hyperammonemia due to N-acetylglutamate synthase deficiency

Summary

hyperammonemia due to N-acetylglutamate synthase deficiency (MONDO:0009377) is a disease caused by NAGS (GenCC Definitive), with 2 cohort genes and 6 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: NAGS (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 639
• Phenotypes (HPO): 42
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		99	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0003217	Hyperglutaminemia	Occasional (5-29%)
HP:0003348	Hyperalaninemia	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0008281	Acute hyperammonemia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0100785	Insomnia	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000708	Atypical behavior	Very rare (<1-4%)
HP:0000725	Psychotic episodes	Very rare (<1-4%)
HP:0000733	Abnormal repetitive mannerisms	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0001271	Polyneuropathy	Very rare (<1-4%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001298	Encephalopathy	Very rare (<1-4%)
HP:0002014	Diarrhea	Very rare (<1-4%)
HP:0002098	Respiratory distress	Very rare (<1-4%)
HP:0002240	Hepatomegaly	Very rare (<1-4%)
HP:0002637	Cerebral ischemia	Very rare (<1-4%)
HP:0002863	Myelodysplasia	Very rare (<1-4%)
HP:0006582	Reye syndrome-like episodes	Very rare (<1-4%)
HP:0010529	Echolalia	Very rare (<1-4%)
HP:0010550	Paraplegia	Very rare (<1-4%)
HP:0031258	Delirium	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperammonemia due to N-acetylglutamate synthase deficiency
Mondo ID	MONDO:0009377
MeSH	C536109
OMIM	237310
Orphanet	927
DOID	DOID:0112258
NCIT	C129307
SNOMED CT	57119000
UMLS	C0268543
MedGen	120649
GARD	0007158
Is cancer (heuristic)	no

Also known as: hyperammonemia due to N-acetylglutamate synthase deficiency · N-acetyl glutamate synthetase deficiency · N-acetylglutamate synthase deficiency · NAG synthetase deficiency · NAGS deficiency · NAGSD

Data availability: 639 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › urea cycle disorder › urea cycle disorder or inherited hyperammonemia › hyperammonemia due to N-acetylglutamate synthase deficiency

Related subtypes (9): arginase deficiency, argininosuccinic aciduria, citrullinemia type I, carbamoyl phosphate synthetase I deficiency disease, ornithine translocase deficiency, ornithine carbamoyltransferase deficiency, hyperinsulinism-hyperammonemia syndrome, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, citrin 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

600 retrieved; paginated sample, class counts are floors:

353 likely benign, 110 uncertain significance, 59 likely pathogenic, 33 pathogenic, 17 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 11 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069451	NM_153006.3(NAGS):c.111_120del (p.Arg38fs)	NAGS	Pathogenic	criteria provided, single submitter
1069900	NM_153006.3(NAGS):c.739C>T (p.Gln247Ter)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070557	NM_153006.3(NAGS):c.777C>A (p.Cys259Ter)	NAGS	Pathogenic	criteria provided, single submitter
1070802	NM_153006.3(NAGS):c.69_78del (p.Gly24fs)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370006	NM_153006.3(NAGS):c.1272C>G (p.Tyr424Ter)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370381	NM_153006.3(NAGS):c.138del (p.Arg47fs)	NAGS	Pathogenic	criteria provided, single submitter
1375065	NM_153006.3(NAGS):c.893del (p.Gly298fs)	NAGS	Pathogenic	criteria provided, single submitter
1378447	NM_153006.3(NAGS):c.1097-1G>C	NAGS	Pathogenic	criteria provided, multiple submitters, no conflicts
1385518	NM_153006.3(NAGS):c.1313dup (p.Thr439fs)	NAGS	Pathogenic	criteria provided, multiple submitters, no conflicts
1402826	NM_153006.3(NAGS):c.299C>A (p.Ser100Ter)	NAGS	Pathogenic	criteria provided, single submitter
1407326	NM_153006.3(NAGS):c.390C>A (p.Cys130Ter)	NAGS	Pathogenic	criteria provided, single submitter
1420832	NM_153006.3(NAGS):c.368G>A (p.Trp123Ter)	NAGS	Pathogenic	criteria provided, single submitter
1445775	NM_153006.3(NAGS):c.46del (p.Ala16fs)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453310	NM_153006.3(NAGS):c.724G>T (p.Glu242Ter)	NAGS	Pathogenic	criteria provided, single submitter
1457560	NM_153006.3(NAGS):c.106_107del (p.Arg36fs)	NAGS	Pathogenic	criteria provided, single submitter
1906136	NM_153006.3(NAGS):c.1108del (p.Leu370fs)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1933213	NM_153006.3(NAGS):c.1037_1070del (p.His346fs)	NAGS	Pathogenic	criteria provided, single submitter
2119764	NM_153006.3(NAGS):c.134del (p.Pro45fs)	NAGS	Pathogenic	criteria provided, single submitter
2131999	NM_153006.3(NAGS):c.116_122dup (p.Arg41fs)	NAGS	Pathogenic	criteria provided, single submitter
2138046	NM_153006.3(NAGS):c.1228T>C (p.Ser410Pro)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2427	NM_153006.3(NAGS):c.1025del (p.Arg342fs)	NAGS	Pathogenic	criteria provided, multiple submitters, no conflicts
2428	NM_153006.3(NAGS):c.971G>A (p.Trp324Ter)	NAGS	Pathogenic	no assertion criteria provided
2429	NM_153006.3(NAGS):c.916-2A>T	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431	NM_153006.3(NAGS):c.835G>A (p.Ala279Thr)	NAGS	Pathogenic	no assertion criteria provided
2433	NM_153006.3(NAGS):c.1450T>C (p.Trp484Arg)	NAGS	Pathogenic	no assertion criteria provided
2434	NM_153006.3(NAGS):c.1299G>C (p.Glu433Asp)	NAGS	Pathogenic	no assertion criteria provided
2676917	NM_153006.3(NAGS):c.310del (p.Arg104fs)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676924	NM_153006.3(NAGS):c.654dup (p.Gly219fs)	NAGS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2711343	NM_153006.3(NAGS):c.343del (p.Ala115fs)	NAGS	Pathogenic	criteria provided, single submitter
2712593	NM_153006.3(NAGS):c.1302del (p.Val435fs)	NAGS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NAGS	Definitive	Autosomal recessive	hyperammonemia due to N-acetylglutamate synthase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAGS	Orphanet:927	Hyperammonemia due to N-acetylglutamate synthase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NAGS	HGNC:17996	ENSG00000161653	Q8N159	N-acetylglutamate synthase, mitochondrial	gencc,clinvar
PYY	HGNC:9748	ENSG00000131096	P10082	Peptide YY	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NAGS	N-acetylglutamate synthase, mitochondrial	Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity.
PYY	Peptide YY	This gut peptide inhibits exocrine pancreatic secretion, has a vasoconstrictory action and inhibitis jejunal and colonic mobility.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NAGS	Kinase	yes	2.3.1.1	GNAT_dom, Asp/Glu/Uridylate_kinase, Vertebrate-like_GNAT_dom
PYY	Other/Unknown	no		Pancreatic_hormone-like, Pancreatic_hormone-like_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
jejunal mucosa	1
right lobe of liver	1
colonic mucosa	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NAGS	160	broad	marker	ileal mucosa, right lobe of liver, jejunal mucosa
PYY	125	tissue_specific	marker	mucosa of sigmoid colon, mucosa of transverse colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NAGS	1,796
PYY	1,317

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PYY	P10082	6
NAGS	Q8N159	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NAGS variants cause NAGS deficiency	1	5710.0×	0.001	NAGS
Urea cycle	1	439.2×	0.007	NAGS
Peptide ligand-binding receptors	1	37.1×	0.044	PYY
Metabolism of amino acids and derivatives	1	33.8×	0.044	NAGS
G alpha (i) signalling events	1	19.5×	0.061	PYY
Metabolism	1	5.8×	0.165	NAGS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-arginine biosynthetic process	1	2808.7×	0.002	NAGS
intestinal epithelial cell differentiation	1	766.0×	0.003	PYY
urea cycle	1	648.1×	0.003	NAGS
glutamate metabolic process	1	561.7×	0.003	NAGS
feeding behavior	1	271.8×	0.004	PYY
neuropeptide signaling pathway	1	86.0×	0.012	PYY

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
NAGS	0	0
PYY	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAGS	2.3.1.1	amino-acid N-acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	NAGS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PYY

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NAGS	0	—
PYY	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03409003	Not specified	RECRUITING	Orphan Europe Carbaglu® Surveillance Protocol
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04908319	Not specified	RECRUITING	Hepatic Histopathology in Urea Cycle Disorders
NCT01421888	Not specified	TERMINATED	The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan