pyruvate dehydrogenase E3 deficiency

Summary

pyruvate dehydrogenase E3 deficiency (MONDO:0009529) is a disease caused by DLD (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DLD (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 632
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002480	Hepatic encephalopathy	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0008344	Elevated plasma branched chain amino acids	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012402	Increased urine alpha-ketoglutarate concentration	Frequent (30-79%)
HP:0100724	Hypercoagulability	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001987	Hyperammonemia	Occasional (5-29%)
HP:0003234	Decreased circulating carnitine concentration	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0010913	Hyperisoleucinemia	Occasional (5-29%)
HP:0030872	Abnormal cardiac ventricular function	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase E3 deficiency
Mondo ID	MONDO:0009529
OMIM	246900
Orphanet	2394
DOID	DOID:0061204
SNOMED CT	29914000
UMLS	C5574660
MedGen	1805500
GARD	0003263
Is cancer (heuristic)	no

Also known as: dihydrolipoamide dehydrogenase deficiency · DLD deficiency · DLDD · E3-deficient maple syrup urine disease · maple syrup urine disease, type III · pyruvate dehydrogenase E3 deficiency

Data availability: 632 ClinVar variants · 7 GenCC gene-disease records.

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 amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › maple syrup urine disease › pyruvate dehydrogenase E3 deficiency

Related subtypes (8): maple syrup urine disease, mild variant, classic maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, maple syrup urine disease type 1A, maple syrup urine disease type 1B, maple syrup urine disease type 2

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:

298 likely benign, 118 uncertain significance, 77 likely pathogenic, 37 pathogenic, 24 benign, 20 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070701	NM_000108.5(DLD):c.1182C>G (p.Tyr394Ter)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072157	NM_000108.5(DLD):c.1396G>T (p.Glu466Ter)	DLD	Pathogenic	criteria provided, single submitter
11966	NM_000108.5(DLD):c.685G>T (p.Gly229Cys)	DLD	Pathogenic	criteria provided, multiple submitters, no conflicts
11970	NM_000108.5(DLD):c.875+1G>A	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11971	NM_000108.5(DLD):c.1123G>A (p.Glu375Lys)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1346904	NM_000108.5(DLD):c.1058T>C (p.Ile353Thr)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353559	NM_000108.5(DLD):c.459T>G (p.Tyr153Ter)	DLD	Pathogenic	criteria provided, single submitter
1359450	NM_000108.5(DLD):c.783del (p.Gln262fs)	DLD	Pathogenic	criteria provided, single submitter
1392784	NM_000108.5(DLD):c.24C>G (p.Tyr8Ter)	DLD	Pathogenic	criteria provided, single submitter
1398789	NC_000007.13:g.(?107556049)(107558012_?)del	DLD	Pathogenic	criteria provided, single submitter
1424970	NM_000108.5(DLD):c.1245_1249del (p.Tyr416fs)	DLD	Pathogenic	criteria provided, single submitter
1454310	NM_000108.5(DLD):c.362del (p.Asp121fs)	DLD	Pathogenic	criteria provided, single submitter
1963983	NM_000108.5(DLD):c.285_286del (p.His96fs)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2017211	NM_000108.5(DLD):c.647del (p.Met216fs)	DLD	Pathogenic	criteria provided, single submitter
2028124	NM_000108.5(DLD):c.987dup (p.Glu330Ter)	DLD	Pathogenic	criteria provided, single submitter
2030397	NM_000108.5(DLD):c.1232_1233del (p.Glu411fs)	DLD	Pathogenic	criteria provided, single submitter
2057359	NM_000108.5(DLD):c.1116_1117del (p.Ile372fs)	DLD	Pathogenic	criteria provided, single submitter
2069354	NM_000108.5(DLD):c.1158C>G (p.Tyr386Ter)	DLD	Pathogenic	criteria provided, single submitter
2106351	NM_000108.5(DLD):c.1464+1G>A	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2113162	NM_000108.5(DLD):c.1139del (p.Gly380fs)	DLD	Pathogenic	criteria provided, single submitter
2422364	NC_000007.13:g.(?107412489)(107559714_?)del	DLD	Pathogenic	criteria provided, single submitter
2674847	NM_000108.5(DLD):c.82dup (p.Ser28fs)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674859	NM_000108.5(DLD):c.184C>T (p.Gln62Ter)	DLD	Pathogenic	criteria provided, single submitter
2674864	NM_000108.5(DLD):c.1214C>A (p.Ser405Ter)	DLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2707325	NM_000108.5(DLD):c.813del (p.Lys271fs)	DLD	Pathogenic	criteria provided, single submitter
2715363	NM_000108.5(DLD):c.104del (p.Tyr35fs)	DLD	Pathogenic	criteria provided, single submitter
2744285	NM_000108.5(DLD):c.988G>T (p.Glu330Ter)	DLD	Pathogenic	criteria provided, single submitter
2752254	NM_000108.5(DLD):c.854C>G (p.Ser285Ter)	DLD	Pathogenic	criteria provided, single submitter
2793857	NM_000108.5(DLD):c.529A>T (p.Lys177Ter)	DLD	Pathogenic	criteria provided, single submitter
2865401	NM_000108.5(DLD):c.3G>A (p.Met1Ile)	DLD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
DLD	Definitive	Autosomal recessive	pyruvate dehydrogenase E3 deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLD	Orphanet:2394	Pyruvate dehydrogenase E3 deficiency

