glutaryl-CoA dehydrogenase deficiency

Summary

glutaryl-CoA dehydrogenase deficiency (MONDO:0009281) is a disease caused by GCDH (GenCC Definitive), with 4 cohort genes and 3 clinical trials.

At a glance

• Prevalence: >1 / 1000 (Specific population) [Orphanet-validated]
• Causal gene: GCDH (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 917
• Phenotypes (HPO): 43
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

9 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	Worldwide	Validated
Point prevalence	>1 / 1000	333	Specific population	Validated
Point prevalence	1-9 / 100 000	2	Specific population	Validated
Prevalence at birth	1-9 / 100 000	2.85	Spain	Validated
Prevalence at birth	1-9 / 1 000 000	0.48	Japan	Validated
Prevalence at birth	1-9 / 1 000 000	0.76	United States	Validated
Prevalence at birth	1-9 / 100 000	2	Israel	Validated
Prevalence at birth	1-9 / 100 000	4.3	Specific population	Validated
Prevalence at birth	1-9 / 1 000 000	0.56	Czech Republic	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0002134	Abnormality of the basal ganglia	Very frequent (80-99%)
HP:0003150	Glutaric aciduria	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001334	Communicating hydrocephalus	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002275	Poor motor coordination	Frequent (30-79%)
HP:0002305	Athetosis	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002339	Abnormal caudate nucleus morphology	Frequent (30-79%)
HP:0004481	Progressive macrocephaly	Frequent (30-79%)
HP:0007132	Pallidal degeneration	Frequent (30-79%)
HP:0009716	Subependymal nodules	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012704	Widened subarachnoid space	Frequent (30-79%)
HP:0012753	T2 hypointense basal ganglia	Frequent (30-79%)
HP:0031982	Abnormal putamen morphology	Frequent (30-79%)
HP:0040194	Increased head circumference	Frequent (30-79%)
HP:0100954	Open operculum	Frequent (30-79%)
HP:0000573	Retinal hemorrhage	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001373	Joint dislocation	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002086	Abnormality of the respiratory system	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002451	Limb dystonia	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0003162	Fasting hypoglycemia	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0006829	Severe muscular hypotonia	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0100309	Subdural hemorrhage	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Very rare (<1-4%)
HP:0012622	Chronic kidney disease	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glutaryl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0009281
MeSH	C536833
OMIM	231670
Orphanet	25
DOID	DOID:0111254
NCIT	C99101
SNOMED CT	76175005
UMLS	C0268595
MedGen	124337
GARD	0006522
Is cancer (heuristic)	no

Also known as: GA1 · GCDHD · glutaric acidemia 1 · glutaric acidemia type 1 · glutaric acidemia type I · glutaric aciduria type 1 · glutaric aciduria, type 1 · glutaricaciduria, type I · glutaryl-CoA dehydrogenase deficiency · glutaryl-coenzyme A dehydrogenase deficiency

Data availability: 917 ClinVar variants · 7 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glutaric aciduria › glutaryl-CoA dehydrogenase deficiency

Related subtypes (2): multiple acyl-CoA dehydrogenase deficiency, glutaric acidemia type 3

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:

308 likely benign, 75 pathogenic, 63 uncertain significance, 63 likely pathogenic, 46 pathogenic/likely pathogenic, 33 conflicting classifications of pathogenicity, 11 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1011761	NM_000159.4(GCDH):c.300G>A (p.Met100Ile)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012927	NM_000159.4(GCDH):c.263G>A (p.Arg88His)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028582	NM_000159.4(GCDH):c.1243+1G>T	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1066472	NM_000159.4(GCDH):c.1199dup (p.Ile401fs)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066567	NM_000159.4(GCDH):c.1213dup (p.Met405fs)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1070251	NM_000159.4(GCDH):c.1168G>A (p.Gly390Arg)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1070458	NM_000159.4(GCDH):c.389T>C (p.Leu130Pro)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070459	NM_000159.4(GCDH):c.91G>T (p.Glu31Ter)	GCDH	Pathogenic	criteria provided, single submitter
1072735	NM_000159.4(GCDH):c.905T>C (p.Leu302Pro)	GCDH	Pathogenic	criteria provided, single submitter
1072736	NM_000159.4(GCDH):c.1157G>A (p.Arg386Gln)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074476	NM_000159.4(GCDH):c.463T>C (p.Tyr155His)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1076497	NM_000159.4(GCDH):c.1175A>G (p.Asn392Ser)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162199	NM_000159.4(GCDH):c.505+1G>A	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1199104	NM_000159.4(GCDH):c.148T>G (p.Trp50Gly)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299668	NM_000159.4(GCDH):c.803G>T (p.Gly268Val)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353095	NM_000159.4(GCDH):c.511G>T (p.Gly171Trp)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361482	NM_000159.4(GCDH):c.1116del (p.Asn373fs)	GCDH	Pathogenic	criteria provided, single submitter
1381101	NM_000159.4(GCDH):c.661_662del (p.Leu221fs)	GCDH	Pathogenic	criteria provided, single submitter
1381918	NM_000159.4(GCDH):c.542_543del (p.Glu181fs)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1383061	NM_000159.4(GCDH):c.467G>T (p.Gly156Val)	GCDH	Pathogenic	criteria provided, single submitter
1383091	NM_000159.4(GCDH):c.775T>C (p.Ser259Pro)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1414622	NM_000159.4(GCDH):c.583G>A (p.Ala195Thr)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426297	NM_000159.4(GCDH):c.1211C>G (p.Ala404Gly)	GCDH	Pathogenic	criteria provided, single submitter
1447879	NM_000159.4(GCDH):c.535C>G (p.Leu179Val)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454092	NM_000159.4(GCDH):c.1064_1065insATTG (p.Lys357fs)	GCDH	Pathogenic	criteria provided, single submitter
1454846	NM_000159.4(GCDH):c.998A>G (p.Gln333Arg)	GCDH	Pathogenic	criteria provided, single submitter
1454982	NM_000159.4(GCDH):c.1123T>C (p.Cys375Arg)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457194	NM_000159.4(GCDH):c.736_737del (p.Ser246fs)	GCDH	Pathogenic	criteria provided, single submitter
1457534	NM_000159.4(GCDH):c.938G>A (p.Arg313Gln)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458728	NC_000019.9:g.(?13004287)(13008687_?)del	GCDH	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
GCDH	Definitive	Autosomal recessive	glutaryl-CoA dehydrogenase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCDH	Orphanet:25	Glutaryl-CoA dehydrogenase deficiency
ACP5	Orphanet:1855	Spondyloenchondrodysplasia

