pyruvate dehydrogenase E3-binding protein deficiency

Summary

pyruvate dehydrogenase E3-binding protein deficiency (MONDO:0009503) is a disease caused by PDHX (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PDHX (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 137
• Phenotypes (HPO): 23

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0002490	Increased CSF lactate	Very frequent (80-99%)
HP:0500231	Abnormal CSF pyruvate family amino acid concentration	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001264	Spastic diplegia	Frequent (30-79%)
HP:0001273	Abnormal corpus callosum morphology	Frequent (30-79%)
HP:0002273	Tetraparesis	Frequent (30-79%)
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0010915	Abnormal circulating pyruvate family amino acid concentration	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002134	Abnormality of the basal ganglia	Occasional (5-29%)
HP:0007109	Periventricular cysts	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Very rare (<1-4%)
HP:0002059	Cerebral atrophy	Very rare (<1-4%)
HP:0002363	Abnormal brainstem morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase E3-binding protein deficiency
Mondo ID	MONDO:0009503
MeSH	C565447
OMIM	245349
Orphanet	255182
UMLS	C1855553
MedGen	343383
GARD	0017237
Is cancer (heuristic)	no

Also known as: 2-oxoglutarate complex deficiency · branched chain alpha-ketoacid dehydrogenase complex deficiency · diaphorase deficiency · dihydrolipoyl dehydrogenase deficiency · Glycine cleavage system L protein deficiency · lacticacidemia due to PDX1 deficiency · lipoamide dehydrogenase deficiency · PDHXD · pyruvate dehydrogenase complex component E3 deficiency · pyruvate dehydrogenase E3-binding protein deficiency · pyruvate dehydrogenase protein X component deficiency

Data availability: 137 ClinVar variants · 6 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 › pyruvate dehydrogenase deficiency › pyruvate dehydrogenase E3-binding protein deficiency

Related subtypes (6): pyruvate dehydrogenase E2 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

137 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 34 benign, 13 conflicting classifications of pathogenicity, 13 pathogenic, 12 likely pathogenic, 7 likely benign, 5 benign/likely benign, 5 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2111	NM_003477.2(PDHX):c.78_162del	LOC130005549	Pathogenic	no assertion criteria provided
2113	NM_003477.3(PDHX):c.88_91del (p.Lys30fs)	LOC130005549	Pathogenic	no assertion criteria provided
3775772	NM_003477.3(PDHX):c.148C>T (p.Gln50Ter)	LOC130005549	Pathogenic	criteria provided, single submitter
162202	NM_003477.3(PDHX):c.1336C>T (p.Arg446Ter)	PDHX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2112	NM_003477.3(PDHX):c.965_1023del (p.Asp322fs)	PDHX	Pathogenic	no assertion criteria provided
2114	NM_003477.3(PDHX):c.641+1G>A	PDHX	Pathogenic	no assertion criteria provided
2115	NM_003477.3(PDHX):c.1024-1G>A	PDHX	Pathogenic	no assertion criteria provided
2116	NM_003477.3(PDHX):c.620del (p.Pro207fs)	PDHX	Pathogenic	no assertion criteria provided
2117	NG_013368.1:g.33923_80418delins[DQ831669.1:28435_34519]	PDHX	Pathogenic	no assertion criteria provided
2118	NM_003477.3(PDHX):c.742C>T (p.Gln248Ter)	PDHX	Pathogenic	criteria provided, multiple submitters, no conflicts
2119	NM_003477.3(PDHX):c.1183-3088_1247+760del	PDHX	Pathogenic	no assertion criteria provided
2158386	NM_003477.3(PDHX):c.1231C>T (p.Gln411Ter)	PDHX	Pathogenic	criteria provided, multiple submitters, no conflicts
2412719	NM_003477.3(PDHX):c.557del (p.Pro186fs)	PDHX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2782785	NM_003477.3(PDHX):c.419_420del (p.His140fs)	PDHX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599570	NM_003477.3(PDHX):c.1182+2T>C	PDHX	Pathogenic	criteria provided, single submitter
373059	NM_003477.3(PDHX):c.793dup (p.Thr265fs)	PDHX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418869	NM_003477.3(PDHX):c.711dup (p.Thr238fs)	PDHX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
650650	NM_003477.3(PDHX):c.850C>T (p.Arg284Ter)	PDHX	Pathogenic	criteria provided, multiple submitters, no conflicts
3062319	NM_003477.3(PDHX):c.70C>T (p.Arg24Ter)	LOC130005549	Likely pathogenic	criteria provided, single submitter
424121	NM_003477.3(PDHX):c.134G>A (p.Trp45Ter)	LOC130005549	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1198487	NM_003477.3(PDHX):c.1426C>T (p.Arg476Ter)	PDHX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722384	NC_000011.9:g.(34953032_34969052)_(34999730_35006116)del	PDHX	Likely pathogenic	criteria provided, single submitter
2441847	NM_003477.3(PDHX):c.1012dup (p.Val338fs)	PDHX	Likely pathogenic	criteria provided, single submitter
2445919	NC_000011.9:g.(34988362_34991685)_(34991834_34999670)del	PDHX	Likely pathogenic	criteria provided, single submitter
2501716	NM_003477.3(PDHX):c.791C>G (p.Ser264Ter)	PDHX	Likely pathogenic	criteria provided, single submitter
3242524	Single allele	PDHX	Likely pathogenic	criteria provided, single submitter
3599569	NM_003477.3(PDHX):c.657_669del (p.Val220fs)	PDHX	Likely pathogenic	criteria provided, single submitter
3778761	NM_003477.3(PDHX):c.188C>G (p.Ser63Ter)	PDHX	Likely pathogenic	criteria provided, single submitter
3780111	NM_003477.3(PDHX):c.797_798insCGGACAACCCAATGCAG (p.Gly273fs)	PDHX	Likely pathogenic	criteria provided, single submitter
931240	NM_003477.3(PDHX):c.1292T>C (p.Val431Ala)	PDHX	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · 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
PDHX	Definitive	Autosomal recessive	pyruvate dehydrogenase E3-binding protein deficiency	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency

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
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	gencc,clinvar
APIP	HGNC:17581	ENSG00000149089	Q96GX9	Methylthioribulose-1-phosphate dehydratase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
APIP	Methylthioribulose-1-phosphate dehydratase	Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P).

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)
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
APIP	Enzyme (other)	yes	4.2.1.109	Aldolase_II/adducin_N, MethylthioRu-1-P_deHdtase_MtnB, Salvage_MtnB_euk

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
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
C1 segment of cervical spinal cord	1
hindlimb stylopod muscle	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
APIP	134	ubiquitous	marker	C1 segment of cervical spinal cord, hindlimb stylopod muscle, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDHX	3,542
APIP	1,585

Intra-cohort edges

A	B	Sources
APIP	PDHX	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDHX	O00330	5
APIP	Q96GX9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Methionine salvage pathway	1	951.7×	0.005	APIP
PDH complex synthesizes acetyl-CoA from PYR	1	815.7×	0.005	PDHX
Formation of apoptosome	1	713.8×	0.005	APIP
Cytochrome c-mediated apoptotic response	1	634.4×	0.005	APIP
Regulation of the apoptosome activity	1	519.1×	0.005	APIP
Apoptotic factor-mediated response	1	439.2×	0.005	APIP
Regulation of pyruvate dehydrogenase (PDH) complex	1	356.9×	0.006	PDHX
Sulfur amino acid metabolism	1	285.5×	0.006	APIP
Signaling by Retinoic Acid	1	203.9×	0.008	PDHX
Intrinsic Pathway for Apoptosis	1	146.4×	0.010	APIP
Apoptosis	1	84.0×	0.015	APIP
Programmed Cell Death	1	73.2×	0.016	APIP
Metabolism of amino acids and derivatives	1	33.8×	0.032	APIP
Metabolism	1	5.8×	0.165	APIP

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
obsolete L-methionine salvage from methylthioadenosine	1	1685.2×	0.003	APIP
pyruvate decarboxylation to acetyl-CoA	1	1053.2×	0.003	PDHX
regulation of ERK1 and ERK2 cascade	1	290.6×	0.007	APIP
pyroptotic inflammatory response	1	255.3×	0.007	APIP
protein homotetramerization	1	118.7×	0.012	APIP
negative regulation of apoptotic process	1	17.4×	0.066	APIP
apoptotic process	1	14.3×	0.068	APIP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDHX	0	0
APIP	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
PDHX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDHX	1.2.1.104	pyruvate dehydrogenase system
APIP	4.2.1.109	methylthioribulose 1-phosphate dehydratase

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	PDHX, APIP
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)
PDHX	1	—
APIP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.