Aspartylglucosaminuria

Mendelian MONDO:0008830 Pathograph 39 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.
29
Phenotypes
39
Pathograph
1
Genes
2
Treatments
8
References
1
Deep Research
🔗

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 link
glycoprotein catabolic process link ↓ DECREASED protein deglycosylation link ↓ DECREASED
lysosome link
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 link
protein folding link ⚠ ABNORMAL protein maturation link ⚠ 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 link ↓ DECREASED
lysosome link
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.
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 link glial cell link
lysosome link
brain link
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.
Show evidence (2 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 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 link cartilage tissue link
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.
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.
⬡

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.
●

Phenotypes

29
Digestive 1
Inguinal hernia OCCASIONAL Inguinal hernia (HP:0000023)
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.
Eye 1
Hypertelorism VERY_FREQUENT Hypertelorism (HP:0000316)
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 Macroorchidism (HP:0000053)
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 Coarse facial features (HP:0000280)
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 Abnormal facial shape (HP:0001999)
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 Macroglossia (HP:0000158)
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 Abnormality of the dentition (HP:0000164)
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 Carious teeth (HP:0000670)
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 Short nose (HP:0003196)
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 Thick vermilion border (HP:0012471)
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 Recurrent respiratory infections (HP:0002205)
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.
Musculoskeletal 2
Scoliosis VERY_FREQUENT Scoliosis (HP:0002650)
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 Pectus carinatum (HP:0000768)
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 5
Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)
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 Delayed speech and language development (HP:0000750)
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)
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 Dyskinesia (HP:0100660)
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 Seizure (HP:0001250)
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Other 11
Gingival overgrowth VERY_FREQUENT Gingival overgrowth (HP:0000212)
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 Large face (HP:0100729)
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 Mandibular prognathia (HP:0000303)
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 Wide nasal bridge (HP:0000431)
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 Microtia (HP:0008551)
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 Umbilical hernia (HP:0001537)
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.
Thickened calvaria FREQUENT Thickened calvaria (HP:0002684)
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 Abnormal cortical bone morphology (HP:0003103)
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 Anterior beaking of lumbar vertebrae (HP:0008430)
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 Abnormal morphology of ulna (HP:0040071)
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 Aspartylglucosaminuria (HP:0012068)
Show evidence (1 reference)
ORPHA:93 SUPPORT Other
"HP:0012068 | Aspartylglucosaminuria | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
🧬

Genetic Associations

1
Biallelic AGA pathogenic variants (CAUSATIVE)
Show evidence (3 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:33439067 SUPPORT Human Clinical
"more than 30 AGA variants have been identified worldwide."
Clinical review supports broader allelic heterogeneity outside Finland.
CGGV:assertion_1f315b4a-1a3b-4deb-90fd-2b73f732a4ba-2022-09-02T160000.000Z SUPPORT Other
"AGA | HGNC:318 | aspartylglucosaminuria | MONDO:0008830 | AR | Definitive"
ClinGen classifies the AGA-aspartylglucosaminuria gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Treatments

2
Supportive and anticipatory care
Action: supportive care MAXO:0000950
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 ↗ Seizure ↗
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.
AAV9/AGA gene replacement therapy
Action: gene therapy MAXO:0001001
AAV9-mediated AGA gene replacement is a preclinical disease-modifying strategy that restored AGA activity, reduced GlcNAc-Asn substrate, and improved neurologic and histopathologic outcomes in Aga-deficient mice. It is not yet an approved human 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 (1 reference)
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.
🔬

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 (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: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.
{ }

Source YAML

click to show 
name: Aspartylglucosaminuria
category: Mendelian
creation_date: '2026-05-03T15:19:05Z'
updated_date: '2026-05-18T11:24:09Z'
synonyms:
- Aspartylglucosaminidase deficiency
- AGU
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
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for aspartylglucosaminuria.
prevalence:
- population: Worldwide
  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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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.
pathophysiology:
- name: AGA lysosomal enzyme 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 (Orphanet structured-database record)"
    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
  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 (Orphanet structured-database record)"
    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.
- name: Neuronal and glial lysosomal storage
  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
  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: 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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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.
- 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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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 (Orphanet structured-database record)"
      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.
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: ORPHA:93
    reference_title: "Aspartylglucosaminuria (Orphanet structured-database record)"
    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: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.
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: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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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: 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012068 | Aspartylglucosaminuria | 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: MAXO:0000533
      label: molecular genetic testing
    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.
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: MAXO:0000950
      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: AAV9/AGA gene replacement therapy
  description: >
    AAV9-mediated AGA gene replacement is a preclinical disease-modifying
    strategy that restored AGA activity, reduced GlcNAc-Asn substrate, and
    improved neurologic and histopathologic outcomes in Aga-deficient mice.
    It is not yet an approved human therapy.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: 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
      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
      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
      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.
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. AAV9/AGA is included only as a
  preclinical disease-modifying candidate, not as approved therapy.
references:
- reference: ORPHA:93
  title: Aspartylglucosaminuria
  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:9930336
  title: Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse.
  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: []
📚

References & Deep Research

References

8
ORPHA:93
Aspartylglucosaminuria
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:9930336
Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse.
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.

Deep Research

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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).