Aspartylglucosaminuria

Mendelian MONDO:0008830 Pathograph 52 Show in embeddings browser Lysosomal Storage Disorder Oligosaccharidosis

Aspartylglucosaminuria is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in AGA, encoding aspartylglucosaminidase. Loss of AGA activity impairs degradation of N-linked glycoprotein-derived glycoasparagines, causing accumulation of glycoasparagines in tissues and body fluids with childhood-onset developmental delay, progressive intellectual disability, psychomotor deterioration, coarse facial features, skeletal findings, and abnormal urinary aspartylglucosamine.

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1
Mappings
1
Definitions
1
Inheritance
5
Pathophys.
41
Phenotypes
52
Pathograph
1
Genes
4
Medical Actions
1
Trials
10
References
1
Deep Research
🏷

Classifications

ISDS Skeletal Nosology
lysosomal storage with skeletal involvement
🔗

Mappings

MONDO
MONDO:0008830 aspartylglucosaminuria
skos:exactMatch Orphanet ORPHA:93
Orphanet ORPHA:93 lists MONDO:0008830 as an exact cross-reference for aspartylglucosaminuria.
📘

Definitions

1
Orphanet aspartylglucosaminuria definition
A rare oligosaccharidosis with facial dysmorphism, progressive intellectual disability, and psychomotor deterioration caused by accumulation of glycoasparagines in tissues and body fluids.
OTHER
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"A rare oligosaccharidosis characterized by facial dysmorphism, progressive intellectual disability and psychomotor deterioration due to accumulation of glycoasparagines in tissues and body fluids."
Orphanet defines the core biochemical and neurodevelopmental phenotype.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Aspartylglucosaminuria is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for aspartylglucosaminuria.
⚙

Pathophysiology

5
AGA lysosomal enzyme deficiency
Biallelic pathogenic variants in AGA reduce functional aspartylglucosaminidase/glycosylasparaginase, a lysosomal enzyme required for hydrolysis of the protein-oligosaccharide linkage in Asn-linked glycoprotein turnover.
AGA hgnc:318 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AGA (hgnc:318). hgnc:318 is a gene from the HUGO Gene Nomenclature Committee.
glycoprotein catabolic process GO:0006516 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycoprotein catabolic process (GO:0006516). GO:0006516 is a biological process from the Gene Ontology. ↓ DECREASED protein deglycosylation GO:0006517 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein deglycosylation (GO:0006517). GO:0006517 is a biological process from the Gene Ontology. ↓ DECREASED
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Downstream
Glycoasparagine substrate accumulation Loss of AGA activity blocks clearance of aspartylglucosamine-containing glycoasparagines.
Show evidence (3 references)
ORPHA:93 SUPPORT Other
"AGA | aspartylglucosaminidase | hgnc:318 | Disease-causing germline mutation(s) in"
Orphanet identifies AGA as the disease-causing gene.
PMID:27906067 SUPPORT Human Clinical
"The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA)"
Review directly supports deficient lysosomal AGA activity as causal.
PMID:10571008 SUPPORT Human Clinical
"AGU mutations occur in the gene (AGA) for glycosylasparaginase, the enzyme necessary for hydrolysis of the protein oligosaccharide linkage in Asn-linked glycoprotein substrates undergoing metabolic turnover."
Biochemical review identifies the affected gene and enzymatic reaction.
AGA protein maturation and folding defects
Many AGA missense variants disrupt folding, dimerization, autocatalytic activation, lysosomal trafficking, or active-site function, lowering mature lysosomal enzyme activity and contributing to genotype-specific severity.
AGA hgnc:318 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AGA (hgnc:318). hgnc:318 is a gene from the HUGO Gene Nomenclature Committee.
protein folding GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ⚠ ABNORMAL protein maturation GO:0051604 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein maturation (GO:0051604). GO:0051604 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
AGA lysosomal enzyme deficiency Defective folding and maturation reduce the amount of active AGA reaching lysosomes.
Show evidence (2 references)
PMID:11309371 SUPPORT In Vitro
"Many of these are predicted to interfere with the complex intracellular maturation and processing of the AGA polypeptide."
Functional mutation study supports impaired AGA maturation as a disease mechanism.
PMID:11309371 SUPPORT In Vitro
"Mutations of the dimer interface prevent dimerization in the ER, whereas active site mutations not only destroy the activity but also affect maturation of the precursor."
Study distinguishes dimerization, active-site, and maturation effects of pathogenic variants.
Glycoasparagine substrate accumulation
Deficient AGA activity causes accumulation of undegraded glycoasparagines, especially aspartylglucosamine/GlcNAc-Asn, in tissue lysosomes and body fluids. Urinary excretion of aspartylglucosamine is the characteristic biochemical signature.
glycoprotein catabolic process GO:0006516 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycoprotein catabolic process (GO:0006516). GO:0006516 is a biological process from the Gene Ontology. ↓ DECREASED
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Downstream
Neuronal and glial lysosomal storage Storage affects lysosomes in brain cells, producing progressive neurodegeneration.
Systemic connective tissue and skeletal involvement Storage in non-neuronal tissues contributes to coarse features, hernias, and skeletal abnormalities.
Aspartylglucosaminuria Accumulated GlcNAc-Asn/aspartylglucosamine is excreted in urine as the biochemical phenotype.
Abnormality of amino acid metabolism Glycoasparagine substrate accumulation is recorded as an abnormal amino-acid-metabolism phenotype.
Show evidence (3 references)
ORPHA:93 SUPPORT Other
"accumulation of glycoasparagines in tissues and body fluids"
Orphanet definition supports glycoasparagine accumulation.
PMID:27906067 SUPPORT Human Clinical
"accumulation of these undegraded glycoasparagines in tissues and body fluids."
Review supports the immediate storage product.
PMID:33186692 SUPPORT Human Clinical
"The accumulated substrate GlcNAc-Asn is excreted in urine of patients in large quantities."
Gene-therapy study summarizes urinary GlcNAc-Asn as a disease biomarker.
Neuronal and glial lysosomal storage
Glycoasparagine accumulation produces lysosomal storage in neurons and glia, brain atrophy, impaired learning, progressive intellectual disability, speech impairment, gait disturbance, dyskinesia, and seizures.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. glial cell CL:0000125 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glial cell (CL:0000125). CL:0000125 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Intellectual disability Progressive brain storage and atrophy impair cognition and adaptive function.
Delayed speech and language development Neurodevelopmental impairment includes prominent speech delay.
Abnormality of speech or vocalization Progressive brain involvement also manifests as abnormal speech and vocalization.
Dyskinesia Progressive CNS involvement contributes to abnormal involuntary movement.
Seizure Progressive brain disease can include seizures.
Atypical behavior Progressive neurologic involvement can include atypical behavioral manifestations.
Sleep disturbance Progressive neurologic disease can include disordered sleep.
Show evidence (3 references)
PMID:9425233 SUPPORT Model Organism
"Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions."
Mouse model directly shows neuronal and glial storage.
PMID:33186692 SUPPORT Model Organism
"Neuronal, glial, and endothelial cells of the frontal cortex, cerebellum, brain stem, and spinal cord of the AGU mice become vacuolated around 6 months old and progressively worsen."
Mouse model shows lysosomal vacuolization in neurons, glia, and endothelial cells across CNS regions, supporting endothelial involvement in CNS storage.
PMID:33186692 SUPPORT Human Clinical
"AGU is a slow but progressive and severe neurodegenerative disease characterized by intellectual disability, skeletal and motor abnormalities, and early mortality."
Preclinical translational paper summarizes the progressive neurodegenerative phenotype.
Systemic connective tissue and skeletal involvement
Non-neuronal lysosomal storage and connective-tissue overgrowth contribute to the coarse facial, gingival/oral, hernia, and skeletal manifestations of aspartylglucosaminuria.
connective tissue UBERON:0002384 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in connective tissue (UBERON:0002384). UBERON:0002384 is an anatomical location from the Uberon multi-species anatomy ontology. cartilage tissue UBERON:0002418 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cartilage tissue (UBERON:0002418). UBERON:0002418 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Gingival overgrowth Connective-tissue overgrowth contributes to gingival enlargement.
Coarse facial features Systemic storage and connective-tissue overgrowth contribute to coarse facial features.
Abnormal facial shape Systemic storage and connective-tissue overgrowth contribute to abnormal facial shape.
Large face Craniofacial connective-tissue and skeletal involvement can manifest as a large face.
Mandibular prognathia Craniofacial skeletal involvement contributes to mandibular prognathia.
Hypertelorism Craniofacial involvement can include hypertelorism.
Wide nasal bridge Craniofacial involvement can include a wide nasal bridge.
Short nose Craniofacial involvement can include a short nose.
Microtia Craniofacial and external-ear involvement can include microtia.
Thick vermilion border Craniofacial soft-tissue involvement can include thick vermilion border.
Macroglossia Oral soft-tissue involvement contributes to macroglossia.
Abnormality of the dentition Oral and craniofacial involvement can include abnormal dentition.
Carious teeth Oral and dental involvement is associated with frequent carious teeth.
Umbilical hernia Connective tissue involvement contributes to hernias.
Inguinal hernia Connective tissue involvement can also manifest as inguinal hernia.
Scoliosis Skeletal involvement contributes to spinal curvature.
Pectus carinatum Skeletal involvement can manifest as pectus carinatum.
Thickened calvaria Cranial skeletal involvement can manifest as calvarial thickening.
Abnormal cortical bone morphology Skeletal involvement can include abnormal cortical bone morphology.
Anterior beaking of lumbar vertebrae Spinal skeletal involvement can manifest as anterior lumbar vertebral beaking.
Abnormal morphology of ulna Appendicular skeletal involvement can include abnormal ulnar morphology.
Macroorchidism Multisystem somatic involvement can include macroorchidism in affected males.
Recurrent respiratory infections Multisystem disease with early somatic involvement is associated with recurrent respiratory infections.
Chronic otitis media Multisystem disease with recurrent infections can include chronic otitis media.
Arthritis Systemic skeletal and connective-tissue involvement can include arthritis.
Joint stiffness Skeletal and connective-tissue involvement can include joint stiffness.
Splenomegaly Multisystem lysosomal storage disease can include splenomegaly.
Pes planus Skeletal and connective-tissue involvement can include pes planus.
Hepatomegaly Multisystem lysosomal storage disease can include hepatomegaly.
Delayed skeletal maturation Skeletal involvement can include delayed skeletal maturation.
Abnormal vertebral morphology Skeletal involvement can include abnormal vertebral morphology.
Beaking of vertebral bodies Spinal skeletal involvement can include vertebral body beaking.
Show evidence (2 references)
PMID:33439067 SUPPORT Human Clinical
"skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures"
Clinical review supports skeletal and connective-tissue involvement.
PMID:27906067 SUPPORT Human Clinical
"It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health."
Review supports broad systemic involvement beyond the CNS.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Aspartylglucosaminuria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

