3-methylglutaconic aciduria type 1

Summary

3-methylglutaconic aciduria type 1 (MONDO:0009610) is a disease caused by AUH (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AUH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 217
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002073	Progressive cerebellar ataxia	Occasional (5-29%)
HP:0002134	Abnormality of the basal ganglia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria type 1
Mondo ID	MONDO:0009610
MeSH	C562801
OMIM	250950
Orphanet	67046
DOID	DOID:0110002
ICD-11	899935975
NCIT	C98683
SNOMED CT	237951008
UMLS	C0342727
MedGen	90994
GARD	0010321
Is cancer (heuristic)	no

Also known as: 3 alpha methylglutaconic aciduria type I · 3 methylglutaconic aciduria type 1 · 3 methylglutaconyl CoA hydratase deficiency · 3-methylglutaconic aciduria caused by mutation in AUH · 3-methylglutaconic aciduria caused by mutation in auh · 3-methylglutaconic aciduria type 1 · 3-METHYLGLUTACONIC aciduria, type I · 3-methylglutaconyl-CoA hydratase deficiency · 3-methylglutaconyl-CoA hydratase deficiency (auh defect) · 3-MGCA type I (3-MGCA-1) · 3MG CoA hydratase deficiency · 3MG-CoA hydratase deficiency · AUH 3-methylglutaconic aciduria · auh 3-methylglutaconic aciduria · MGA1 · MGCA1

Data availability: 217 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: 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 › inborn organic aciduria › classic organic aciduria › 3-methylglutaconic aciduria › 3-methylglutaconic aciduria type 1

Related subtypes (9): 3-methylglutaconic aciduria type 4, 3-methylglutaconic aciduria type 3, Barth syndrome, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria type 8, 3-methylglutaconic aciduria type 9, 3-methylglutaconic aciduria, type VIIA

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

217 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 62 likely benign, 20 pathogenic, 12 conflicting classifications of pathogenicity, 9 likely pathogenic, 8 benign, 5 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1321874	NG_008017.1:g.?_(11043_41520)del	AUH	Pathogenic	no assertion criteria provided
1332814	NM_001698.3(AUH):c.505+1G>C	AUH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333620	NM_001698.3(AUH):c.330+1G>A	AUH	Pathogenic	criteria provided, single submitter
1444539	NC_000009.12:g.91220993dup	AUH	Pathogenic	criteria provided, single submitter
1452715	NM_001698.3(AUH):c.721C>T (p.Arg241Ter)	AUH	Pathogenic	criteria provided, single submitter
214149	NM_001698.3(AUH):c.824C>T (p.Ala275Val)	AUH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2802918	NM_001698.3(AUH):c.516dup (p.Val173fs)	AUH	Pathogenic	criteria provided, single submitter
2812871	NM_001698.3(AUH):c.471del (p.Phe157fs)	AUH	Pathogenic	criteria provided, single submitter
3004570	NM_001698.3(AUH):c.419-2A>G	AUH	Pathogenic	criteria provided, single submitter
30079	NM_001698.3(AUH):c.559G>A (p.Gly187Ser)	AUH	Pathogenic	criteria provided, single submitter
30080	NM_001698.3(AUH):c.650G>A (p.Gly217Asp)	AUH	Pathogenic	no assertion criteria provided
619968	NC_000009.12:g.(?91355882)(91361889_?)del	AUH	Pathogenic	criteria provided, single submitter
831476	NC_000009.12:g.(?91220785)(91221012_?)del	AUH	Pathogenic	criteria provided, single submitter
850052	NM_001698.3(AUH):c.197del (p.Gly66fs)	AUH	Pathogenic	criteria provided, multiple submitters, no conflicts
9056	NM_001698.3(AUH):c.589C>T (p.Arg197Ter)	AUH	Pathogenic	criteria provided, multiple submitters, no conflicts
9057	NM_001698.3(AUH):c.895-1G>A	AUH	Pathogenic	no assertion criteria provided
9058	NM_001698.3(AUH):c.80del (p.Ser27fs)	AUH	Pathogenic	no assertion criteria provided
9059	NM_001698.3(AUH):c.263-2A>G	AUH	Pathogenic	criteria provided, single submitter
9060	NM_001698.3(AUH):c.943-2A>G	AUH	Pathogenic/Likely pathogenic	no assertion criteria provided
1976807	NM_001698.3(AUH):c.39dup (p.Ser14fs)	LOC130002059	Pathogenic	criteria provided, single submitter
3620179	NM_001698.3(AUH):c.95del (p.Pro32fs)	LOC130002059	Pathogenic	criteria provided, single submitter
3723023	NM_001698.3(AUH):c.197dup (p.Tyr67fs)	LOC130002059	Pathogenic	criteria provided, single submitter
9589	NC_012920.1(MT-TL1):m.3243A>G	MT-TL1	Pathogenic	reviewed by expert panel
1067674	NM_001698.3(AUH):c.656-2_656-1del	AUH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332813	NM_001698.3(AUH):c.556G>T (p.Gly186Cys)	AUH	Likely pathogenic	criteria provided, single submitter
2424217	NC_000009.11:g.(?94118145)(94118457_?)del	AUH	Likely pathogenic	criteria provided, single submitter
3382011	NM_001698.3(AUH):c.612_613insC (p.Met205fs)	AUH	Likely pathogenic	criteria provided, single submitter
3892997	NM_001698.3(AUH):c.262+1G>C	AUH	Likely pathogenic	criteria provided, single submitter
529797	NM_001698.3(AUH):c.719C>T (p.Ala240Val)	AUH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
642421	NM_001698.3(AUH):c.599-2A>G	AUH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
AUH	Definitive	Autosomal recessive	3-methylglutaconic aciduria type 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AUH	Orphanet:67046	3-methylglutaconic aciduria type 1
MT-TL1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TL1	Orphanet:324525	Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation
MT-TL1	Orphanet:480	Kearns-Sayre syndrome
MT-TL1	Orphanet:550	MELAS
MT-TL1	Orphanet:551	MERRF
MT-TL1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AUH	HGNC:890	ENSG00000148090	Q13825	Methylglutaconyl-CoA hydratase, mitochondrial	gencc,clinvar
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	clinvar
NFIL3	HGNC:7787	ENSG00000165030	Q16649	Nuclear factor interleukin-3-regulated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AUH	Methylglutaconyl-CoA hydratase, mitochondrial	Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
NFIL3	Nuclear factor interleukin-3-regulated protein	Acts as a transcriptional regulator that recognizes and binds to the sequence 5’-[GA]TTA[CT]GTAA[CT]-3’, a sequence present in many cellular and viral promoters.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AUH	Enzyme (other)	yes	4.2.1.18	Enoyl-CoA_hydra/iso, Enoyl-CoA_hydra_C, Enoyl-CoA_hyd/isom_CS
MT-TL1	Other/Unknown	no
NFIL3	Transcription factor	no		bZIP, Vert_IL3-reg_TF, NFIL3/E4BP4

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	1
nephron tubule	1
renal medulla	1
caudate nucleus	1
frontal cortex	1
right frontal lobe	1
mucosa of stomach	1
pericardium	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AUH	290	ubiquitous	marker	renal medulla, lateral nuclear group of thalamus, nephron tubule
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
NFIL3	290	ubiquitous	marker	vena cava, pericardium, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AUH	2,102
NFIL3	2,037
MT-TL1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AUH	Q13825	3
NFIL3	Q16649	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
3-methylglutaconic aciduria	1	11420.0×	6e-04	AUH
Diseases of branched-chain amino acid catabolism	1	1903.3×	0.002	AUH
Branched-chain amino acid catabolism	1	475.8×	0.005	AUH
Diseases of metabolism	1	80.4×	0.021	AUH
Metabolism of amino acids and derivatives	1	67.6×	0.021	AUH
Disease	1	13.1×	0.086	AUH
Metabolism	1	11.6×	0.086	AUH

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-leucine catabolic process	1	1203.7×	0.011	AUH
natural killer cell differentiation	1	443.5×	0.013	NFIL3
cellular response to interleukin-4	1	324.1×	0.013	NFIL3
fatty acid beta-oxidation	1	187.2×	0.017	AUH
circadian rhythm	1	122.1×	0.021	NFIL3
transcription by RNA polymerase II	1	35.3×	0.061	NFIL3
immune response	1	23.5×	0.078	NFIL3
positive regulation of gene expression	1	19.4×	0.081	NFIL3
regulation of DNA-templated transcription	1	15.8×	0.081	NFIL3
negative regulation of DNA-templated transcription	1	15.8×	0.081	NFIL3
positive regulation of DNA-templated transcription	1	14.0×	0.083	NFIL3
negative regulation of transcription by RNA polymerase II	1	8.9×	0.119	NFIL3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	NFIL3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
AUH	0	0
MT-TL1	0	0
NFIL3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AUH	4.2.1.18	methylglutaconyl-CoA hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	AUH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MT-TL1, NFIL3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AUH	0	—
MT-TL1	0	—
NFIL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan