D-2-hydroxyglutaric aciduria

Summary

D-2-hydroxyglutaric aciduria (MONDO:0010924) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	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:0001263	Global developmental delay	Very frequent (80-99%)
HP:0012321	D-2-hydroxyglutaric aciduria	Very frequent (80-99%)
HP:0040146	D-2-hydroxyglutaric acidemia	Very frequent (80-99%)
HP:6000246	Elevated CSF D-2-hydroxyglutaric acid concentration	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0010307	Stridor	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	D-2-hydroxyglutaric aciduria
Mondo ID	MONDO:0010924
OMIM	600721
Orphanet	79315
DOID	DOID:0050575
ICD-11	1170122566
SNOMED CT	237960000
UMLS	C1833429
MedGen	322192
GARD	0005661
Is cancer (heuristic)	no

Also known as: D-2-HGA · D-2-hydroxyglutaric acidemia · D-2-hydroxyglutaric aciduria 1 · D-2-hydroxyglutaric aciduria type 1 · D2HA · D2HGA

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › 2-hydroxyglutaric aciduria › D-2-hydroxyglutaric aciduria

Related subtypes (2): L-2-hydroxyglutaric aciduria, D,L-2-hydroxyglutaric aciduria

Subtypes (2): d-2-hydroxyglutaric aciduria 2, D-2-hydroxyglutaric aciduria 1

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
210809	NM_152783.5(D2HGDH):c.1027del (p.Ser343fs)	D2HGDH	Pathogenic	criteria provided, single submitter
210815	NM_152783.5(D2HGDH):c.1306+2T>C	D2HGDH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 13 · 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
D2HGDH	Strong	Autosomal recessive	D-2-hydroxyglutaric aciduria 1	4
IDH2	Strong	Autosomal dominant	d-2-hydroxyglutaric aciduria 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
D2HGDH	Orphanet:79315	D-2-hydroxyglutaric aciduria
IDH2	Orphanet:163634	Maffucci syndrome
IDH2	Orphanet:251589	Anaplastic astrocytoma
IDH2	Orphanet:251598	Protoplasmic astrocytoma
IDH2	Orphanet:251601	Fibrillary astrocytoma
IDH2	Orphanet:251604	Gemistocytic astrocytoma
IDH2	Orphanet:251627	Oligodendroglioma
IDH2	Orphanet:251630	Anaplastic oligodendroglioma
IDH2	Orphanet:251656	Oligoastrocytoma
IDH2	Orphanet:251663	Anaplastic oligoastrocytoma
IDH2	Orphanet:296	Ollier disease
IDH2	Orphanet:79315	D-2-hydroxyglutaric aciduria
IDH2	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features

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
D2HGDH	HGNC:28358	ENSG00000180902	Q8N465	D-2-hydroxyglutarate dehydrogenase, mitochondrial	gencc,clinvar
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
D2HGDH	D-2-hydroxyglutarate dehydrogenase, mitochondrial	Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.

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)
D2HGDH	Enzyme (other)	yes	1.1.99.39	FAD-bd_oxidored_4_C, Oxid_FAD_bind_N, FAD-linked_Oxase-like_C
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom

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
pancreatic ductal cell	1
right uterine tube	1
tendon of biceps brachii	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
D2HGDH	223	ubiquitous	marker	right uterine tube, pancreatic ductal cell, tendon of biceps brachii
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IDH2	4,912
D2HGDH	1,885

Intra-cohort edges

A	B	Sources
D2HGDH	IDH2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IDH2	P48735	11
D2HGDH	Q8N465	6

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
Interconversion of 2-oxoglutarate and 2-hydroxyglutarate	1	1903.3×	0.003	D2HGDH
Maturation of TCA enzymes and regulation of TCA cycle	1	285.5×	0.008	IDH2
Citric acid cycle (TCA cycle)	1	211.5×	0.008	IDH2
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.012	IDH2
Mitochondrial protein degradation	1	57.1×	0.017	IDH2

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 metabolic process	2	936.2×	2e-05	D2HGDH, IDH2
tartrate metabolic process	1	8426.0×	8e-04	D2HGDH
glyoxylate cycle	1	4213.0×	8e-04	IDH2
negative regulation of glial cell migration	1	4213.0×	8e-04	IDH2
negative regulation of matrix metallopeptidase secretion	1	4213.0×	8e-04	IDH2
isocitrate metabolic process	1	1685.2×	0.002	IDH2
response to manganese ion	1	1404.3×	0.002	D2HGDH
NADP+ biosynthetic process	1	1203.7×	0.002	IDH2
response to cobalt ion	1	1203.7×	0.002	D2HGDH
lactate metabolic process	1	936.2×	0.002	D2HGDH
malate metabolic process	1	936.2×	0.002	D2HGDH
negative regulation of glial cell proliferation	1	842.6×	0.002	IDH2
NADP+ metabolic process	1	766.0×	0.002	IDH2
response to zinc ion	1	312.1×	0.004	D2HGDH
tricarboxylic acid cycle	1	255.3×	0.004	IDH2
protein destabilization	1	145.3×	0.007	D2HGDH
carbohydrate metabolic process	1	68.0×	0.015	IDH2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
IDH2	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IDH2	7	4
D2HGDH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRELOSIDENIB	2	IDH2
RANOSIDENIB	2	IDH2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
IDH2	84	Binding:84

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
D2HGDH	1.1.99.39	D-2-hydroxyglutarate dehydrogenase
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)

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

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)
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRELOSIDENIB	2	IDH2
RANOSIDENIB	2	IDH2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IDH2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	D2HGDH
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)
D2HGDH	0	IDH2

Clinical trials & evidence

Clinical trials

Clinical trials: 0.