41
Cardiovascular 1
Splenomegaly OCCASIONAL HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001744 | Splenomegaly | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Digestive 2
Inguinal hernia OCCASIONAL HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"HP:0000023 | Inguinal hernia | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:33439067 SUPPORT Human Clinical
"developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias"
Clinical review includes inguinal and abdominal hernias among early diagnostic clues.
Hepatomegaly OCCASIONAL HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002240 | Hepatomegaly | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Ear 1
Chronic otitis media OCCASIONAL HP:0000389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic otitis media (HP:0000389). HP:0000389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000389 | Chronic otitis media | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Eye 1
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000316 | Hypertelorism | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Genitourinary 1
Macroorchidism FREQUENT HP:0000053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macroorchidism (HP:0000053). HP:0000053 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000053 | Macroorchidism | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Head and Neck 7
Coarse facial features FREQUENT HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000280 | Coarse facial features | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormal facial shape VERY_FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001999 | Abnormal facial shape | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Macroglossia FREQUENT HP:0000158 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macroglossia (HP:0000158). HP:0000158 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000158 | Macroglossia | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormality of the dentition FREQUENT HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000164 | Abnormality of the dentition | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Carious teeth FREQUENT HP:0000670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000670 | Carious teeth | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Short nose VERY_FREQUENT HP:0003196 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short nose (HP:0003196). HP:0003196 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0003196 | Short nose | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Thick vermilion border VERY_FREQUENT HP:0012471 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thick vermilion border (HP:0012471). HP:0012471 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0012471 | Thick vermilion border | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Immune 1
Recurrent respiratory infections OCCASIONAL HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"HP:0002205 | Recurrent respiratory infections | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:33439067 SUPPORT Human Clinical
"recurring upper respiratory and ear infections"
Clinical review supports recurrent respiratory and ear infections as early features.
Limbs 1
Pes planus OCCASIONAL HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001763 | Pes planus | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Musculoskeletal 6
Arthritis OCCASIONAL HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001369 | Arthritis | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Joint stiffness OCCASIONAL HP:0001387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint stiffness (HP:0001387). HP:0001387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001387 | Joint stiffness | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Delayed skeletal maturation OCCASIONAL HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002750 | Delayed skeletal maturation | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormal vertebral morphology OCCASIONAL HP:0003468 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal vertebral morphology (HP:0003468). HP:0003468 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0003468 | Abnormal vertebral morphology | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Scoliosis VERY_FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002650 | Scoliosis | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Pectus carinatum FREQUENT HP:0000768 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus carinatum (HP:0000768). HP:0000768 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000768 | Pectus carinatum | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Nervous System 7
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"HP:0001249 | Intellectual disability | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:27906067 SUPPORT Human Clinical
"Progressive intellectual and physical disability is the main symptom"
Review directly supports progressive intellectual disability.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000750 | Delayed speech and language development | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormality of speech or vocalization VERY_FREQUENT Abnormal speech pattern HP:0002167 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of speech or vocalization, annotated with Abnormal speech pattern (HP:0002167). HP:0002167 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002167 | Abnormality of speech or vocalization | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Dyskinesia VERY_FREQUENT HP:0100660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyskinesia (HP:0100660). HP:0100660 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0100660 | Dyskinesia | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Atypical behavior OCCASIONAL HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000708 | Atypical behavior | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Sleep disturbance OCCASIONAL HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002360 | Sleep abnormality | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Other 13
Gingival overgrowth VERY_FREQUENT HP:0000212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival overgrowth (HP:0000212). HP:0000212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000212 | Gingival overgrowth | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Large face VERY_FREQUENT HP:0100729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large face (HP:0100729). HP:0100729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0100729 | Large face | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Mandibular prognathia VERY_FREQUENT HP:0000303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular prognathia (HP:0000303). HP:0000303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000303 | Mandibular prognathia | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Wide nasal bridge VERY_FREQUENT HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0000431 | Wide nasal bridge | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Microtia VERY_FREQUENT HP:0008551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microtia (HP:0008551). HP:0008551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0008551 | Microtia | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Umbilical hernia VERY_FREQUENT HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001537 | Umbilical hernia | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Beaking of vertebral bodies OCCASIONAL HP:0004568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Beaking of vertebral bodies (HP:0004568). HP:0004568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0004568 | Beaking of vertebral bodies | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Thickened calvaria FREQUENT HP:0002684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened calvaria (HP:0002684). HP:0002684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0002684 | Thickened calvaria | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormal cortical bone morphology FREQUENT HP:0003103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cortical bone morphology (HP:0003103). HP:0003103 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0003103 | Abnormal cortical bone morphology | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Anterior beaking of lumbar vertebrae FREQUENT HP:0008430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anterior beaking of lumbar vertebrae (HP:0008430). HP:0008430 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0008430 | Anterior beaking of lumbar vertebrae | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormal morphology of ulna FREQUENT HP:0040071 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal morphology of ulna (HP:0040071). HP:0040071 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0040071 | Abnormal morphology of ulna | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Aspartylglucosaminuria VERY_FREQUENT HP:0012068 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aspartylglucosaminuria (HP:0012068). HP:0012068 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0012068 | Aspartylglucosaminuria | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormality of amino acid metabolism VERY_FREQUENT HP:0004337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of amino acid metabolism (HP:0004337). HP:0004337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0004337 | Abnormality of amino acid metabolism | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
🧬

Genetic Associations

1
Biallelic AGA pathogenic variants (CAUSATIVE)
Gene: AGA hgnc:318 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AGA (hgnc:318). hgnc:318 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (4 references)
PMID:27906067 SUPPORT Human Clinical
"A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population."
Review supports the common Finnish founder pathogenic variant.
PMID:27906067 SUPPORT Human Clinical
"Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population."
Review quantifies the AGU_Fin founder allele as homozygous in about 98% of Finnish AGU cases.
PMID:33439067 SUPPORT Human Clinical
"more than 30 AGA variants have been identified worldwide."
Clinical review supports broader allelic heterogeneity outside Finland.
+ 1 more reference
🗃️

External Assertions

1
Orphanet Aspartylglucosaminuria disease record
Orphanet structured disease record ORPHA:93
Orphanet's ORPHA:93 structured record for Aspartylglucosaminuria includes the exact MONDO cross-reference, definition, autosomal recessive inheritance, epidemiology, AGA gene association, and HPO phenotype annotations used in this entry.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"MONDO:0008830 | Exact"
Orphanet maps ORPHA:93 to the same MONDO identifier used by this entry.
ORPHA:93 SUPPORT Other
"OMIM:208400 | Exact"
Orphanet lists OMIM:208400 as an exact external cross-reference.
💊

Medical Actions

4
Supportive and anticipatory care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No approved disease-modifying therapy is currently available; supportive care focuses on early interventions, management of neurodevelopmental, seizure, infection, sleep, orthopedic, and functional complications, and anticipatory guidance.
Target Phenotypes: Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology. Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33439067 SUPPORT Human Clinical
"Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance"
Clinical review supports supportive/anticipatory management in the absence of curative therapy.
Hematopoietic stem cell transplantation
Action: bone marrow transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bone marrow transplantation (NCIT:C15194). NCIT:C15194 is a clinical intervention from the NCI Thesaurus. Ontology label: Bone Marrow Transplantation NCIT:C15194
Allogeneic bone marrow / hematopoietic stem cell transplantation has been attempted in AGU patients in Finland and Sweden but, unlike in some other lysosomal storage disorders, has not shown clinical benefit or proven effective in curing the disease.
Show evidence (2 references)
PMID:27906067 SUPPORT Human Clinical
"Allogenic stem cell transplantation has not proved effective in curing AGU."
Review states allogeneic stem cell transplantation has not proven effective in AGU.
PMID:33186692 SUPPORT Human Clinical
"Limited attempts at bone marrow transplantation (BMT) have not shown any benefit."
Corroborates that bone marrow transplantation attempts in AGU have shown no benefit.
Enzyme replacement therapy (preclinical)
Action: enzyme replacement or supplementation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is enzyme replacement or supplementation therapy, annotated with Protein Replacement Therapy (NCIT:C16221). NCIT:C16221 is a clinical intervention from the NCI Thesaurus. Ontology label: Protein Replacement Therapy NCIT:C16221
Recombinant human AGA/glycosylasparaginase enzyme replacement corrected the pathophysiology in non-neuronal tissues of AGU mice and partially reduced brain substrate storage, but peripheral administration does not adequately reach the central nervous system and long-term dosing can provoke immune responses that abolish efficacy. It is not an approved human therapy.
Mechanism Target:
RESTORES AGA lysosomal enzyme deficiency — Recombinant AGA supplies functional enzyme, correcting non-neuronal tissue pathophysiology in AGU mice.
Show evidence (1 reference)
PMID:27906067 SUPPORT Model Organism
"Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals."
Mouse ERT corrected non-neuronal pathophysiology, supporting enzyme restoration.
INHIBITS Glycoasparagine substrate accumulation — Recombinant AGA reduced accumulated aspartylglucosamine, though brain reduction was only partial (up to 40%).
Show evidence (1 reference)
PMID:27906067 SUPPORT Model Organism
"The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol."
Mouse ERT partially reduced brain substrate accumulation, illustrating the CNS-penetration limitation.
Show evidence (2 references)
PMID:33186692 SUPPORT Other
"Enzyme replacement therapy (ERT) has the potential to be an effective treatment, but peripheral administration does not adequately treat the central nervous system (CNS)."
Documents the central limitation of ERT (poor CNS penetration) motivating CNS-directed gene therapy.
PMID:33186692 SUPPORT Model Organism
"Moreover, long-term ERT in a mouse model has been shown to induce immune responses, which abolish its therapeutic effects."
Long-term ERT in the mouse model induced immune responses abolishing efficacy, a further limitation.
scAAV9/AGA gene replacement therapy (investigational)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
AAV9-mediated AGA gene replacement restored AGA activity, reduced GlcNAc-Asn substrate, and improved neurologic and histopathologic outcomes in Aga-deficient mice. A first-in-human phase 1/2 study of intrathecal scAAV9/AGA (danagalex) is registered but not yet recruiting, so no human safety or efficacy result is established and the intervention is not an approved therapy.
Mechanism Target:
RESTORES AGA lysosomal enzyme deficiency — AAV9/AGA supplies a functional AGA transgene to restore enzyme activity.
Show evidence (1 reference)
PMID:33186692 SUPPORT Model Organism
"AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity"
Preclinical mouse study supports restoration of AGA activity after gene transfer.
INHIBITS Glycoasparagine substrate accumulation — Restored AGA activity reduces the accumulated GlcNAc-Asn substrate burden in Aga-deficient mice.
Show evidence (1 reference)
PMID:33186692 SUPPORT Model Organism
"rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids"
Mouse AAV9/AGA data support direct reduction of the storage substrate downstream of enzyme restoration.
INHIBITS Neuronal and glial lysosomal storage — AAV9/AGA reduced central nervous system pathology in the mouse model.
Show evidence (2 references)
PMID:33186692 SUPPORT Model Organism
"dose-dependent preservation of Purkinje neurons in the cerebellum"
Preservation of cerebellar neurons supports disease-modifying impact on the neuronal storage branch.
PMID:33186692 SUPPORT Model Organism
"significantly reduced gliosis in the brain"
Reduced gliosis supports inhibition of downstream glial pathology in the mouse model.
Show evidence (2 references)
PMID:33186692 SUPPORT Model Organism
"treatment of Aga-/- mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation."
Preclinical study supports AAV9/AGA as a translational gene-replacement candidate.
clinicaltrials:NCT07530796 SUPPORT Other
"The goal of this clinical trial is to learn if the treatment is a safe, tolerable, and efficacious treatment for adults and children with Aspartylglucosaminuria (AGU)."
The registry supports clinical-development status only; it does not provide human safety or efficacy results.
🔬

Biochemical Markers

2
Increased urinary aspartylglucosamine (INCREASED)
Context: Aspartylglucosamine/GlcNAc-Asn is excreted in urine in large quantities and provides a characteristic biochemical marker of AGA deficiency.
Pathograph Readouts
Readout Of Glycoasparagine substrate accumulation Positive Diagnostic
Increased urinary aspartylglucosamine reports glycoasparagine substrate accumulation downstream of AGA deficiency.
Show evidence (1 reference)
PMID:33186692 SUPPORT Human Clinical
"Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
The human urinary biomarker directly reports accumulated GlcNAc-Asn substrate.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"HP:0012068 | Aspartylglucosaminuria | Very frequent (99-80%)"
Orphanet lists the urinary biochemical phenotype as very frequent.
PMID:33186692 SUPPORT Human Clinical
"Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
Study supports urinary GlcNAc-Asn as the diagnostic biochemical substrate.
Reduced aspartylglucosaminidase activity (DECREASED)
Context: Reduced AGA/glycosylasparaginase enzyme activity is the primary biochemical defect.
Pathograph Readouts
Readout Of AGA lysosomal enzyme deficiency Negative Diagnostic
Reduced aspartylglucosaminidase activity reports the primary AGA lysosomal enzyme defect.
Show evidence (1 reference)
PMID:36982794 SUPPORT Human Clinical
"We have here established and validated a fluorometric AGA activity assay for human serum samples from healthy donors and AGU patients."
The validated serum assay measures the deficient AGA enzyme activity in affected individuals.
Show evidence (2 references)
PMID:27906067 SUPPORT Human Clinical
"The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA)"
Review supports reduced AGA enzymatic activity as causal.
PMID:36982794 SUPPORT Human Clinical
"Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by the deficiency of the lysosomal hydrolase aspartylglucosaminidase (AGA)."
The human serum-assay study confirms deficient AGA activity as the primary biochemical defect.
🔬

Diagnosis

3
Urinary aspartylglucosamine testing
Biochemical diagnosis can be supported by detecting large urinary amounts of aspartylglucosamine/GlcNAc-Asn.
Results: Increased urinary aspartylglucosamine supports AGA deficiency.
Show evidence (1 reference)
PMID:33186692 SUPPORT Human Clinical
"Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
Study supports urinary GlcNAc-Asn as a diagnostic biomarker.
AGA molecular genetic testing
Molecular testing confirms diagnosis by identifying biallelic pathogenic AGA variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic AGA variants confirm aspartylglucosaminuria.
Show evidence (1 reference)
PMID:33439067 SUPPORT Human Clinical
"AGU is caused by pathogenic variants in the aspartylglucosaminidase (AGA) gene"
Clinical review supports AGA sequencing as confirmatory molecular testing.
Serum AGA enzyme activity assay
A validated fluorometric serum assay can demonstrate deficient aspartylglucosaminidase activity and support biochemical diagnosis; molecular testing remains appropriate for genetic confirmation.
Results: Markedly reduced serum AGA activity supports aspartylglucosaminuria.
Show evidence (1 reference)
PMID:36982794 SUPPORT Human Clinical
"We show that the validated AGA activity assay is suitable for the assessment of AGA activity in the serum of healthy donors and AGU patients, and it can be used for diagnostics of AGU and, potentially, for following a treatment effect."
This directly supports serum AGA activity measurement as a diagnostic biochemical assay.
📈

Progression

1
Childhood-onset progressive neurodevelopmental disease
Age: Childhood onward
Children may appear relatively well in infancy, then develop delayed speech, learning impairment, behavioral changes, and progressive intellectual and physical disability. Adult patients often become highly dependent on supportive care, with premature death commonly before age 50.
Show evidence (3 references)
ORPHA:93 SUPPORT Other
"Age of onset: Childhood"
Orphanet records childhood onset for aspartylglucosaminuria.
PMID:27906067 SUPPORT Human Clinical
"Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50"
Review describes the progressive natural history and premature mortality.
PMID:33186692 SUPPORT Human Clinical
"The median lifespan of AGU patients is approximately 30 to 40 years."
Provides a quantitative median-lifespan estimate for AGU patients.
📊

Prevalence

1
Worldwide
Unknown Unknown
Orphanet records worldwide point prevalence as unknown, with higher prevalence at birth reported in Finland and rarer prevalence at birth in Australia and Sweden.
Show evidence (2 references)
ORPHA:93 SUPPORT Other
"Unknown | Worldwide | Point prevalence | ORPHANET"
Orphanet records worldwide point prevalence as unknown.
ORPHA:93 SUPPORT Other
"1-9 / 100 000 | Finland | Prevalence at birth | PMID:27906067"
Orphanet records a higher Finnish birth-prevalence band.
🔬

Clinical Trials

1
NCT07530796 PHASE_I NOT_RECRUITING
Open-label, single-center phase 1/2 study of one intrathecal dose of scAAV9/AGA (danagalex) in an estimated nine participants aged 4-45 years, with primary safety and tolerability assessment and secondary biochemical and functional outcomes.
Show evidence (1 reference)
clinicaltrials:NCT07530796 SUPPORT Other
"The goal of this clinical trial is to learn if the treatment is a safe, tolerable, and efficacious treatment for adults and children with Aspartylglucosaminuria (AGU)."
The registry establishes a planned first-in-human scAAV9/AGA study in children and adults with AGU.
{ }

