Developmental and epileptic encephalopathy, 51

disease

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Also known as DEE51developmental and epileptic encephalopathy 51early infantile epileptic encephalopathy caused by mutation in MDH2EIEE51epileptic encephalopathy, early infantile, 51epileptic encephalopathy, early infantile, type 51MDH2 early infantile epileptic encephalopathy

Summary

Developmental and epileptic encephalopathy, 51 (MONDO:0015025) is a disease caused by MDH2 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: MDH2 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 51
Mondo ID	MONDO:0015025
OMIM	617339
DOID	DOID:0080433
UMLS	C4479208
MedGen	1372686
GARD	0025055
Is cancer (heuristic)	no

Also known as: DEE51 · developmental and epileptic encephalopathy 51 · early infantile epileptic encephalopathy caused by mutation in MDH2 · EIEE51 · epileptic encephalopathy, early infantile, 51 · epileptic encephalopathy, early infantile, 51; EIEE51 · epileptic encephalopathy, early infantile, type 51 · MDH2 early infantile epileptic encephalopathy

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 51

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

34 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 9 conflicting classifications of pathogenicity, 4 pathogenic, 3 benign/likely benign, 2 likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1520513	NM_005918.4(MDH2):c.157dup (p.Leu53fs)	MDH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265770	NM_005918.4(MDH2):c.620C>T (p.Pro207Leu)	MDH2	Pathogenic	no assertion criteria provided
266121	NM_005918.4(MDH2):c.596del (p.Gly199fs)	MDH2	Pathogenic	criteria provided, single submitter
267277	NM_005918.4(MDH2):c.109G>A (p.Gly37Arg)	MDH2	Pathogenic	no assertion criteria provided
3384890	NC_000007.13:g.(75687397_75689690)(75696827?)del	MDH2	Pathogenic	criteria provided, single submitter
1804008	NM_005918.4(MDH2):c.884G>T (p.Gly295Val)	MDH2	Likely pathogenic	criteria provided, single submitter
1385252	NM_005918.4(MDH2):c.580G>A (p.Val194Ile)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1542405	NM_005918.4(MDH2):c.685C>G (p.Arg229Gly)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1746283	NM_005918.4(MDH2):c.523G>A (p.Val175Ile)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1759510	NM_005918.4(MDH2):c.755C>T (p.Ala252Val)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1779552	NM_005918.4(MDH2):c.175G>A (p.Ala59Thr)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1781861	NM_005918.4(MDH2):c.187G>A (p.Gly63Arg)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2227825	NM_005918.4(MDH2):c.751A>G (p.Met251Val)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265769	NM_005918.4(MDH2):c.398C>T (p.Pro133Leu)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713898	NM_005918.4(MDH2):c.415G>A (p.Val139Ile)	MDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030034	NM_005918.4(MDH2):c.376G>A (p.Ala126Thr)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030035	NM_005918.4(MDH2):c.421G>A (p.Ala141Thr)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030036	NM_005918.4(MDH2):c.4C>G (p.Leu2Val)	MDH2	Uncertain significance	criteria provided, single submitter
1033044	NM_005918.4(MDH2):c.465C>G (p.Phe155Leu)	MDH2	Uncertain significance	criteria provided, single submitter
1098585	NM_005918.4(MDH2):c.899A>G (p.Glu300Gly)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1361694	NM_005918.4(MDH2):c.478G>A (p.Val160Met)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1407836	NM_005918.4(MDH2):c.517G>A (p.Asp173Asn)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1446996	NM_005918.4(MDH2):c.555+3A>G	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1475511	NM_005918.4(MDH2):c.885+5G>A	MDH2	Uncertain significance	criteria provided, single submitter
1498288	NM_005918.4(MDH2):c.790G>A (p.Asp264Asn)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433681	NM_005918.4(MDH2):c.704C>G (p.Thr235Arg)	MDH2	Uncertain significance	criteria provided, single submitter
2433682	NM_005918.4(MDH2):c.817G>A (p.Val273Met)	MDH2	Uncertain significance	criteria provided, single submitter
983138	NM_005918.4(MDH2):c.686G>A (p.Arg229Gln)	MDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1629544	NM_005918.4(MDH2):c.235+11C>T	MDH2	Likely benign	criteria provided, multiple submitters, no conflicts
1629809	NM_005918.4(MDH2):c.177G>A (p.Ala59=)	MDH2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
MDH2	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 51	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MDH2	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MDH2	HGNC:6971	ENSG00000146701	P40926	Malate dehydrogenase, mitochondrial	gencc,clinvar

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MDH2	Enzyme (other)	yes	1.1.1.37	Lactate/malate_DH_N, Malate_DH_AS, L-lactate/malate_DH

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of tongue	1
heart right ventricle	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MDH2	301	ubiquitous	marker	body of tongue, heart right ventricle, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MDH2	5,749

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MDH2	P40926	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Malate-aspartate shuttle	1	1268.9×	0.006	MDH2
Citric acid cycle (TCA cycle)	1	423.0×	0.008	MDH2
Mitochondrial protein degradation	1	114.2×	0.016	MDH2
Respiratory electron transport	1	95.2×	0.016	MDH2
Aerobic respiration and respiratory electron transport	1	88.5×	0.016	MDH2
Metabolism of proteins	1	12.4×	0.086	MDH2
Metabolism	1	11.6×	0.086	MDH2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
malate metabolic process	1	1872.4×	0.001	MDH2
malate-aspartate shuttle	1	1872.4×	0.001	MDH2
tricarboxylic acid cycle	1	510.7×	0.003	MDH2
gluconeogenesis	1	324.1×	0.004	MDH2
aerobic respiration	1	247.8×	0.004	MDH2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
MDH2	LEVOTHYROXINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MDH2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVOTHYROXINE	4	MDH2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MDH2	28	Binding:28

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MDH2	1.1.1.37	(S)-malate dehydrogenase (NAD+, oxaloacetate-forming)

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
LEVOTHYROXINE	4	MDH2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MDH2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: MDH2