Pyruvate dehydrogenase phosphatase deficiency

Summary

Pyruvate dehydrogenase phosphatase deficiency (MONDO:0012120) is a disease caused by PDP1 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PDP1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 52
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0003348	Hyperalaninemia	Frequent (30-79%)
HP:0003648	Lacticaciduria	Frequent (30-79%)
HP:0008358	Hyperprolinemia	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011342	Mild global developmental delay	Frequent (30-79%)
HP:0040328	Focal hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase phosphatase deficiency
Mondo ID	MONDO:0012120
MeSH	C536258
OMIM	608782
Orphanet	79246
ICD-11	1709497558
UMLS	C1837429
MedGen	332448
GARD	0009888
Is cancer (heuristic)	no

Also known as: PDH phosphatase deficiency · PDHPD · pyruvate dehydrogenase phosphatase deficiency

Data availability: 52 ClinVar variants · 5 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 phosphatase deficiency

Related subtypes (6): pyruvate dehydrogenase E2 deficiency, pyruvate dehydrogenase E3-binding protein deficiency, pyruvate dehydrogenase E3 deficiency, pyruvate dehydrogenase E1-alpha 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

52 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 11 likely pathogenic, 5 likely benign, 3 benign, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2677598	NM_000925.4(PDHB):c.716_717del (p.Val239fs)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677600	NM_000925.4(PDHB):c.211C>T (p.Arg71Ter)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4663	NM_018444.4(PDP1):c.851_853del (p.Leu284del)	PDP1	Pathogenic	no assertion criteria provided
4664	NM_018444.4(PDP1):c.277G>T (p.Glu93Ter)	PDP1	Pathogenic	no assertion criteria provided
2677597	NM_000925.4(PDHB):c.352C>T (p.Gln118Ter)	PDHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677599	NM_000925.4(PDHB):c.934+1G>A	PDHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776790	NM_000925.4(PDHB):c.575G>A (p.Arg192Gln)	PDHB	Likely pathogenic	criteria provided, single submitter
4814480	NM_000925.4(PDHB):c.2T>C (p.Met1Thr)	PDHB	Likely pathogenic	criteria provided, single submitter
4814481	NM_000925.4(PDHB):c.377C>A (p.Ser126Ter)	PDHB	Likely pathogenic	criteria provided, single submitter
4814482	NM_000925.4(PDHB):c.518dup (p.Val174fs)	PDHB	Likely pathogenic	criteria provided, single submitter
4814483	NM_000925.4(PDHB):c.562A>T (p.Lys188Ter)	PDHB	Likely pathogenic	criteria provided, single submitter
4814484	NM_000925.4(PDHB):c.875_876del (p.Val292fs)	PDHB	Likely pathogenic	criteria provided, single submitter
4814485	NM_000925.4(PDHB):c.934+1G>T	PDHB	Likely pathogenic	criteria provided, single submitter
3596009	NM_018444.4(PDP1):c.48dup (p.Leu17fs)	PDP1	Likely pathogenic	criteria provided, single submitter
982568	NM_018444.4(PDP1):c.500dup (p.Leu167fs)	PDP1	Likely pathogenic	criteria provided, single submitter
978588	NM_000925.4(PDHB):c.106C>T (p.Arg36Cys)	PDHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214971	NM_018444.4(PDP1):c.1595C>T (p.Ala532Val)	PDP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4767004	NM_018444.4(PDP1):c.437del (p.His146fs)	PDP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036385	NM_000925.4(PDHB):c.38G>A (p.Arg13Gln)	LOC129936949	Uncertain significance	criteria provided, multiple submitters, no conflicts
4059494	NM_000925.4(PDHB):c.18C>T (p.Gly6=)	LOC129936949	Uncertain significance	no assertion criteria provided
2184557	NM_000925.4(PDHB):c.1050A>G (p.Ile350Met)	PDHB	Uncertain significance	criteria provided, single submitter
4059489	NM_000925.4(PDHB):c.610T>A (p.Leu204Met)	PDHB	Uncertain significance	no assertion criteria provided
4059490	NM_000925.4(PDHB):c.382G>C (p.Ala128Pro)	PDHB	Uncertain significance	no assertion criteria provided
4059491	NM_000925.4(PDHB):c.724C>T (p.His242Tyr)	PDHB	Uncertain significance	no assertion criteria provided
4059492	NM_000925.4(PDHB):c.1042G>A (p.Asp348Asn)	PDHB	Uncertain significance	no assertion criteria provided
4059493	NM_000925.4(PDHB):c.793-7del	PDHB	Uncertain significance	no assertion criteria provided
4059495	NM_000925.4(PDHB):c.542A>C (p.Glu181Ala)	PDHB	Uncertain significance	no assertion criteria provided
4059496	NM_000925.4(PDHB):c.701-8del	PDHB	Uncertain significance	no assertion criteria provided
4059498	NM_000925.4(PDHB):c.209G>A (p.Ser70Asn)	PDHB	Uncertain significance	no assertion criteria provided
4059499	NM_000925.4(PDHB):c.793-2dup	PDHB	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 2 · 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
PDP1	Strong	Autosomal recessive	pyruvate dehydrogenase phosphatase deficiency	6
PLPP6	Strong	Autosomal recessive	pyruvate dehydrogenase phosphatase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDP1	Orphanet:79246	Pyruvate dehydrogenase phosphatase deficiency
PDHB	Orphanet:255138	Pyruvate dehydrogenase E1-beta deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLPP6	HGNC:23682	ENSG00000205808	Q8IY26	Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6	gencc,clinvar
PDP1	HGNC:9279	ENSG00000164951	Q9P0J1	[Pyruvate dehydrogenase [acetyl-transferring]]-phosphatase 1, mitochondrial	gencc,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)
PLPP6	Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6	Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates.
PDP1	[Pyruvate dehydrogenase [acetyl-transferring]]-phosphatase 1, mitochondrial	Mitochondrial enzyme that catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex (PDC), thereby stimulating the conversion of pyruvate into acetyl-CoA.
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: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Phosphatase	1	28.0×	0.106
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLPP6	Other/Unknown	no		PAP2/HPO, PAP2/HPO_sf
PDP1	Phosphatase	yes	3.1.3.43	PP2C_BS, PPM-type_phosphatase-like_dom, PP2C
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.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	2
ileal mucosa	1
oocyte	1
secondary oocyte	1
buccal mucosa cell	1
lateral nuclear group of thalamus	1
endothelial cell	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLPP6	227	ubiquitous	marker	secondary oocyte, oocyte, ileal mucosa
PDP1	280	ubiquitous	marker	lateral nuclear group of thalamus, buccal mucosa cell, biceps brachii
PDHB	299	ubiquitous	marker	endothelial cell, heart right ventricle, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDHB	3,784
PDP1	1,952
PLPP6	681