Source YAML

click to show 
name: Aspartylglucosaminuria
category: Mendelian
creation_date: '2026-05-03T15:19:05Z'
synonyms:
- Aspartylglucosaminidase deficiency
- AGU
- Aspartylglucosaminuria, AGA-related
description: >
  Aspartylglucosaminuria is a rare autosomal recessive lysosomal storage
  disorder caused by biallelic pathogenic variants in AGA, encoding
  aspartylglucosaminidase. Loss of AGA activity impairs degradation of
  N-linked glycoprotein-derived glycoasparagines, causing accumulation of
  glycoasparagines in tissues and body fluids with childhood-onset
  developmental delay, progressive intellectual disability, psychomotor
  deterioration, coarse facial features, skeletal findings, and abnormal
  urinary aspartylglucosamine.
disease_term:
  preferred_term: aspartylglucosaminuria
  term:
    id: MONDO:0008830
    label: aspartylglucosaminuria
parents:
- Lysosomal Storage Disorder
- Oligosaccharidosis
classifications:
  isds_skeletal_category:
  - classification_value: lysosomal_storage_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 27 "Lysosomal
      storage diseases with skeletal involvement (dysostosis multiplex group)";
      listed as "Aspartylglucosaminuria".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008830
      label: aspartylglucosaminuria
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:93
    mapping_justification: >
      Orphanet ORPHA:93 lists MONDO:0008830 as an exact cross-reference for
      aspartylglucosaminuria.
external_assertions:
- name: Orphanet Aspartylglucosaminuria disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:93
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=93
  description: >
    Orphanet's ORPHA:93 structured record for Aspartylglucosaminuria includes
    the exact MONDO cross-reference, definition, autosomal recessive
    inheritance, epidemiology, AGA gene association, and HPO phenotype
    annotations used in this entry.
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0008830 | Exact"
    explanation: Orphanet maps ORPHA:93 to the same MONDO identifier used by this entry.
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:208400 | Exact"
    explanation: Orphanet lists OMIM:208400 as an exact external cross-reference.
definitions:
- name: Orphanet aspartylglucosaminuria definition
  definition_type: OTHER
  description: >
    A rare oligosaccharidosis with facial dysmorphism, progressive intellectual
    disability, and psychomotor deterioration caused by accumulation of
    glycoasparagines in tissues and body fluids.
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare oligosaccharidosis characterized by facial dysmorphism, progressive intellectual disability and psychomotor deterioration due to accumulation of glycoasparagines in tissues and body fluids."
    explanation: Orphanet defines the core biochemical and neurodevelopmental phenotype.
inheritance:
- name: Autosomal recessive inheritance
  description: Aspartylglucosaminuria is inherited in an autosomal recessive pattern.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for aspartylglucosaminuria.
prevalence:
- population: Worldwide
  prevalence_class: UNKNOWN
  percentage: Unknown
  notes: >
    Orphanet records worldwide point prevalence as unknown, with higher
    prevalence at birth reported in Finland and rarer prevalence at birth in
    Australia and Sweden.
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records worldwide point prevalence as unknown.
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Finland | Prevalence at birth | PMID:27906067"
    explanation: Orphanet records a higher Finnish birth-prevalence band.
progression:
- phase: Childhood-onset progressive neurodevelopmental disease
  age_range: Childhood onward
  notes: >
    Children may appear relatively well in infancy, then develop delayed speech,
    learning impairment, behavioral changes, and progressive intellectual and
    physical disability. Adult patients often become highly dependent on
    supportive care, with premature death commonly before age 50.
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset for aspartylglucosaminuria.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50"
    explanation: Review describes the progressive natural history and premature mortality.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median lifespan of AGU patients is approximately 30 to 40 years."
    explanation: Provides a quantitative median-lifespan estimate for AGU patients.
pathophysiology:
- name: AGA lysosomal enzyme deficiency
  conforms_to: "lysosomal_substrate_accumulation#Lysosomal Hydrolase or Cofactor Deficiency"
  description: >
    Biallelic pathogenic variants in AGA reduce functional
    aspartylglucosaminidase/glycosylasparaginase, a lysosomal enzyme required
    for hydrolysis of the protein-oligosaccharide linkage in Asn-linked
    glycoprotein turnover.
  genes:
  - preferred_term: AGA
    term:
      id: hgnc:318
      label: AGA
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  - preferred_term: protein deglycosylation
    modifier: DECREASED
    term:
      id: GO:0006517
      label: protein deglycosylation
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AGA | aspartylglucosaminidase | hgnc:318 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies AGA as the disease-causing gene.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA)"
    explanation: Review directly supports deficient lysosomal AGA activity as causal.
  - reference: PMID:10571008
    reference_title: "Aspartylglycosaminuria: biochemistry and molecular biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AGU mutations occur in the gene (AGA) for glycosylasparaginase, the enzyme necessary for hydrolysis of the protein oligosaccharide linkage in Asn-linked glycoprotein substrates undergoing metabolic turnover."
    explanation: Biochemical review identifies the affected gene and enzymatic reaction.
  downstream:
  - target: Glycoasparagine substrate accumulation
    causal_link_type: DIRECT
    description: Loss of AGA activity blocks clearance of aspartylglucosamine-containing glycoasparagines.
    evidence:
    - reference: PMID:10571008
      reference_title: "Aspartylglycosaminuria: biochemistry and molecular biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Loss of glycosylasparaginase activity leads to accumulation of the linkage unit Asn-GlcNAc in tissue lysosomes."
      explanation: This biochemical review directly links loss of AGA/glycosylasparaginase activity to lysosomal Asn-GlcNAc substrate accumulation.
- name: AGA protein maturation and folding defects
  description: >
    Many AGA missense variants disrupt folding, dimerization, autocatalytic
    activation, lysosomal trafficking, or active-site function, lowering mature
    lysosomal enzyme activity and contributing to genotype-specific severity.
  genes:
  - preferred_term: AGA
    term:
      id: hgnc:318
      label: AGA
  biological_processes:
  - preferred_term: protein folding
    modifier: ABNORMAL
    term:
      id: GO:0006457
      label: protein folding
  - preferred_term: protein maturation
    modifier: ABNORMAL
    term:
      id: GO:0051604
      label: protein maturation
  evidence:
  - reference: PMID:11309371
    reference_title: "Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Many of these are predicted to interfere with the complex intracellular maturation and processing of the AGA polypeptide."
    explanation: Functional mutation study supports impaired AGA maturation as a disease mechanism.
  - reference: PMID:11309371
    reference_title: "Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations of the dimer interface prevent dimerization in the ER, whereas active site mutations not only destroy the activity but also affect maturation of the precursor."
    explanation: Study distinguishes dimerization, active-site, and maturation effects of pathogenic variants.
  downstream:
  - target: AGA lysosomal enzyme deficiency
    causal_link_type: DIRECT
    description: Defective folding and maturation reduce the amount of active AGA reaching lysosomes.
    evidence:
    - reference: PMID:11309371
      reference_title: "Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Many of these are predicted to interfere with the complex intracellular maturation and processing of the AGA polypeptide."
      explanation: Functional mutation analysis supports the edge from folding/maturation defects to reduced mature AGA enzyme.
- name: Glycoasparagine substrate accumulation
  conforms_to: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  description: >
    Deficient AGA activity causes accumulation of undegraded glycoasparagines,
    especially aspartylglucosamine/GlcNAc-Asn, in tissue lysosomes and body
    fluids. Urinary excretion of aspartylglucosamine is the characteristic
    biochemical signature.
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  chemical_entities:
  - preferred_term: glycoasparagine / GlcNAc-Asn substrate
    modifier: INCREASED
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "accumulation of glycoasparagines in tissues and body fluids"
    explanation: Orphanet definition supports glycoasparagine accumulation.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accumulation of these undegraded glycoasparagines in tissues and body fluids."
    explanation: Review supports the immediate storage product.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The accumulated substrate GlcNAc-Asn is excreted in urine of patients in large quantities."
    explanation: Gene-therapy study summarizes urinary GlcNAc-Asn as a disease biomarker.
  downstream:
  - target: Neuronal and glial lysosomal storage
    causal_link_type: DIRECT
    description: Storage affects lysosomes in brain cells, producing progressive neurodegeneration.
    evidence:
    - reference: PMID:10571008
      reference_title: "Aspartylglycosaminuria: biochemistry and molecular biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Storage of this fragment affects the pathophysiology of neuronal cells most severely."
      explanation: This directly supports neuronal cells as a major downstream target of Asn-GlcNAc storage.
  - target: Systemic connective tissue and skeletal involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glycoasparagine storage in non-neuronal tissues
    - cellular dysfunction and connective-tissue or skeletal remodeling
    description: Storage in non-neuronal tissues contributes to coarse features, hernias, and skeletal abnormalities.
    evidence:
    - reference: PMID:33439067
      reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "AGU is caused by pathogenic variants in the aspartylglucosaminidase (AGA) gene, leading to glycoasparagine accumulation and cellular dysfunction."
      explanation: This supports the storage-to-cellular-dysfunction bridge; the specific connective-tissue and skeletal intermediates are compressed into the downstream node.
  - target: Aspartylglucosaminuria
    causal_link_type: DIRECT
    description: Accumulated GlcNAc-Asn/aspartylglucosamine is excreted in urine as the biochemical phenotype.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The accumulated substrate GlcNAc-Asn is excreted in urine of patients in large quantities."
      explanation: This directly links substrate accumulation to the urinary aspartylglucosamine phenotype.
  - target: Abnormality of amino acid metabolism
    causal_link_type: DIRECT
    description: Glycoasparagine substrate accumulation is recorded as an abnormal amino-acid-metabolism phenotype.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004337 | Abnormality of amino acid metabolism | Very frequent (99-80%)"
      explanation: Orphanet records abnormality of amino acid metabolism as a very frequent biochemical phenotype.
- name: Neuronal and glial lysosomal storage
  conforms_to: "lysosomal_substrate_accumulation#Storage-Cell Cytotoxicity and Neuroinflammation"
  description: >
    Glycoasparagine accumulation produces lysosomal storage in neurons and glia,
    brain atrophy, impaired learning, progressive intellectual disability,
    speech impairment, gait disturbance, dyskinesia, and seizures.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:9425233
    reference_title: "Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions."
    explanation: Mouse model directly shows neuronal and glial storage.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Neuronal, glial, and endothelial cells of the frontal cortex, cerebellum, brain stem, and spinal cord of the AGU mice become vacuolated around 6 months old and progressively worsen."
    explanation: Mouse model shows lysosomal vacuolization in neurons, glia, and endothelial cells across CNS regions, supporting endothelial involvement in CNS storage.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AGU is a slow but progressive and severe neurodegenerative disease characterized by intellectual disability, skeletal and motor abnormalities, and early mortality."
    explanation: Preclinical translational paper summarizes the progressive neurodegenerative phenotype.
  downstream:
  - target: Intellectual disability
    causal_link_type: DIRECT
    description: Progressive brain storage and atrophy impair cognition and adaptive function.
    evidence:
    - reference: PMID:33439067
      reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: This directly connects neurodegenerative lysosomal storage disease to progressive intellectual disability.
  - target: Delayed speech and language development
    causal_link_type: DIRECT
    description: Neurodevelopmental impairment includes prominent speech delay.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "AGU patients have developmental delays including delayed speech and impaired learning caused by progressive brain atrophy."
      explanation: This directly supports delayed speech as a consequence of progressive brain involvement.
  - target: Abnormality of speech or vocalization
    causal_link_type: DIRECT
    description: Progressive brain involvement also manifests as abnormal speech and vocalization.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002167 | Abnormality of speech or vocalization | Very frequent (99-80%)"
      explanation: Orphanet supports abnormal speech/vocalization as a very frequent neurodevelopmental manifestation.
  - target: Dyskinesia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive motor-system involvement
    description: Progressive CNS involvement contributes to abnormal involuntary movement.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100660 | Dyskinesia | Very frequent (99-80%)"
      explanation: Orphanet supports dyskinesia as a very frequent manifestation downstream of neurologic disease.
  - target: Seizure
    causal_link_type: DIRECT
    description: Progressive brain disease can include seizures.
    evidence:
    - reference: PMID:33439067
      reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures"
      explanation: Clinical review lists seizures among the core manifestations of AGU.
  - target: Atypical behavior
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive brain involvement
    description: Progressive neurologic involvement can include atypical behavioral manifestations.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000708 | Atypical behavior | Occasional (29-5%)"
      explanation: Orphanet records atypical behavior as an occasional neurologic phenotype.
  - target: Sleep disturbance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive brain involvement
    description: Progressive neurologic disease can include disordered sleep.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002360 | Sleep abnormality | Occasional (29-5%)"
      explanation: Orphanet records sleep abnormality as an occasional phenotype.
- name: Systemic connective tissue and skeletal involvement
  description: >
    Non-neuronal lysosomal storage and connective-tissue overgrowth contribute
    to the coarse facial, gingival/oral, hernia, and skeletal manifestations of
    aspartylglucosaminuria.
  locations:
  - preferred_term: connective tissue
    term:
      id: UBERON:0002384
      label: connective tissue
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  evidence:
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures"
    explanation: Clinical review supports skeletal and connective-tissue involvement.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health."
    explanation: Review supports broad systemic involvement beyond the CNS.
  downstream:
  - target: Gingival overgrowth
    causal_link_type: DIRECT
    description: Connective-tissue overgrowth contributes to gingival enlargement.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000212 | Gingival overgrowth | Very frequent (99-80%)"
      explanation: Orphanet supports gingival overgrowth as a very frequent manifestation of the systemic connective-tissue branch.
  - target: Coarse facial features
    causal_link_type: DIRECT
    description: Systemic storage and connective-tissue overgrowth contribute to coarse facial features.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000280 | Coarse facial features | Frequent (79-30%)"
      explanation: Orphanet supports coarse facial features as a frequent manifestation of AGU.
  - target: Abnormal facial shape
    causal_link_type: DIRECT
    description: Systemic storage and connective-tissue overgrowth contribute to abnormal facial shape.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001999 | Abnormal facial shape | Very frequent (99-80%)"
      explanation: Orphanet supports abnormal facial shape as a very frequent craniofacial manifestation.
  - target: Large face
    causal_link_type: DIRECT
    description: Craniofacial connective-tissue and skeletal involvement can manifest as a large face.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100729 | Large face | Very frequent (99-80%)"
      explanation: Orphanet supports large face as a very frequent craniofacial manifestation.
  - target: Mandibular prognathia
    causal_link_type: DIRECT
    description: Craniofacial skeletal involvement contributes to mandibular prognathia.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000303 | Mandibular prognathia | Very frequent (99-80%)"
      explanation: Orphanet supports mandibular prognathia as a very frequent craniofacial manifestation.
  - target: Hypertelorism
    causal_link_type: DIRECT
    description: Craniofacial involvement can include hypertelorism.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
      explanation: Orphanet supports hypertelorism as a very frequent craniofacial manifestation.
  - target: Wide nasal bridge
    causal_link_type: DIRECT
    description: Craniofacial involvement can include a wide nasal bridge.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000431 | Wide nasal bridge | Very frequent (99-80%)"
      explanation: Orphanet supports wide nasal bridge as a very frequent craniofacial manifestation.
  - target: Short nose
    causal_link_type: DIRECT
    description: Craniofacial involvement can include a short nose.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003196 | Short nose | Very frequent (99-80%)"
      explanation: Orphanet supports short nose as a very frequent craniofacial manifestation.
  - target: Microtia
    causal_link_type: DIRECT
    description: Craniofacial and external-ear involvement can include microtia.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008551 | Microtia | Very frequent (99-80%)"
      explanation: Orphanet supports microtia as a very frequent external-ear manifestation.
  - target: Thick vermilion border
    causal_link_type: DIRECT
    description: Craniofacial soft-tissue involvement can include thick vermilion border.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012471 | Thick vermilion border | Very frequent (99-80%)"
      explanation: Orphanet supports thick vermilion border as a very frequent craniofacial manifestation.
  - target: Macroglossia
    causal_link_type: DIRECT
    description: Oral soft-tissue involvement contributes to macroglossia.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000158 | Macroglossia | Frequent (79-30%)"
      explanation: Orphanet supports macroglossia as a frequent oral manifestation.
  - target: Abnormality of the dentition
    causal_link_type: DIRECT
    description: Oral and craniofacial involvement can include abnormal dentition.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000164 | Abnormality of the dentition | Frequent (79-30%)"
      explanation: Orphanet supports abnormal dentition as a frequent oral manifestation.
  - target: Carious teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oral and dental involvement is associated with frequent carious teeth.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000670 | Carious teeth | Frequent (79-30%)"
      explanation: Orphanet supports carious teeth as a frequent dental manifestation.
  - target: Umbilical hernia
    causal_link_type: DIRECT
    description: Connective tissue involvement contributes to hernias.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001537 | Umbilical hernia | Very frequent (99-80%)"
      explanation: Orphanet supports umbilical hernia as a very frequent manifestation.
  - target: Inguinal hernia
    causal_link_type: DIRECT
    description: Connective tissue involvement can also manifest as inguinal hernia.
    evidence:
    - reference: PMID:33439067
      reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias"
      explanation: Clinical review includes inguinal and abdominal hernias among early AGU diagnostic features.
  - target: Scoliosis
    causal_link_type: DIRECT
    description: Skeletal involvement contributes to spinal curvature.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002650 | Scoliosis | Very frequent (99-80%)"
      explanation: Orphanet supports scoliosis as a very frequent skeletal manifestation.
  - target: Pectus carinatum
    causal_link_type: DIRECT
    description: Skeletal involvement can manifest as pectus carinatum.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000768 | Pectus carinatum | Frequent (79-30%)"
      explanation: Orphanet supports pectus carinatum as a frequent skeletal manifestation.
  - target: Thickened calvaria
    causal_link_type: DIRECT
    description: Cranial skeletal involvement can manifest as calvarial thickening.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002684 | Thickened calvaria | Frequent (79-30%)"
      explanation: Orphanet supports thickened calvaria as a frequent skeletal manifestation.
  - target: Abnormal cortical bone morphology
    causal_link_type: DIRECT
    description: Skeletal involvement can include abnormal cortical bone morphology.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003103 | Abnormal cortical bone morphology | Frequent (79-30%)"
      explanation: Orphanet supports abnormal cortical bone morphology as a frequent skeletal manifestation.
  - target: Anterior beaking of lumbar vertebrae
    causal_link_type: DIRECT
    description: Spinal skeletal involvement can manifest as anterior lumbar vertebral beaking.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008430 | Anterior beaking of lumbar vertebrae | Frequent (79-30%)"
      explanation: Orphanet supports anterior beaking of lumbar vertebrae as a frequent skeletal manifestation.
  - target: Abnormal morphology of ulna
    causal_link_type: DIRECT
    description: Appendicular skeletal involvement can include abnormal ulnar morphology.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0040071 | Abnormal morphology of ulna | Frequent (79-30%)"
      explanation: Orphanet supports abnormal ulnar morphology as a frequent skeletal manifestation.
  - target: Macroorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem somatic involvement can include macroorchidism in affected males.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000053 | Macroorchidism | Frequent (79-30%)"
      explanation: Orphanet supports macroorchidism as a frequent genitourinary manifestation.
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem disease with early somatic involvement is associated with recurrent respiratory infections.
    evidence:
    - reference: PMID:27906067
      reference_title: "Aspartylglycosaminuria: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU."
      explanation: The review links early systemic AGU findings with respiratory infections.
  - target: Chronic otitis media
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem disease with recurrent infections can include chronic otitis media.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000389 | Chronic otitis media | Occasional (29-5%)"
      explanation: Orphanet records chronic otitis media as an occasional phenotype.
  - target: Arthritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Systemic skeletal and connective-tissue involvement can include arthritis.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001369 | Arthritis | Occasional (29-5%)"
      explanation: Orphanet records arthritis as an occasional phenotype.
  - target: Joint stiffness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Skeletal and connective-tissue involvement can include joint stiffness.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001387 | Joint stiffness | Occasional (29-5%)"
      explanation: Orphanet records joint stiffness as an occasional phenotype.
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem lysosomal storage disease can include splenomegaly.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001744 | Splenomegaly | Occasional (29-5%)"
      explanation: Orphanet records splenomegaly as an occasional phenotype.
  - target: Pes planus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Skeletal and connective-tissue involvement can include pes planus.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001763 | Pes planus | Occasional (29-5%)"
      explanation: Orphanet records pes planus as an occasional phenotype.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem lysosomal storage disease can include hepatomegaly.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002240 | Hepatomegaly | Occasional (29-5%)"
      explanation: Orphanet records hepatomegaly as an occasional phenotype.
  - target: Delayed skeletal maturation
    causal_link_type: DIRECT
    description: Skeletal involvement can include delayed skeletal maturation.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002750 | Delayed skeletal maturation | Occasional (29-5%)"
      explanation: Orphanet records delayed skeletal maturation as an occasional skeletal phenotype.
  - target: Abnormal vertebral morphology
    causal_link_type: DIRECT
    description: Skeletal involvement can include abnormal vertebral morphology.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003468 | Abnormal vertebral morphology | Occasional (29-5%)"
      explanation: Orphanet records abnormal vertebral morphology as an occasional skeletal phenotype.
  - target: Beaking of vertebral bodies
    causal_link_type: DIRECT
    description: Spinal skeletal involvement can include vertebral body beaking.
    evidence:
    - reference: ORPHA:93
      reference_title: "Aspartylglucosaminuria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004568 | Beaking of vertebral bodies | Occasional (29-5%)"
      explanation: Orphanet records beaking of vertebral bodies as an occasional skeletal phenotype.
