3-hydroxy-3-methylglutaric aciduria

Summary

3-hydroxy-3-methylglutaric aciduria (MONDO:0009520) is a disease caused by HMGCL (GenCC Definitive), with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: HMGCL (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 498
• Phenotypes (HPO): 54
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.8	Portugal	Validated
Prevalence at birth	<1 / 1 000 000		United States	Validated
Prevalence at birth	<1 / 1 000 000		China	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0001958	Nonketotic hypoglycemia	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0003344	3-Methylglutaric aciduria	Very frequent (80-99%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001988	Recurrent hypoglycemia	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002149	Hyperuricemia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002572	Episodic vomiting	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0006561	Lipid accumulation in hepatocytes	Frequent (30-79%)
HP:0006582	Reye syndrome-like episodes	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0002919	Ketonuria	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001894	Thrombocytosis	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0001257	Spasticity	Very rare (<1-4%)
HP:0001260	Dysarthria	Very rare (<1-4%)
HP:0001325	Hypoglycemic coma	Very rare (<1-4%)
HP:0001644	Dilated cardiomyopathy	Very rare (<1-4%)
HP:0001695	Cardiac arrest	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-hydroxy-3-methylglutaric aciduria
Mondo ID	MONDO:0009520
MeSH	C538324
OMIM	246450
Orphanet	20
DOID	DOID:0070541
ICD-11	795785192
NCIT	C84523
SNOMED CT	410059004
UMLS	C1533587
MedGen	735832
GARD	0008387
Is cancer (heuristic)	no

Also known as: 3-hydroxy-3-methylglutaric aciduria · 3-hydroxy-3-methylglutaryl-CoA lyase deficiency · 3-OH 3-Methyl glutaric aciduria · defect in leucine metabolism · deficiency of hydroxymethylglutaryl-CoA lyase · HMG CoA lyase deficiency · HMG-CoA lyase deficiency · HMGCLD · Hydroxymethylglutaric aciduria · hydroxymethylglutaryl-CoA lyase deficiency

Data availability: 498 ClinVar variants · 6 GenCC gene-disease records · 2 cell lines.

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 energy metabolism › disorder of fatty acid and ketone body metabolism › disorder of fatty acid oxidation and ketogenesis › 3-hydroxy-3-methylglutaric aciduria

Related subtypes (9): very long chain acyl-CoA dehydrogenase deficiency, carnitine-acylcarnitine translocase deficiency, systemic primary carnitine deficiency disease, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, acyl-CoA dehydrogenase 9 deficiency, acyl-CoA dehydrogenase deficiency, 3-hydroxyacyl-CoA dehydrogenase deficiency, long chain acyl-CoA dehydrogenase 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

498 retrieved; paginated sample, class counts are floors:

249 likely benign, 109 uncertain significance, 51 pathogenic, 42 likely pathogenic, 20 pathogenic/likely pathogenic, 13 conflicting classifications of pathogenicity, 9 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076611	NC_000001.10:g.(?24140670)(24194786_?)del	FUCA1	Pathogenic	criteria provided, single submitter
3247673	NC_000001.10:g.(?24125085)(24151905_?)del	GALE	Pathogenic	criteria provided, single submitter
3247677	NC_000001.10:g.(?24122439)(24144093_?)del	GALE	Pathogenic	criteria provided, single submitter
1074299	NM_000191.3(HMGCL):c.308_317dup (p.Thr107fs)	HMGCL	Pathogenic	criteria provided, multiple submitters, no conflicts
11954	NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)	HMGCL	Pathogenic	criteria provided, multiple submitters, no conflicts
11956	NG_013061.1:g.(9952_12876)_(19725_22136)del	HMGCL	Pathogenic	no assertion criteria provided
11957	NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)	HMGCL	Pathogenic	criteria provided, multiple submitters, no conflicts
1323058	NM_000191.3(HMGCL):c.621del (p.Val208fs)	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323059	NM_000191.3(HMGCL):c.71C>A (p.Ser24Ter)	HMGCL	Pathogenic	criteria provided, single submitter
1324535	NM_000191.3(HMGCL):c.769del (p.Asp257fs)	HMGCL	Pathogenic	criteria provided, single submitter
1369836	NM_000191.3(HMGCL):c.545del (p.Pro182fs)	HMGCL	Pathogenic	criteria provided, single submitter
1397934	NM_000191.3(HMGCL):c.501C>A (p.Tyr167Ter)	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410691	NC_000001.10:g.(?24137216)(24151915_?)del	HMGCL	Pathogenic	criteria provided, single submitter
1424729	NM_000191.3(HMGCL):c.610del (p.Asp204fs)	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425974	NM_000191.3(HMGCL):c.392del (p.Ala130_Ser131insTer)	HMGCL	Pathogenic	criteria provided, single submitter
1457586	NM_000191.3(HMGCL):c.242G>A (p.Trp81Ter)	HMGCL	Pathogenic	criteria provided, single submitter
1458760	NC_000001.10:g.(?24140670)(24140838_?)del	HMGCL	Pathogenic	criteria provided, single submitter
1459181	NM_000191.3(HMGCL):c.208_209del (p.Val70fs)	HMGCL	Pathogenic	criteria provided, single submitter
1459698	NC_000001.10:g.(?24128943)(24131025_?)del	HMGCL	Pathogenic	criteria provided, single submitter
1459880	NM_000191.3(HMGCL):c.133C>T (p.Gln45Ter)	HMGCL	Pathogenic	criteria provided, single submitter
1472739	NM_000191.3(HMGCL):c.252+1G>A	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167180	NM_000191.3(HMGCL):c.698A>G (p.His233Arg)	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685878	NM_000191.3(HMGCL):c.230del (p.Val77fs)	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195033	NM_000191.3(HMGCL):c.109G>T (p.Glu37Ter)	HMGCL	Pathogenic	criteria provided, multiple submitters, no conflicts
1993106	NM_000191.3(HMGCL):c.250C>T (p.Gln84Ter)	HMGCL	Pathogenic	criteria provided, single submitter
1997196	NM_000191.3(HMGCL):c.178_187del (p.Ile60fs)	HMGCL	Pathogenic	criteria provided, single submitter
1999926	NM_000191.3(HMGCL):c.690_698del (p.Ala231_His233del)	HMGCL	Pathogenic	criteria provided, single submitter
2025158	NM_000191.3(HMGCL):c.349_361del	HMGCL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2096036	NM_000191.3(HMGCL):c.874_876+31del	HMGCL	Pathogenic	criteria provided, single submitter
2107245	NM_000191.3(HMGCL):c.394_406dup (p.Lys136fs)	HMGCL	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
HMGCL	Definitive	Autosomal recessive	3-hydroxy-3-methylglutaric aciduria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMGCL	Orphanet:20	3-hydroxy-3-methylglutaric aciduria
FUCA1	Orphanet:349	Fucosidosis
GALE	Orphanet:308473	Erythrocyte galactose epimerase deficiency
GALE	Orphanet:308487	Generalized galactose epimerase deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HMGCL	HGNC:5005	ENSG00000117305	P35914	Hydroxymethylglutaryl-CoA lyase, mitochondrial	gencc,clinvar
FUCA1	HGNC:4006	ENSG00000179163	P04066	Tissue alpha-L-fucosidase	clinvar
GALE	HGNC:4116	ENSG00000117308	Q14376	UDP-glucose 4-epimerase	clinvar
PLA2G2A	HGNC:9031	ENSG00000188257	P14555	Phospholipase A2, membrane associated	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMGCL	Hydroxymethylglutaryl-CoA lyase, mitochondrial	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis.
FUCA1	Tissue alpha-L-fucosidase	Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N-acetylglucosamine of the carbohydrate moieties of glycoproteins.
GALE	UDP-glucose 4-epimerase	Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.
PLA2G2A	Phospholipase A2, membrane associated	Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration.

Protein-family classification

Druggable: 4 · 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
Enzyme (other)	4	12.0×	5e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HMGCL	Enzyme (other)	yes	4.1.3.4	HMG_CoA_lyase_AS, PYR_CT, Aldolase_TIM
FUCA1	Enzyme (other)	yes	3.2.1.51	Glyco_hydro_29, Glyco_hydro_b, FUC_metazoa-typ
GALE	Enzyme (other)	yes	5.1.3.2	UDP_G4E, NAD(P)-bd_dom, NAD(P)-bd_dom_sf
PLA2G2A	Enzyme (other)	yes	3.1.1.4	PLA2, PLA2-like_dom, PLA2_Asp_AS

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
liver	1
right lobe of liver	1
colonic mucosa	1
ileal mucosa	1
mucosa of sigmoid colon	1
lower esophagus mucosa	1
rectum	1
palpebral conjunctiva	1
pericardium	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HMGCL	295	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon
FUCA1	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, ileal mucosa
GALE	248	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, rectum
PLA2G2A	220	broad	marker	palpebral conjunctiva, pericardium, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGCL	2,440
GALE	2,133
PLA2G2A	1,616
FUCA1	1,125

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLA2G2A	P14555	17
GALE	Q14376	11
HMGCL	P35914	4
FUCA1	P04066	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GALE causes EDG	1	2855.0×	0.005	GALE
Galactose catabolism	1	407.9×	0.011	GALE
Synthesis of Ketone Bodies	1	356.9×	0.011	HMGCL
Reactions specific to the complex N-glycan synthesis pathway	1	285.5×	0.011	FUCA1
Acyl chain remodelling of PI	1	167.9×	0.014	PLA2G2A
Acyl chain remodelling of PG	1	158.6×	0.014	PLA2G2A
Acyl chain remodelling of PS	1	129.8×	0.014	PLA2G2A
Acyl chain remodelling of PC	1	105.7×	0.015	PLA2G2A
Acyl chain remodelling of PE	1	98.5×	0.015	PLA2G2A
Synthesis of PA	1	73.2×	0.018	PLA2G2A
Antimicrobial peptides	1	56.0×	0.021	PLA2G2A
Peroxisomal protein import	1	43.3×	0.025	HMGCL
Neutrophil degranulation	1	5.8×	0.162	FUCA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of neutrophil activation	1	4213.0×	0.004	PLA2G2A
glycolipid catabolic process	1	2106.5×	0.004	FUCA1
beta-D-galactose catabolic process via UDP-galactose, Leloir pathway	1	842.6×	0.004	GALE
phosphatidylethanolamine metabolic process	1	842.6×	0.004	PLA2G2A
glycoside catabolic process	1	702.2×	0.004	FUCA1
galactose catabolic process	1	702.2×	0.004	GALE
phosphatidic acid metabolic process	1	702.2×	0.004	PLA2G2A
ketone body biosynthetic process	1	702.2×	0.004	HMGCL
fucose metabolic process	1	601.9×	0.004	FUCA1
L-leucine catabolic process	1	601.9×	0.004	HMGCL
intestinal stem cell homeostasis	1	601.9×	0.004	PLA2G2A
angiotensin-activated signaling pathway	1	383.0×	0.006	PLA2G2A
phosphatidylglycerol metabolic process	1	351.1×	0.006	PLA2G2A
low-density lipoprotein particle remodeling	1	263.3×	0.007	PLA2G2A
positive regulation of macrophage derived foam cell differentiation	1	210.7×	0.008	PLA2G2A
phosphatidylcholine metabolic process	1	200.6×	0.008	PLA2G2A
arachidonate secretion	1	175.5×	0.009	PLA2G2A
phospholipid metabolic process	1	86.0×	0.017	PLA2G2A
negative regulation of T cell proliferation	1	82.6×	0.017	PLA2G2A
killing of cells of another organism	1	68.0×	0.020	PLA2G2A
lipid catabolic process	1	61.1×	0.021	PLA2G2A
mitochondrion organization	1	38.0×	0.032	HMGCL
positive regulation of inflammatory response	1	36.3×	0.032	PLA2G2A
defense response to Gram-positive bacterium	1	31.9×	0.035	PLA2G2A
lipid metabolic process	1	22.9×	0.046	HMGCL
positive regulation of ERK1 and ERK2 cascade	1	21.3×	0.048	PLA2G2A
inflammatory response	1	9.4×	0.102	PLA2G2A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GALE	HALOPROGIN
PLA2G2A	DEXAMETHASONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GALE	4	4
PLA2G2A	2	4
FUCA1	1	2
HMGCL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HALOPROGIN	4	GALE
DIETHYLSTILBESTROL	4	GALE
ETHACRYNIC ACID	4	GALE
DEXAMETHASONE	4	PLA2G2A
EBSELEN	3	GALE
DUVOGLUSTAT	2	FUCA1
VARESPLADIB	2	PLA2G2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PLA2G2A	111	Binding:100, Functional:11
FUCA1	83	Binding:79, ADMET:4
GALE	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMGCL	4.1.3.4	hydroxymethylglutaryl-CoA lyase
FUCA1	3.2.1.51	alpha-L-fucosidase
GALE	5.1.3.2, 5.1.3.7	UDP-glucose 4-epimerase, UDP-N-acetylglucosamine 4-epimerase
PLA2G2A	3.1.1.4	phospholipase A2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PLA2G2A	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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.

Compound	Max phase	Cohort target (bioactivity)
HALOPROGIN	4	GALE
DIETHYLSTILBESTROL	4	GALE
ETHACRYNIC ACID	4	GALE
DEXAMETHASONE	4	PLA2G2A
EBSELEN	3	GALE
DUVOGLUSTAT	2	FUCA1
VARESPLADIB	2	PLA2G2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GALE, PLA2G2A
B	Phased (≥1) drug, not yet approved	1	FUCA1
C	Druggable family + PDB, no drug	1	HMGCL
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)
HMGCL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan