Oxoglutaricaciduria

Summary

Oxoglutaricaciduria (MONDO:0008759) is a disease caused by OGDH (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: OGDH (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 164
• Phenotypes (HPO): 10

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000816	Abnormality of Krebs cycle metabolism	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0012401	Abnormal urine alpha-ketoglutarate concentration	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0010286	Abnormal salivary gland morphology	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	oxoglutaricaciduria
Mondo ID	MONDO:0008759
MeSH	C536582
OMIM	203740
Orphanet	31
DOID	DOID:0081326
SNOMED CT	733630004
UMLS	C2752074
MedGen	414553
GARD	0000617
Is cancer (heuristic)	no

Also known as: 2 alpha ketoglutarate dehydrogenase deficiency · Alpha KGD deficiency · Alpha-ketoglutarate dehydrogenase deficiency · oxoglutarate dehydrogenase deficiency

Data availability: 164 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › oxoglutaricaciduria

Related subtypes (13): multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, mitochondrial pyruvate carrier deficiency, mitochondrial oxidative phosphorylation disorder, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency, OPA1-related optic atrophy with or without extraocular features

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

164 retrieved; paginated sample, class counts are floors:

81 likely benign, 47 uncertain significance, 19 benign, 9 benign/likely benign, 4 pathogenic, 3 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1331346	NM_002541.4(OGDH):c.959A>G (p.Asn320Ser)	OGDH	Pathogenic	no assertion criteria provided
2443830	NM_002541.4(OGDH):c.890C>A (p.Ser297Tyr)	OGDH	Pathogenic	no assertion criteria provided
2443831	NM_002541.4(OGDH):c.566C>T (p.Pro189Leu)	OGDH	Pathogenic	no assertion criteria provided
2443832	NM_002541.4(OGDH):c.935G>A (p.Arg312Lys)	OGDH	Pathogenic	no assertion criteria provided
3340144	NM_002541.4(OGDH):c.1669-9A>G	OGDH	Likely pathogenic	criteria provided, single submitter
1355335	NM_002541.4(OGDH):c.7C>T (p.His3Tyr)	OGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1445925	NM_002541.4(OGDH):c.1456G>A (p.Val486Met)	OGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
770374	NM_002541.4(OGDH):c.2458A>T (p.Asn820Tyr)	OGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2637941	NM_001933.5(DLST):c.1307T>A (p.Leu436His)	DLST	Uncertain significance	criteria provided, single submitter
1020921	NM_002541.4(OGDH):c.2126A>G (p.Asn709Ser)	OGDH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029459	NM_002541.4(OGDH):c.2422G>A (p.Val808Ile)	OGDH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356125	NM_002541.4(OGDH):c.2951+4A>G	OGDH	Uncertain significance	criteria provided, single submitter
1357689	NM_002541.4(OGDH):c.881T>C (p.Ile294Thr)	OGDH	Uncertain significance	criteria provided, single submitter
1381193	NM_002541.4(OGDH):c.1474G>T (p.Glu492Ter)	OGDH	Uncertain significance	criteria provided, single submitter
1388894	NM_002541.4(OGDH):c.798G>T (p.Glu266Asp)	OGDH	Uncertain significance	criteria provided, single submitter
1414760	NM_002541.4(OGDH):c.2722G>A (p.Val908Met)	OGDH	Uncertain significance	criteria provided, single submitter
1447719	NM_002541.4(OGDH):c.505A>G (p.Thr169Ala)	OGDH	Uncertain significance	criteria provided, single submitter
1484653	NM_002541.4(OGDH):c.2849A>G (p.Asn950Ser)	OGDH	Uncertain significance	criteria provided, single submitter
1492984	NM_002541.4(OGDH):c.2433C>A (p.Asp811Glu)	OGDH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1720710	NM_002541.4(OGDH):c.1837A>G (p.Ile613Val)	OGDH	Uncertain significance	criteria provided, single submitter
1898873	NM_002541.4(OGDH):c.770G>A (p.Arg257Lys)	OGDH	Uncertain significance	criteria provided, single submitter
1912674	NM_002541.4(OGDH):c.958A>G (p.Asn320Asp)	OGDH	Uncertain significance	criteria provided, single submitter
1956205	NM_002541.4(OGDH):c.2052-3C>T	OGDH	Uncertain significance	criteria provided, single submitter
1967044	NM_002541.4(OGDH):c.2358+6C>T	OGDH	Uncertain significance	criteria provided, single submitter
1993762	NM_002541.4(OGDH):c.1817C>G (p.Ser606Cys)	OGDH	Uncertain significance	criteria provided, single submitter
2054392	NM_002541.4(OGDH):c.1936G>T (p.Val646Leu)	OGDH	Uncertain significance	criteria provided, multiple submitters, no conflicts
2054870	NM_002541.4(OGDH):c.1595A>G (p.Lys532Arg)	OGDH	Uncertain significance	criteria provided, multiple submitters, no conflicts
2059400	NM_002541.4(OGDH):c.80G>T (p.Arg27Ile)	OGDH	Uncertain significance	criteria provided, single submitter
2063368	NM_002541.4(OGDH):c.1979C>T (p.Ala660Val)	OGDH	Uncertain significance	criteria provided, single submitter
2063678	NM_002541.4(OGDH):c.89C>T (p.Ala30Val)	OGDH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
OGDH	Strong	Autosomal recessive	oxoglutaricaciduria	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OGDH	Orphanet:31	Oxoglutaric aciduria
DLST	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma

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
OGDH	HGNC:8124	ENSG00000105953	Q02218	2-oxoglutarate dehydrogenase complex component E1	gencc,clinvar
DLST	HGNC:2911	ENSG00000119689	P36957	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OGDH	2-oxoglutarate dehydrogenase complex component E1	2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC).
DLST	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex.

Protein-family classification

Druggable: 2 · 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)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OGDH	Enzyme (other)	yes	1.2.1.105	DH_E1, Transketolase-like_Pyr-bd, 2oxoglutarate_DH_E1
DLST	Enzyme (other)	yes	1.2.1.105	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS

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
apex of heart	2
gastrocnemius	1
hindlimb stylopod muscle	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OGDH	270	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
DLST	283	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLST	3,692
OGDH	3,095

Intra-cohort edges

A	B	Sources
DLST	OGDH	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OGDH	Q02218	3
DLST	P36957	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
OGDH complex synthesizes succinyl-CoA from 2-OG	2	2855.0×	5e-07	OGDH, DLST
Glycine degradation	2	1631.4×	8e-07	OGDH, DLST
OADH complex synthesizes glutaryl-CoA from 2-OA	1	1903.3×	9e-04	DLST
Protein lipoylation	1	519.1×	0.002	DLST
Mitochondrial protein degradation	1	57.1×	0.017	OGDH

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
2-oxoglutarate decarboxylation to succinyl-CoA	2	5617.3×	3e-07	OGDH, DLST
succinyl-CoA metabolic process	2	3370.4×	5e-07	OGDH, DLST
2-oxoglutarate metabolic process	2	936.2×	5e-06	OGDH, DLST
tricarboxylic acid cycle	2	510.7×	1e-05	OGDH, DLST
generation of precursor metabolites and energy	2	343.9×	2e-05	OGDH, DLST
olfactory bulb mitral cell layer development	1	4213.0×	6e-04	OGDH
obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine	1	2808.7×	7e-04	DLST
tangential migration from the subventricular zone to the olfactory bulb	1	1685.2×	0.001	OGDH
cerebellar cortex development	1	1053.2×	0.001	OGDH
pyramidal neuron development	1	1053.2×	0.001	OGDH
thalamus development	1	702.2×	0.002	OGDH
striatum development	1	561.7×	0.002	OGDH
glycolytic process	1	191.5×	0.006	OGDH
hippocampus development	1	115.4×	0.009	OGDH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OGDH	0	0
DLST	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
OGDH	5	Binding:5
DLST	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OGDH	1.2.1.105	2-oxoglutarate dehydrogenase system
DLST	1.2.1.105	2-oxoglutarate dehydrogenase system

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	2	OGDH, DLST
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
OGDH	5	—
DLST	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.