biochemical:
- name: Increased urinary aspartylglucosamine
  presence: INCREASED
  context: >
    Aspartylglucosamine/GlcNAc-Asn is excreted in urine in large quantities and
    provides a characteristic biochemical marker of AGA deficiency.
  biomarker_term:
    preferred_term: aspartylglucosamine / GlcNAc-Asn
  readouts:
  - target: Glycoasparagine substrate accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary aspartylglucosamine reports glycoasparagine substrate accumulation downstream of AGA deficiency.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
      explanation: The human urinary biomarker directly reports accumulated GlcNAc-Asn substrate.
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012068 | Aspartylglucosaminuria | Very frequent (99-80%)"
    explanation: Orphanet lists the urinary biochemical phenotype as very frequent.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
    explanation: Study supports urinary GlcNAc-Asn as the diagnostic biochemical substrate.
- name: Reduced aspartylglucosaminidase activity
  presence: DECREASED
  context: Reduced AGA/glycosylasparaginase enzyme activity is the primary biochemical defect.
  readouts:
  - target: AGA lysosomal enzyme deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced aspartylglucosaminidase activity reports the primary AGA lysosomal enzyme defect.
    evidence:
    - reference: PMID:36982794
      reference_title: "Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have here established and validated a fluorometric AGA activity assay for human serum samples from healthy donors and AGU patients."
      explanation: The validated serum assay measures the deficient AGA enzyme activity in affected individuals.
  evidence:
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA)"
    explanation: Review supports reduced AGA enzymatic activity as causal.
  - reference: PMID:36982794
    reference_title: "Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by the deficiency of the lysosomal hydrolase aspartylglucosaminidase (AGA)."
    explanation: The human serum-assay study confirms deficient AGA activity as the primary biochemical defect.
genetic:
- name: Biallelic AGA pathogenic variants
  gene_term:
    preferred_term: AGA
    term:
      id: hgnc:318
      label: AGA
  association: CAUSATIVE
  features: >
    Aspartylglucosaminuria is caused by biallelic pathogenic AGA variants. The
    Finnish founder allele causes C163S in the AGA enzyme protein and accounts
    for most Finnish cases, while many rarer pathogenic variants have been
    described worldwide.
  evidence:
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population."
    explanation: Review supports the common Finnish founder pathogenic variant.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population."
    explanation: Review quantifies the AGU_Fin founder allele as homozygous in about 98% of Finnish AGU cases.
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than 30 AGA variants have been identified worldwide."
    explanation: Clinical review supports broader allelic heterogeneity outside Finland.
  - reference: CGGV:assertion_1f315b4a-1a3b-4deb-90fd-2b73f732a4ba-2022-09-02T160000.000Z
    reference_title: "AGA / aspartylglucosaminuria (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AGA | HGNC:318 | aspartylglucosaminuria | MONDO:0008830 | AR | Definitive"
    explanation: ClinGen classifies the AGA-aspartylglucosaminuria gene-disease relationship as definitive with autosomal recessive inheritance.
phenotypes:
- name: Intellectual disability
  frequency: VERY_FREQUENT
  description: Progressive intellectual disability is a core neurologic manifestation.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive intellectual and physical disability is the main symptom"
    explanation: Review directly supports progressive intellectual disability.
- name: Delayed speech and language development
  frequency: VERY_FREQUENT
  description: Delayed speech and language development is a very frequent early neurodevelopmental feature.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000750 | Delayed speech and language development | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormality of speech or vocalization
  frequency: VERY_FREQUENT
  description: Speech and vocalization abnormalities are very frequent.
  phenotype_term:
    preferred_term: Abnormality of speech or vocalization
    term:
      id: HP:0002167
      label: Abnormal speech pattern
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002167 | Abnormality of speech or vocalization | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Dyskinesia
  frequency: VERY_FREQUENT
  description: Dyskinesia is a very frequent motor manifestation.
  phenotype_term:
    preferred_term: Dyskinesia
    term:
      id: HP:0100660
      label: Dyskinesia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100660 | Dyskinesia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Seizure
  frequency: OCCASIONAL
  description: Seizures occur in a subset of affected individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Atypical behavior
  frequency: OCCASIONAL
  description: Atypical behavior can occur with progressive neurologic involvement.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000708 | Atypical behavior | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Sleep disturbance
  frequency: OCCASIONAL
  description: Sleep disturbance is an occasional neurologic or behavioral feature.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002360 | Sleep abnormality | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Gingival overgrowth
  frequency: VERY_FREQUENT
  description: Gingival overgrowth is a very frequent connective-tissue/facial feature.
  phenotype_term:
    preferred_term: Gingival overgrowth
    term:
      id: HP:0000212
      label: Gingival overgrowth
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000212 | Gingival overgrowth | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Coarse facial features
  frequency: FREQUENT
  description: Coarse facial features are frequent.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000280 | Coarse facial features | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormal facial shape
  frequency: VERY_FREQUENT
  description: Abnormal facial shape is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001999 | Abnormal facial shape | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Large face
  frequency: VERY_FREQUENT
  description: Large face is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Large face
    term:
      id: HP:0100729
      label: Large face
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100729 | Large face | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Mandibular prognathia
  frequency: VERY_FREQUENT
  description: Mandibular prognathia is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000303 | Mandibular prognathia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Macroglossia
  frequency: FREQUENT
  description: Macroglossia is a frequent oral feature.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000158 | Macroglossia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormality of the dentition
  frequency: FREQUENT
  description: Dental abnormalities are frequent.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000164 | Abnormality of the dentition | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Carious teeth
  frequency: FREQUENT
  description: Carious teeth are frequent.
  phenotype_term:
    preferred_term: Carious teeth
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000670 | Carious teeth | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hypertelorism
  frequency: VERY_FREQUENT
  description: Hypertelorism is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Wide nasal bridge
  frequency: VERY_FREQUENT
  description: Wide nasal bridge is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000431 | Wide nasal bridge | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Short nose
  frequency: VERY_FREQUENT
  description: Short nose is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003196 | Short nose | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Microtia
  frequency: VERY_FREQUENT
  description: Microtia is a very frequent external ear feature.
  phenotype_term:
    preferred_term: Microtia
    term:
      id: HP:0008551
      label: Microtia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008551 | Microtia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Thick vermilion border
  frequency: VERY_FREQUENT
  description: Thick vermilion border is a very frequent craniofacial feature.
  phenotype_term:
    preferred_term: Thick vermilion border
    term:
      id: HP:0012471
      label: Thick vermilion border
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012471 | Thick vermilion border | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Umbilical hernia
  frequency: VERY_FREQUENT
  description: Umbilical hernia is very frequent.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001537 | Umbilical hernia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Inguinal hernia
  frequency: OCCASIONAL
  description: Inguinal hernia occurs in a subset of patients and is useful for early recognition.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000023 | Inguinal hernia | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias"
    explanation: Clinical review includes inguinal and abdominal hernias among early diagnostic clues.
- name: Macroorchidism
  frequency: FREQUENT
  description: Macroorchidism is a frequent genitourinary feature.
  phenotype_term:
    preferred_term: Macroorchidism
    term:
      id: HP:0000053
      label: Macroorchidism
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000053 | Macroorchidism | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Recurrent respiratory infections
  frequency: OCCASIONAL
  description: Recurrent upper respiratory infections are a recognized early feature.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurring upper respiratory and ear infections"
    explanation: Clinical review supports recurrent respiratory and ear infections as early features.
- name: Chronic otitis media
  frequency: OCCASIONAL
  description: Chronic otitis media can occur as part of recurrent ENT infection involvement.
  phenotype_term:
    preferred_term: Chronic otitis media
    term:
      id: HP:0000389
      label: Chronic otitis media
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000389 | Chronic otitis media | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Arthritis
  frequency: OCCASIONAL
  description: Arthritis is an occasional musculoskeletal manifestation.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001369 | Arthritis | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Joint stiffness
  frequency: OCCASIONAL
  description: Joint stiffness is an occasional musculoskeletal manifestation.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001387 | Joint stiffness | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Splenomegaly
  frequency: OCCASIONAL
  description: Splenomegaly is an occasional systemic manifestation.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Pes planus
  frequency: OCCASIONAL
  description: Pes planus is an occasional skeletal or connective-tissue manifestation.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001763 | Pes planus | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hepatomegaly
  frequency: OCCASIONAL
  description: Hepatomegaly is an occasional systemic storage-disease manifestation.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Delayed skeletal maturation
  frequency: OCCASIONAL
  description: Delayed skeletal maturation is an occasional skeletal manifestation.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002750 | Delayed skeletal maturation | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormal vertebral morphology
  frequency: OCCASIONAL
  description: Abnormal vertebral morphology is an occasional skeletal manifestation.
  phenotype_term:
    preferred_term: Abnormal vertebral morphology
    term:
      id: HP:0003468
      label: Abnormal vertebral morphology
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003468 | Abnormal vertebral morphology | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Beaking of vertebral bodies
  frequency: OCCASIONAL
  description: Vertebral body beaking is an occasional spinal skeletal manifestation.
  phenotype_term:
    preferred_term: Beaking of vertebral bodies
    term:
      id: HP:0004568
      label: Beaking of vertebral bodies
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004568 | Beaking of vertebral bodies | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Scoliosis
  frequency: VERY_FREQUENT
  description: Scoliosis is a very frequent skeletal manifestation.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Pectus carinatum
  frequency: FREQUENT
  description: Pectus carinatum is a frequent skeletal feature.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000768 | Pectus carinatum | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Thickened calvaria
  frequency: FREQUENT
  description: Thickened calvaria is a frequent cranial skeletal feature.
  phenotype_term:
    preferred_term: Thickened calvaria
    term:
      id: HP:0002684
      label: Thickened calvaria
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002684 | Thickened calvaria | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormal cortical bone morphology
  frequency: FREQUENT
  description: Abnormal cortical bone morphology is frequent.
  phenotype_term:
