Pyruvate dehydrogenase deficiency

Summary

Pyruvate dehydrogenase deficiency (MONDO:0019169) is a disease (an umbrella term covering 7 Mondo subtypes) with 4 cohort genes and 5 clinical trials. The dominant Reactome pathway is PDH complex synthesizes acetyl-CoA from PYR (3 cohort genes). Top therapeutic interventions include phenylbutanoic acid, triheptanoin, and dichloroacetic acid.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 145
• Phenotypes (HPO): 35
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0100453	Osteolytic defects of the middle phalanx of the 4th toe	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000275	Narrow face	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001012	Multiple lipomas	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0100021	Cerebral palsy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase deficiency
Mondo ID	MONDO:0019169
OMIM	312170
Orphanet	765
DOID	DOID:3649
ICD-11	1124597954
NCIT	C103968
SNOMED CT	46683007
UMLS	C0034345
MedGen	19610
GARD	0007513
NORD	1641
Is cancer (heuristic)	no

Also known as: PDH · PDHC · pyruvate decarboxylase deficiency · Pyruvate Dehydrogenase Complex Deficiency · pyruvate dehydrogenase complex deficiency · pyruvate dehydrogenase deficiency

Data availability: 145 ClinVar variants · 9 ClinGen variant curations · 6 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

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

Related subtypes (13): oxoglutaricaciduria, 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, OPA1-related optic atrophy with or without extraocular features

Subtypes (7): pyruvate dehydrogenase E2 deficiency, pyruvate dehydrogenase E3-binding protein deficiency, pyruvate dehydrogenase E3 deficiency, pyruvate dehydrogenase E1-alpha deficiency, pyruvate dehydrogenase phosphatase deficiency, pyruvate dehydrogenase E1-beta deficiency, lipoic acid synthetase deficiency

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

145 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 24 conflicting classifications of pathogenicity, 23 benign, 14 benign/likely benign, 10 likely benign, 6 pathogenic, 6 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10880	NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)	PDHA1	Pathogenic	reviewed by expert panel
214935	NM_000284.4(PDHA1):c.910C>T (p.Arg304Ter)	PDHA1	Pathogenic	reviewed by expert panel
214936	NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)	PDHA1	Pathogenic	reviewed by expert panel
214941	NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)	PDHA1	Pathogenic	reviewed by expert panel
488569	NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)	PDHA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488571	NM_000284.4(PDHA1):c.930AAG[1] (p.Arg311del)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
627558	NM_000284.4(PDHA1):c.225G>T (p.Glu75Asp)	PDHA1	Pathogenic	criteria provided, single submitter
3362257	NM_004424.5(E4F1):c.430A>C (p.Lys144Gln)	E4F1	Likely pathogenic	criteria provided, single submitter
214938	NM_000284.4(PDHA1):c.214C>T (p.Arg72Cys)	PDHA1	Likely pathogenic	reviewed by expert panel
3366665	NM_000284.4(PDHA1):c.677G>A (p.Arg226His)	PDHA1	Likely pathogenic	criteria provided, single submitter
3375522	NM_000284.4(PDHA1):c.733A>G (p.Arg245Gly)	PDHA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4818107	NM_000284.4(PDHA1):c.734G>A (p.Arg245Lys)	PDHA1	Likely pathogenic	criteria provided, single submitter
495793	NM_000284.4(PDHA1):c.1050_1133dup (p.Gln351_Arg378dup)	PDHA1	Likely pathogenic	criteria provided, single submitter
137095	NM_000108.5(DLD):c.543A>T (p.Ile181=)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203672	NM_000108.5(DLD):c.100A>G (p.Thr34Ala)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203680	NM_000108.5(DLD):c.763A>C (p.Met255Leu)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203681	NM_000108.5(DLD):c.788G>A (p.Arg263His)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358564	NM_000108.5(DLD):c.74A>C (p.Gln25Pro)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358571	NM_000108.5(DLD):c.1465-7C>G	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358572	NM_000108.5(DLD):c.1503G>A (p.Ala501=)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358578	NM_000108.5(DLD):c.*470G>A	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358591	NM_000108.5(DLD):c.*1736T>C	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382483	NM_000108.5(DLD):c.321A>G (p.Ala107=)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
578582	NM_000108.5(DLD):c.55C>G (p.Arg19Gly)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
751771	NM_000108.5(DLD):c.375G>A (p.Glu125=)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909641	NM_000108.5(DLD):c.*1876G>A	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911148	NM_000108.5(DLD):c.30C>A (p.Ser10=)	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911751	NM_000108.5(DLD):c.*1640A>G	DLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211893	NM_000284.4(PDHA1):c.984T>C (p.Asn328=)	PDHA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214934	NM_000284.4(PDHA1):c.854A>G (p.Gln285Arg)	PDHA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLD	Orphanet:2394	Pyruvate dehydrogenase E3 deficiency
PDHA1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
PDHB	Orphanet:255138	Pyruvate dehydrogenase E1-beta deficiency

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
DLD	HGNC:2898	ENSG00000091140	P09622	Dihydrolipoyl dehydrogenase, mitochondrial	clinvar
E4F1	HGNC:3121	ENSG00000167967	Q66K89	Transcription factor E4F1	clinvar
PDHA1	HGNC:8806	ENSG00000131828	P08559	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	clinvar
PDHB	HGNC:8808	ENSG00000168291	P11177	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial	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).
E4F1	Transcription factor E4F1	May function as a transcriptional repressor.
PDHA1	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.
PDHB	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial	Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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)	3	9.0×	0.004
Transcription factor	1	2.1×	0.403

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
E4F1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
PDHA1	Enzyme (other)	yes	1.2.1.104	DH_E1, Pyrv_DH_E1_asu_subgrp-y, THDP-binding
PDHB	Enzyme (other)	yes	1.2.1.104	Transketolase-like_Pyr-bd, Transketo_C/PFOR_II, PDHB_mito-type

Expression context

Cohort genes with no expression data: 0.

4 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
biceps brachii	2
heart right ventricle	2
skeletal muscle tissue of biceps brachii	1
lower esophagus mucosa	1
right hemisphere of cerebellum	1
sural nerve	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
endothelial cell	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
E4F1	138	ubiquitous	marker	right hemisphere of cerebellum, lower esophagus mucosa, sural nerve
PDHA1	290	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
PDHB	299	ubiquitous	marker	endothelial cell, heart right ventricle, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLD	5,041
PDHA1	5,038
PDHB	3,784
E4F1	1,965

Intra-cohort edges

A	B	Sources
DLD	PDHA1	biogrid_interaction, intact, string_interaction
DLD	PDHB	biogrid_interaction, intact, string_interaction
PDHA1	PDHB	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLD	P09622	17
PDHA1	P08559	9
PDHB	P11177	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
E4F1	Q66K89	53.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
PDH complex synthesizes acetyl-CoA from PYR	3	1631.4×	2e-09	DLD, PDHA1, PDHB
Regulation of pyruvate dehydrogenase (PDH) complex	3	713.8×	1e-08	DLD, PDHA1, PDHB
Signaling by Retinoic Acid	3	407.9×	6e-08	DLD, PDHA1, PDHB
Mitochondrial protein degradation	3	114.2×	2e-06	DLD, PDHA1, PDHB
OADH complex synthesizes glutaryl-CoA from 2-OA	1	1268.9×	0.002	DLD
OGDH complex synthesizes succinyl-CoA from 2-OG	1	951.7×	0.002	DLD
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	1	951.7×	0.002	DLD
Loss-of-function mutations in DBT cause MSUD2	1	951.7×	0.002	DLD
Loss-of-function mutations in DLD cause MSUD3/DLDD	1	951.7×	0.002	DLD
Branched-chain ketoacid dehydrogenase kinase deficiency	1	761.3×	0.002	DLD
H139Hfs13* PPM1K causes a mild variant of MSUD	1	761.3×	0.002	DLD
Glycine degradation	1	543.8×	0.002	DLD
Branched-chain amino acid catabolism	1	158.6×	0.006	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyruvate decarboxylation to acetyl-CoA	3	1579.9×	6e-09	DLD, PDHA1, PDHB
tricarboxylic acid cycle	2	255.3×	2e-04	PDHA1, PDHB
glucose metabolic process	2	127.7×	7e-04	PDHA1, PDHB
regulation of mitotic cell cycle, embryonic	1	4213.0×	0.001	E4F1
obsolete L-lysine catabolic process to acetyl-CoA	1	4213.0×	0.001	DLD
2-oxoglutarate decarboxylation to succinyl-CoA	1	1404.3×	0.003	DLD
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	1	1053.2×	0.003	DLD
branched-chain amino acid catabolic process	1	263.3×	0.009	DLD
regulation of cell cycle process	1	247.8×	0.009	E4F1
2-oxoglutarate metabolic process	1	234.1×	0.009	DLD
gastrulation	1	175.5×	0.011	DLD
sperm capacitation	1	168.5×	0.011	DLD
mitochondrial electron transport, NADH to ubiquinone	1	89.6×	0.019	DLD
regulation of membrane potential	1	57.7×	0.027	DLD
DNA replication	1	41.3×	0.035	E4F1
regulation of cell cycle	1	18.6×	0.072	E4F1
cell division	1	11.5×	0.109	E4F1
protein ubiquitination	1	10.3×	0.114	E4F1
proteolysis	1	8.6×	0.129	DLD
negative regulation of transcription by RNA polymerase II	1	4.4×	0.228	E4F1
positive regulation of transcription by RNA polymerase II	1	3.7×	0.255	E4F1
regulation of transcription by RNA polymerase II	1	2.9×	0.302	E4F1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
E4F1	0	0
PDHA1	0	0
PDHB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PDHB	3	Binding:3
DLD	1	Binding:1
PDHA1	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
PDHA1	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)
PDHB	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)

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

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	3	DLD, PDHA1, PDHB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	E4F1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DLD	1	—
E4F1	0	—
PDHA1	1	—
PDHB	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02616484	PHASE3	ACTIVE_NOT_RECRUITING	Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
NCT03734263	PHASE2	COMPLETED	Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
NCT06340685	PHASE1	RECRUITING	Triheptanoin for Children With Primary-Specific Pyruvate Dehydrogenase Complex (PDC) Deficiency
NCT06931262	Not specified	AVAILABLE	Expanded Access Treatment Protocol With DCA for Patients With PDCD
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYLBUTANOIC ACID	4	2
TRIHEPTANOIN	4	1
DICHLOROACETIC ACID	3	2