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
DLD	HGNC:2898	ENSG00000091140	P09622	Dihydrolipoyl dehydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLD	Dihydrolipoyl dehydrogenase, mitochondrial	Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex).

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)
DLD	Enzyme (other)	yes	1.2.1.104	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Lipoamide_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
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLD	301	ubiquitous	marker	heart right ventricle, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLD	5,041

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLD	P09622	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
OADH complex synthesizes glutaryl-CoA from 2-OA	1	3806.7×	8e-04	DLD
OGDH complex synthesizes succinyl-CoA from 2-OG	1	2855.0×	8e-04	DLD
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	1	2855.0×	8e-04	DLD
Loss-of-function mutations in DBT cause MSUD2	1	2855.0×	8e-04	DLD
Loss-of-function mutations in DLD cause MSUD3/DLDD	1	2855.0×	8e-04	DLD
Branched-chain ketoacid dehydrogenase kinase deficiency	1	2284.0×	8e-04	DLD
H139Hfs13* PPM1K causes a mild variant of MSUD	1	2284.0×	8e-04	DLD
Glycine degradation	1	1631.4×	9e-04	DLD
PDH complex synthesizes acetyl-CoA from PYR	1	1631.4×	9e-04	DLD
Regulation of pyruvate dehydrogenase (PDH) complex	1	713.8×	0.002	DLD
Branched-chain amino acid catabolism	1	475.8×	0.002	DLD
Signaling by Retinoic Acid	1	407.9×	0.003	DLD
Mitochondrial protein degradation	1	114.2×	0.009	DLD

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-lysine catabolic process to acetyl-CoA	1	16852.0×	7e-04	DLD
2-oxoglutarate decarboxylation to succinyl-CoA	1	5617.3×	9e-04	DLD
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	1	4213.0×	9e-04	DLD
pyruvate decarboxylation to acetyl-CoA	1	2106.5×	0.001	DLD
branched-chain amino acid catabolic process	1	1053.2×	0.002	DLD
2-oxoglutarate metabolic process	1	936.2×	0.002	DLD
gastrulation	1	702.2×	0.002	DLD
sperm capacitation	1	674.1×	0.002	DLD
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.003	DLD
regulation of membrane potential	1	230.8×	0.005	DLD
proteolysis	1	34.2×	0.029	DLD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
DLD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DLD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DLD	1.2.1.104, 1.2.1.105, 1.4.1.27, 1.8.1.4	pyruvate dehydrogenase system, 2-oxoglutarate dehydrogenase system, glycine cleavage system, dihydrolipoyl dehydrogenase

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

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	1	DLD
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)
DLD	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.