    preferred_term: Abnormal cortical bone morphology
    term:
      id: HP:0003103
      label: Abnormal cortical bone morphology
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003103 | Abnormal cortical bone morphology | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Anterior beaking of lumbar vertebrae
  frequency: FREQUENT
  description: Anterior beaking of lumbar vertebrae is a frequent spinal feature.
  phenotype_term:
    preferred_term: Anterior beaking of lumbar vertebrae
    term:
      id: HP:0008430
      label: Anterior beaking of lumbar vertebrae
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008430 | Anterior beaking of lumbar vertebrae | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormal morphology of ulna
  frequency: FREQUENT
  description: Abnormal morphology of ulna is a frequent skeletal feature.
  phenotype_term:
    preferred_term: Abnormal morphology of ulna
    term:
      id: HP:0040071
      label: Abnormal morphology of ulna
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040071 | Abnormal morphology of ulna | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Aspartylglucosaminuria
  frequency: VERY_FREQUENT
  description: Urinary aspartylglucosamine is the characteristic biochemical phenotype.
  phenotype_term:
    preferred_term: Aspartylglucosaminuria
    term:
      id: HP:0012068
      label: Aspartylglucosaminuria
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012068 | Aspartylglucosaminuria | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormality of amino acid metabolism
  frequency: VERY_FREQUENT
  description: Abnormal amino-acid-related metabolism reflects the glycoasparagine storage phenotype.
  phenotype_term:
    preferred_term: Abnormality of amino acid metabolism
    term:
      id: HP:0004337
      label: Abnormality of amino acid metabolism
  evidence:
  - reference: ORPHA:93
    reference_title: "Aspartylglucosaminuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004337 | Abnormality of amino acid metabolism | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
diagnosis:
- name: Urinary aspartylglucosamine testing
  description: >
    Biochemical diagnosis can be supported by detecting large urinary amounts
    of aspartylglucosamine/GlcNAc-Asn.
  results: Increased urinary aspartylglucosamine supports AGA deficiency.
  evidence:
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large amounts of GlcNAc-Asn substrate can be readily detected in urine of AGU patients and is thereby used as a diagnostic biomarker."
    explanation: Study supports urinary GlcNAc-Asn as a diagnostic biomarker.
- name: AGA molecular genetic testing
  description: Molecular testing confirms diagnosis by identifying biallelic pathogenic AGA variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: AGA
        term:
          id: hgnc:318
          label: AGA
  results: Biallelic pathogenic AGA variants confirm aspartylglucosaminuria.
  evidence:
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AGU is caused by pathogenic variants in the aspartylglucosaminidase (AGA) gene"
    explanation: Clinical review supports AGA sequencing as confirmatory molecular testing.
- name: Serum AGA enzyme activity assay
  description: >
    A validated fluorometric serum assay can demonstrate deficient
    aspartylglucosaminidase activity and support biochemical diagnosis; molecular
    testing remains appropriate for genetic confirmation.
  results: Markedly reduced serum AGA activity supports aspartylglucosaminuria.
  evidence:
  - reference: PMID:36982794
    reference_title: "Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the validated AGA activity assay is suitable for the assessment of AGA activity in the serum of healthy donors and AGU patients, and it can be used for diagnostics of AGU and, potentially, for following a treatment effect."
    explanation: This directly supports serum AGA activity measurement as a diagnostic biochemical assay.
treatments:
- name: Supportive and anticipatory care
  description: >
    No approved disease-modifying therapy is currently available; supportive
    care focuses on early interventions, management of neurodevelopmental,
    seizure, infection, sleep, orthopedic, and functional complications, and
    anticipatory guidance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33439067
    reference_title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance"
    explanation: Clinical review supports supportive/anticipatory management in the absence of curative therapy.
- name: Hematopoietic stem cell transplantation
  description: >
    Allogeneic bone marrow / hematopoietic stem cell transplantation has been
    attempted in AGU patients in Finland and Sweden but, unlike in some other
    lysosomal storage disorders, has not shown clinical benefit or proven
    effective in curing the disease.
  treatment_term:
    preferred_term: bone marrow transplantation
    term:
      id: NCIT:C15194
      label: Bone Marrow Transplantation
  evidence:
  - reference: PMID:27906067
    reference_title: "Aspartylglycosaminuria: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allogenic stem cell transplantation has not proved effective in curing AGU."
    explanation: Review states allogeneic stem cell transplantation has not proven effective in AGU.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limited attempts at bone marrow transplantation (BMT) have not shown any benefit."
    explanation: Corroborates that bone marrow transplantation attempts in AGU have shown no benefit.
- name: Enzyme replacement therapy (preclinical)
  description: >
    Recombinant human AGA/glycosylasparaginase enzyme replacement corrected the
    pathophysiology in non-neuronal tissues of AGU mice and partially reduced
    brain substrate storage, but peripheral administration does not adequately
    reach the central nervous system and long-term dosing can provoke immune
    responses that abolish efficacy. It is not an approved human therapy.
  treatment_term:
    preferred_term: enzyme replacement or supplementation therapy
    term:
      id: NCIT:C16221
      label: Protein Replacement Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: AGA lysosomal enzyme deficiency
    treatment_effect: RESTORES
    description: Recombinant AGA supplies functional enzyme, correcting non-neuronal tissue pathophysiology in AGU mice.
    evidence:
    - reference: PMID:27906067
      reference_title: "Aspartylglycosaminuria: a review."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals."
      explanation: Mouse ERT corrected non-neuronal pathophysiology, supporting enzyme restoration.
  - target: Glycoasparagine substrate accumulation
    treatment_effect: INHIBITS
    description: Recombinant AGA reduced accumulated aspartylglucosamine, though brain reduction was only partial (up to 40%).
    evidence:
    - reference: PMID:27906067
      reference_title: "Aspartylglycosaminuria: a review."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol."
      explanation: Mouse ERT partially reduced brain substrate accumulation, illustrating the CNS-penetration limitation.
  evidence:
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Enzyme replacement therapy (ERT) has the potential to be an effective treatment, but peripheral administration does not adequately treat the central nervous system (CNS)."
    explanation: Documents the central limitation of ERT (poor CNS penetration) motivating CNS-directed gene therapy.
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, long-term ERT in a mouse model has been shown to induce immune responses, which abolish its therapeutic effects."
    explanation: Long-term ERT in the mouse model induced immune responses abolishing efficacy, a further limitation.
- name: scAAV9/AGA gene replacement therapy (investigational)
  description: >
    AAV9-mediated AGA gene replacement restored AGA activity, reduced GlcNAc-Asn
    substrate, and improved neurologic and histopathologic outcomes in
    Aga-deficient mice. A first-in-human phase 1/2 study of intrathecal
    scAAV9/AGA (danagalex) is registered but not yet recruiting, so no human
    safety or efficacy result is established and the intervention is not an
    approved therapy.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  therapeutic_modality: GENE_THERAPY
  target_mechanisms:
  - target: AGA lysosomal enzyme deficiency
    treatment_effect: RESTORES
    description: AAV9/AGA supplies a functional AGA transgene to restore enzyme activity.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity"
      explanation: Preclinical mouse study supports restoration of AGA activity after gene transfer.
  - target: Glycoasparagine substrate accumulation
    treatment_effect: INHIBITS
    description: Restored AGA activity reduces the accumulated GlcNAc-Asn substrate burden in Aga-deficient mice.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids"
      explanation: Mouse AAV9/AGA data support direct reduction of the storage substrate downstream of enzyme restoration.
  - target: Neuronal and glial lysosomal storage
    treatment_effect: INHIBITS
    description: AAV9/AGA reduced central nervous system pathology in the mouse model.
    evidence:
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "dose-dependent preservation of Purkinje neurons in the cerebellum"
      explanation: Preservation of cerebellar neurons supports disease-modifying impact on the neuronal storage branch.
    - reference: PMID:33186692
      reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "significantly reduced gliosis in the brain"
      explanation: Reduced gliosis supports inhibition of downstream glial pathology in the mouse model.
  evidence:
  - reference: PMID:33186692
    reference_title: "Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "treatment of Aga-/- mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation."
    explanation: Preclinical study supports AAV9/AGA as a translational gene-replacement candidate.
  - reference: clinicaltrials:NCT07530796
    reference_title: "An Open-Label, Single Center, Phase 1/2 Study to Evaluate the Safety and Efficacy of DANAGALEX (scAAV9/AGA) in Participants With Aspartylglucosaminuria (AGU)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The goal of this clinical trial is to learn if the treatment is a safe, tolerable, and efficacious treatment for adults and children with Aspartylglucosaminuria (AGU)."
    explanation: The registry supports clinical-development status only; it does not provide human safety or efficacy results.
clinical_trials:
- name: NCT07530796
  phase: PHASE_I
  status: NOT_RECRUITING
  description: >
    Open-label, single-center phase 1/2 study of one intrathecal dose of
    scAAV9/AGA (danagalex) in an estimated nine participants aged 4-45 years,
    with primary safety and tolerability assessment and secondary biochemical
    and functional outcomes.
  notes: >
    ClinicalTrials.gov reported NOT_YET_RECRUITING and last verified the record
    in April 2026; this is represented as NOT_RECRUITING because the schema has
    no separate not-yet-recruiting value. The combined phase 1/2 design is
    represented as PHASE_I because the schema accepts a single phase.
  evidence:
  - reference: clinicaltrials:NCT07530796
    reference_title: "An Open-Label, Single Center, Phase 1/2 Study to Evaluate the Safety and Efficacy of DANAGALEX (scAAV9/AGA) in Participants With Aspartylglucosaminuria (AGU)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The goal of this clinical trial is to learn if the treatment is a safe, tolerable, and efficacious treatment for adults and children with Aspartylglucosaminuria (AGU)."
    explanation: The registry establishes a planned first-in-human scAAV9/AGA study in children and adults with AGU.
notes: >
  This curation uses ORPHA:93 as the direct disease mapping and focuses on the
  compact causal chain from AGA pathogenic variants to impaired lysosomal
  glycoprotein degradation, glycoasparagine/GlcNAc-Asn storage, neuronal and
  glial lysosomal storage, progressive neurodevelopmental decline, and systemic
  connective-tissue/skeletal involvement. scAAV9/AGA is included as an
  investigational candidate with strong mouse evidence and a registered phase
  1/2 study that was not yet recruiting as of April 2026; it is not an approved
  therapy and no human efficacy is asserted.
references:
- reference: ORPHA:93
  title: Aspartylglucosaminuria
  findings: []
- reference: CGGV:assertion_1f315b4a-1a3b-4deb-90fd-2b73f732a4ba-2022-09-02T160000.000Z
  title: AGA / aspartylglucosaminuria (Definitive)
  findings: []
- reference: PMID:10571008
  title: "Aspartylglycosaminuria: biochemistry and molecular biology."
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:11309371
  title: "Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations."
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:27906067
  title: "Aspartylglycosaminuria: a review."
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:33439067
  title: "Aspartylglucosaminuria: Clinical Presentation and Potential Therapies."
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:9425233
  title: Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients.
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:33186692
  title: Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation.
  found_in:
  - Aspartylglucosaminuria-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:36982794
  title: "Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies."
  findings: []
- reference: clinicaltrials:NCT07530796
  title: "An Open-Label, Single Center, Phase 1/2 Study to Evaluate the Safety and Efficacy of DANAGALEX (scAAV9/AGA) in Participants With Aspartylglucosaminuria (AGU)"
  findings: []
📚

References & Deep Research

References

10
ORPHA:93
Aspartylglucosaminuria
No top-level findings curated for this source.
No top-level findings curated for this source.
PMID:10571008
Aspartylglycosaminuria: biochemistry and molecular biology.
No top-level findings curated for this source.
PMID:11309371
Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations.
No top-level findings curated for this source.
PMID:27906067
Aspartylglycosaminuria: a review.
No top-level findings curated for this source.
PMID:33439067
Aspartylglucosaminuria: Clinical Presentation and Potential Therapies.
No top-level findings curated for this source.
PMID:9425233
Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients.
No top-level findings curated for this source.
PMID:33186692
Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation.
No top-level findings curated for this source.
PMID:36982794
Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies.
No top-level findings curated for this source.
clinicaltrials:NCT07530796
An Open-Label, Single Center, Phase 1/2 Study to Evaluate the Safety and Efficacy of DANAGALEX (scAAV9/AGA) in Participants With Aspartylglucosaminuria (AGU)
No top-level findings curated for this source.

Deep Research

1
Cyberian Codex ▸
Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease
codex-local-synthesis 7 citations 2026-05-03T16:14:23Z

Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in AGA, the gene encoding aspartylglucosaminidase/glycosylasparaginase. AGA is required for hydrolysis of the protein-oligosaccharide linkage in Asn-linked glycoproteins during lysosomal turnover; loss of enzyme activity causes storage of glycoasparagines, including GlcNAc-Asn/aspartylglucosamine, in tissues and body fluids (PMID:10571008; PMID:27906067; https://pubmed.ncbi.nlm.nih.gov/27906067/).

The most direct molecular mechanism is loss of mature active AGA. Structural and cell-biologic work shows that disease-causing AGA variants can disrupt folding, dimerization in the endoplasmic reticulum, intracellular maturation/processing, or active-site function, converging on reduced lysosomal enzyme activity (PMID:11309371). The Finnish founder allele causes a C163S amino acid substitution and is a common cause in Finland, while broader clinical reviews describe more than 30 pathogenic AGA variants worldwide (PMID:27906067; PMID:33439067).

The immediate biochemical consequence is accumulation and urinary excretion of glycoasparagine substrate. Reviews describe accumulation of undegraded glycoasparagines in tissues and body fluids, and translational studies identify large amounts of urinary GlcNAc-Asn as a diagnostic biomarker for AGU (PMID:27906067; PMID:33186692).

The nervous system is the most clinically important target. Biochemical reviews emphasize severe effects on neuronal cells, and the AGU mouse model shows absent AGA activity, urinary aspartylglucosamine excretion, lysosomal storage vacuoles in neurons and glia, brain atrophy, and deep-gray-matter MRI abnormalities that parallel human disease (PMID:10571008; PMID:9425233). This cellular storage mechanism accounts for childhood onset with delayed speech and learning, progressive intellectual disability, psychomotor decline, gait/motor abnormalities, dyskinesia, and seizures (PMID:27906067; PMID:33439067).

AGU is also systemic. Clinical reviews describe coarse facial features, skeletal abnormalities, connective-tissue overgrowth, hernias, recurrent respiratory and ear infections, and progressive physical disability (PMID:27906067; PMID:33439067). These features are consistent with non-neuronal lysosomal storage and connective-tissue involvement, though the strongest mechanistic evidence is for substrate accumulation and lysosomal storage rather than a single downstream structural pathway.

There is no approved curative or disease-modifying therapy. Current management is supportive and anticipatory. Reviews report that human enzyme replacement trials have not been reported and allogeneic stem-cell transplantation has not proved effective. Preclinical enzyme and gene-transfer studies show biological correctability: adenovirus-mediated AGA reduced lysosomal storage in liver and partly in periventricular brain, while systemic AAV9/AGA in Aga-deficient mice produced sustained AGA activity, dose-dependent substrate clearance, reduced gliosis, and preservation of cerebellar Purkinje neurons (PMID:27906067; PMID:9930336; PMID:33186692).