Intra-cohort edges

A	B	Sources
PDHB	PDP1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDHB	P11177	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDP1	Q9P0J1	83.41
PLPP6	Q8IY26	73.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 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
Regulation of pyruvate dehydrogenase (PDH) complex	2	475.8×	3e-05	PDP1, PDHB
PDH complex synthesizes acetyl-CoA from PYR	1	543.8×	0.005	PDHB
Lanosterol biosynthesis	1	253.8×	0.007	PLPP6
Signaling by Retinoic Acid	1	135.9×	0.009	PDHB
Mitochondrial protein degradation	1	38.1×	0.026	PDHB

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
geranyl diphosphate metabolic process	1	2808.7×	0.001	PLPP6
farnesyl diphosphate catabolic process	1	2808.7×	0.001	PLPP6
positive regulation of pyruvate decarboxylation to acetyl-CoA	1	2808.7×	0.001	PDP1
geranylgeranyl diphosphate catabolic process	1	2808.7×	0.001	PLPP6
protein prenylation	1	1872.4×	0.001	PLPP6
positive regulation of neutrophil activation	1	1872.4×	0.001	PLPP6
isoprenoid metabolic process	1	1123.5×	0.002	PLPP6
pyruvate decarboxylation to acetyl-CoA	1	702.2×	0.002	PDHB
peptidyl-threonine dephosphorylation	1	624.1×	0.002	PDP1
phospholipid dephosphorylation	1	351.1×	0.004	PLPP6
tricarboxylic acid cycle	1	170.2×	0.007	PDHB
cholesterol biosynthetic process	1	140.4×	0.008	PLPP6
glucose metabolic process	1	85.1×	0.013	PDHB
innate immune response	1	11.2×	0.087	PLPP6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLPP6	0	0
PDP1	0	0
PDHB	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
PDHB	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDP1	3.1.3.43	[pyruvate dehydrogenase (acetyl-transferring)]-phosphatase
PDHB	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	PDHB
D	Druggable family + AlphaFold only, no drug	1	PDP1
E	Difficult family or no structure, no drug	1	PLPP6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLPP6	0	—
PDP1	0	—
PDHB	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency