioral phenotypes [Chen et al 2021]. The Rare Trait Hope Fund is supporting a toxicology, dose determination, and biodistribution study in larger animals and preparing an investigational new drug application for FDA approval to start clinical trials in individuals with aspartylglucosaminuria.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Aspartylglucosaminuria is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an AGA pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an AGA pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with aspartylglucosaminuria are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AGA pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the AGA pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ancestry. AGA founder variants have been identified in the Palestinian Arab community in Jerusalem and in individuals from eastern Finland (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the AGA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AGA encodes aspartylglucosaminidase (AGA), which is initially synthesized in an inactive form. Subsequent autoproteolysis results in an active hydrolase with separate alpha and beta subunits. Mature AGA hydrolyzes glycoasparagine N(4)-(β-N-acetylglucosaminyl)-L-asparagine, which connects carbohydrate to the side chain of an asparagine [Pande et al 2018]. This allows for free sugars and amino acids to be degraded through their respective pathways within the lysosome.

AGA pathogenic variants impair the autoproteolysis of AGA precursors. The abnormal AGA molecules are misprocessed and retained at the pre-autoproteolysis stage as single-chain precursors, which results in reduced production or activity of AGA [Sui et al 2014]. Deficiency of AGA causes impaired degradation of glycoproteins within the lysosome and toxic accumulation of glycoasparagines, which impair cellular function [Goodspeed et al 2021].

Mechanism of disease causation. Loss of function

Author Notes

Dr Kimberly Goodspeed (ude.nretsewhtuostu@deepsdoog.ylrebmik) is actively involved in clinical research regarding individuals with aspartylglucosaminuria. Dr Goodspeed would be happy to communicate with persons who have any questions regarding diagnosis of aspartylglucosaminuria or other considerations.

Dr Goodspeed (ude.nretsewhtuostu@deepsdoog.ylrebmik) and Dr Michel Tchan (ua.vog.wsn.htlaeh@nahct.lehcim) are also interested in hearing from clinicians treating families affected by aspartylglucosaminuria in whom no causative variants have been identified through molecular genetic testing.

Contact Dr Xin Chen (ude.nretsewhtuostu@nehc.nix) to inquire about review of AGA variants of uncertain significance.

Acknowledgments

We would like to thank the Rare Trait Hope Fund (USA), the UNC TraCS Institute (550KR121511), and AFM-Téléthon (France, Award 19715) for their funding support to the preclinical studies of gene transfer therapy.

Revision History

• 18 January 2024 (sw) Review posted live
• 14 August 2023 (kg) Original submission

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