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
GCDH	HGNC:4189	ENSG00000105607	Q92947	Glutaryl-CoA dehydrogenase, mitochondrial	gencc,clinvar
ACP5	HGNC:124	ENSG00000102575	P13686	Tartrate-resistant acid phosphatase type 5	clinvar
SYCE2	HGNC:27411	ENSG00000161860	Q6PIF2	Synaptonemal complex central element protein 2	clinvar
WDR83OS	HGNC:30203	ENSG00000105583	Q9Y284	PAT complex subunit Asterix	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCDH	Glutaryl-CoA dehydrogenase, mitochondrial	Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism.
ACP5	Tartrate-resistant acid phosphatase type 5	Involved in osteopontin/bone sialoprotein dephosphorylation.
SYCE2	Synaptonemal complex central element protein 2	Major component of the transverse central element of synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase.
WDR83OS	PAT complex subunit Asterix	Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCDH	Enzyme (other)	yes	1.3.8.6	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
ACP5	Enzyme (other)	yes	3.1.3.2	Calcineurin-like_PHP, Acid_PPase, Metallo-depent_PP-like
SYCE2	Other/Unknown	no		Syce2
WDR83OS	Other/Unknown	no		ASTER

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
liver	1
right lobe of liver	1
periodontal ligament	1
right lung	1
upper lobe of left lung	1
left testis	1
right testis	1
testis	1
fallopian tube	1
pituitary gland	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCDH	259	ubiquitous	marker	right lobe of liver, liver, apex of heart
ACP5	233	broad	marker	periodontal ligament, upper lobe of left lung, right lung
SYCE2	160	broad	yes	right testis, left testis, testis
WDR83OS	134	ubiquitous	marker	right adrenal gland, pituitary gland, fallopian tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACP5	2,983
GCDH	2,573
WDR83OS	979
SYCE2	677

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCDH	Q92947	4
ACP5	P13686	2
SYCE2	Q6PIF2	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDR83OS	Q9Y284	62.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B2 (riboflavin) metabolism	1	543.8×	0.008	ACP5
Lysine catabolism	1	380.7×	0.008	GCDH
Meiosis	1	95.2×	0.021	SYCE2
Reproduction	1	63.4×	0.024	SYCE2
Meiotic synapsis	1	47.0×	0.025	SYCE2
Cell Cycle	1	12.0×	0.081	SYCE2

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
negative regulation of superoxide anion generation	1	2106.5×	0.007	ACP5
obsolete L-tryptophan metabolic process	1	1404.3×	0.007	GCDH
fatty-acyl-CoA biosynthetic process	1	468.1×	0.009	GCDH
multi-pass transmembrane protein insertion into ER membrane	1	468.1×	0.009	WDR83OS
protein insertion into ER membrane	1	383.0×	0.009	WDR83OS
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	351.1×	0.009	GCDH
negative regulation of macrophage cytokine production	1	300.9×	0.009	ACP5
negative regulation of interleukin-12 production	1	263.3×	0.009	ACP5
negative regulation of nitric oxide biosynthetic process	1	247.8×	0.009	ACP5
nitric oxide biosynthetic process	1	175.5×	0.010	ACP5
superoxide anion generation	1	168.5×	0.010	ACP5
synaptonemal complex assembly	1	162.0×	0.010	SYCE2
bone morphogenesis	1	150.5×	0.010	ACP5
bone resorption	1	145.3×	0.010	ACP5
negative regulation of interleukin-1 beta production	1	127.7×	0.011	ACP5
response to cytokine	1	93.6×	0.014	ACP5
negative regulation of tumor necrosis factor production	1	62.9×	0.020	ACP5
negative regulation of inflammatory response	1	34.2×	0.033	ACP5
defense response to Gram-positive bacterium	1	31.9×	0.033	ACP5
response to lipopolysaccharide	1	31.2×	0.033	ACP5
cell division	1	11.5×	0.084	SYCE2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
GCDH	BALSALAZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCDH	1	4
ACP5	0	0
SYCE2	0	0
WDR83OS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BALSALAZIDE	4	GCDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GCDH	15	Binding:14, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCDH	1.3.8.6	glutaryl-CoA dehydrogenase (ETF)
ACP5	3.1.3.2	acid phosphatase

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

1 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)
BALSALAZIDE	4	GCDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GCDH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACP5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SYCE2, WDR83OS

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)
ACP5	0	—
SYCE2	0	—
WDR83OS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06217861	PHASE1	RECRUITING	A Study to Evaluate the Tolerability, Safety and Efficacy of VGM-R02b
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