Aspartylglucosaminuria

Summary

Aspartylglucosaminuria (MONDO:0008830) is a disease caused by AGA (GenCC Definitive), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include cyclophosphamide anhydrous.

At a glance

• Prevalence: 1-9 / 1 000 000 (Australia) [Orphanet-validated]
• Causal gene: AGA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 523
• Phenotypes (HPO): 43
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.2	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.62	Sweden	Validated
Prevalence at birth	1-9 / 100 000	3.35	Finland	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000212	Gingival overgrowth	Very frequent (80-99%)
HP:0000303	Mandibular prognathia	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001537	Umbilical hernia	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0004337	Abnormality of amino acid metabolism	Very frequent (80-99%)
HP:0008551	Microtia	Very frequent (80-99%)
HP:0012068	Aspartylglucosaminuria	Very frequent (80-99%)
HP:0012471	Thick vermilion border	Very frequent (80-99%)
HP:0100660	Dyskinesia	Very frequent (80-99%)
HP:0100729	Large face	Very frequent (80-99%)
HP:0000053	Macroorchidism	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0002684	Thickened calvaria	Frequent (30-79%)
HP:0003103	Abnormal cortical bone morphology	Frequent (30-79%)
HP:0008430	Anterior beaking of lumbar vertebrae	Frequent (30-79%)
HP:0040071	Abnormal morphology of ulna	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000389	Chronic otitis media	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0003468	Abnormal vertebral morphology	Occasional (5-29%)
HP:0004568	Beaking of vertebral bodies	Occasional (5-29%)
HP:0011276	Vascular skin abnormality	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aspartylglucosaminuria
Mondo ID	MONDO:0008830
MeSH	D054880
OMIM	208400
Orphanet	93
DOID	DOID:0050461
ICD-11	2143470200
NCIT	C61273
SNOMED CT	54954004
UMLS	C0268225
MedGen	78649
GARD	0005854
MedDRA	10068220
NORD	813
Is cancer (heuristic)	no

Also known as: AGU · Aspartylglucosamidase (AGA) deficiency · aspartylglucosaminidase deficiency · aspartylglucosaminuria · Aspartylglycosaminuria · aspartylglycosaminuria · glycosylasparaginase deficiency

Data availability: 523 ClinVar variants · 6 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › oligosaccharidosis › aspartylglucosaminuria

Related subtypes (6): fucosidosis, alpha-mannosidosis, beta-mannosidosis, galactosialidosis, sialidosis, alpha-N-acetylgalactosaminidase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

523 retrieved; paginated sample, class counts are floors:

234 likely benign, 129 uncertain significance, 58 likely pathogenic, 36 pathogenic, 28 pathogenic/likely pathogenic, 16 benign, 11 conflicting classifications of pathogenicity, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068996	NC_000004.11:g.(?178363393)(178363667_?)del	AGA	Pathogenic	criteria provided, single submitter
1070108	NM_000027.4(AGA):c.595G>T (p.Glu199Ter)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071135	NM_000027.4(AGA):c.128-2A>G	AGA	Pathogenic	criteria provided, multiple submitters, no conflicts
1072287	NM_000027.4(AGA):c.454C>T (p.Gln152Ter)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075443	NM_000027.4(AGA):c.698+1del	AGA	Pathogenic	criteria provided, single submitter
1341346	NM_000027.4(AGA):c.202C>T (p.Gln68Ter)	AGA	Pathogenic	criteria provided, single submitter
1351725	NM_000027.4(AGA):c.187dup (p.Met63fs)	AGA	Pathogenic	criteria provided, multiple submitters, no conflicts
1357402	NM_000027.4(AGA):c.268dup (p.Met90fs)	AGA	Pathogenic	criteria provided, single submitter
1446399	NM_000027.4(AGA):c.509dup (p.Asn170fs)	AGA	Pathogenic	criteria provided, single submitter
1455592	NM_000027.4(AGA):c.519dup (p.Asp174fs)	AGA	Pathogenic	criteria provided, single submitter
1879068	NM_000027.4(AGA):c.1018G>T (p.Glu340Ter)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1980037	NM_000027.4(AGA):c.375_378del (p.Thr125_Leu126insTer)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2008973	NM_000027.4(AGA):c.9del (p.Lys4fs)	AGA	Pathogenic	criteria provided, single submitter
2029864	NM_000027.4(AGA):c.665del (p.Thr222fs)	AGA	Pathogenic	criteria provided, single submitter
2108081	NM_000027.4(AGA):c.55del (p.Ala19fs)	AGA	Pathogenic	criteria provided, multiple submitters, no conflicts
2109804	NM_000027.4(AGA):c.172G>T (p.Glu58Ter)	AGA	Pathogenic	criteria provided, single submitter
219	NM_000027.4(AGA):c.488G>C (p.Cys163Ser)	AGA	Pathogenic	criteria provided, multiple submitters, no conflicts
220	NM_000027.4(AGA):c.904G>A (p.Gly302Arg)	AGA	Pathogenic	no assertion criteria provided
223	NM_000027.4(AGA):c.302C>T (p.Ala101Val)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224	NM_000027.4(AGA):c.102_108del (p.Thr33_Trp34insTer)	AGA	Pathogenic/Likely pathogenic	no assertion criteria provided
225	NM_000027.4(AGA):c.800dup (p.Pro268fs)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
226	NM_000027.4(AGA):c.127_128insATGCGG (p.Ala42_Ala43insAspAla)	AGA	Pathogenic/Likely pathogenic	no assertion criteria provided
227	NM_000027.4(AGA):c.940+1G>T	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
229	NM_000027.4(AGA):c.214T>C (p.Ser72Pro)	AGA	Pathogenic	criteria provided, multiple submitters, no conflicts
2422151	NC_000004.11:g.(?178357420)(178363667_?)del	AGA	Pathogenic	criteria provided, single submitter
2422152	NC_000004.11:g.(?178351918)(178357515_?)del	AGA	Pathogenic	criteria provided, single submitter
2444302	NM_000027.4(AGA):c.52C>T (p.Gln18Ter)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680772	NM_000027.4(AGA):c.389_390del (p.Glu130fs)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680792	NM_000027.4(AGA):c.198_201del (p.Arg66fs)	AGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2789512	NM_000027.4(AGA):c.797dup (p.Leu267fs)	AGA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AGA	Definitive	Autosomal recessive	aspartylglucosaminuria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGA	Orphanet:93	Aspartylglucosaminuria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AGA	HGNC:318	ENSG00000038002	P20933	N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AGA	N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase	Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGA	Protease	yes	3.5.1.26	Peptidase_T2, Ntn_hydrolases_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus squamous epithelium	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGA	287	ubiquitous	marker	esophagus squamous epithelium, squamous epithelium, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGA	929

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGA	P20933	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Innate Immune System	1	25.5×	0.065	AGA
Neutrophil degranulation	1	23.1×	0.065	AGA
Immune System	1	13.0×	0.077	AGA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein deglycosylation	1	8426.0×	2e-04	AGA
proteolysis	1	34.2×	0.029	AGA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGA	3.5.1.26	N4-(beta-N-acetylglucosaminyl)-L-asparaginase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AGA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AGA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	3
Not specified	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT07530796	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of scAAV9/AGA Gene Therapy in Participants With Aspartylglucosaminuria (AGU)
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT03853876	Not specified	TERMINATED	A Natural History Study of Aspartylglucosaminuria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	2