pyruvate dehydrogenase E1-alpha deficiency

Summary

pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717) is a disease caused by PDHA1 (GenCC Definitive), with 7 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PDHA1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 767
• Phenotypes (HPO): 55
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001518	Small for gestational age	Very frequent (80-99%)
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:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002171	Gliosis	Frequent (30-79%)
HP:0002187	Intellectual disability, profound	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0003542	Increased serum pyruvate	Frequent (30-79%)
HP:0004902	Congenital lactic acidosis	Frequent (30-79%)
HP:0006956	Dilation of lateral ventricles	Frequent (30-79%)
HP:0011193	EEG with focal spikes	Frequent (30-79%)
HP:0011196	EEG with focal sharp waves	Frequent (30-79%)
HP:0011199	EEG with generalized sharp slow waves	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0025361	Abnormality of medullary pyramid morphology	Frequent (30-79%)
HP:0030917	Low APGAR score	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000954	Single transverse palmar crease	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001338	Partial agenesis of the corpus callosum	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002100	Recurrent aspiration pneumonia	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0002350	Cerebellar cyst	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002643	Neonatal respiratory distress	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0006799	Basal ganglia cysts	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)
HP:0006999	Basal ganglia gliosis	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0010576	Intracranial cystic lesion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase E1-alpha deficiency
Mondo ID	MONDO:0010717
MeSH	C564071
OMIM	312170
Orphanet	79243
SNOMED CT	124593001
UMLS	C1839413
MedGen	326486
GARD	0004620
Is cancer (heuristic)	no

Also known as: ataxia with lactic acidosis 1 · ataxia, intermittent, with pyruvate dehydrogenase, or decarboxylase, deficiency · PDHAD · pyruvate decarboxylase deficiency · pyruvate dehydrogenase complex E1 component subunit alpha deficiency · pyruvate dehydrogenase E1-alpha deficiency · pyruvate dehydrogenase e1-alpha deficiency, X-linked dominant

Data availability: 767 ClinVar variants · 8 GenCC gene-disease records · 1 cell line.

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 E1-alpha deficiency

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

600 retrieved; paginated sample, class counts are floors:

178 pathogenic, 178 likely benign, 121 likely pathogenic, 51 uncertain significance, 35 benign, 16 conflicting classifications of pathogenicity, 13 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243867	NC_000023.10:g.(?17393881)(20284750_?)del	ADGRG2	Pathogenic	criteria provided, single submitter
1028668	NM_000284.4(PDHA1):c.899+2T>A	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
10871	NM_000284.4(PDHA1):c.1167_1170del (p.Ser390fs)	PDHA1	Pathogenic	no assertion criteria provided
10872	NM_000284.4(PDHA1):c.934_940del (p.Ser312fs)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
10873	NM_000284.4(PDHA1):c.1133G>A (p.Arg378His)	PDHA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10874	NM_000284.4(PDHA1):c.938_940del (p.Lys313del)	PDHA1	Pathogenic	no assertion criteria provided
10875	NM_000284.4(PDHA1):c.1159_1160del (p.Lys387fs)	PDHA1	Pathogenic	no assertion criteria provided
10876	NM_000284.4(PDHA1):c.1073_1092del (p.Glu358fs)	PDHA1	Pathogenic	no assertion criteria provided
10877	NM_000284.4(PDHA1):c.900-3_917dup	PDHA1	Pathogenic/Likely pathogenic	no assertion criteria provided
10878	NM_000284.4(PDHA1):c.787C>G (p.Arg263Gly)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
10879	NM_000284.4(PDHA1):c.904C>T (p.Arg302Cys)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
10880	NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)	PDHA1	Pathogenic	reviewed by expert panel
10881	NM_000284.4(PDHA1):c.773A>C (p.Asp258Ala)	PDHA1	Pathogenic	no assertion criteria provided
10882	NM_000284.4(PDHA1):c.615C>G (p.Phe205Leu)	PDHA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10883	NM_000284.4(PDHA1):c.727T>A (p.Tyr243Asn)	PDHA1	Pathogenic	no assertion criteria provided
10886	NM_000284.4(PDHA1):c.861_862insT (p.Arg288fs)	PDHA1	Pathogenic	no assertion criteria provided
10887	NM_000284.4(PDHA1):c.29G>C (p.Arg10Pro)	PDHA1	Pathogenic/Likely pathogenic	no assertion criteria provided
10888	NM_000284.4(PDHA1):c.991_1003dup (p.Leu335fs)	PDHA1	Pathogenic	no assertion criteria provided
10889	NM_000284.4(PDHA1):c.1074_1109dup (p.Pro359_Ser370dup)	PDHA1	Pathogenic	no assertion criteria provided
10890	NM_000284.4(PDHA1):c.863G>A (p.Arg288His)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
10891	NM_000284.4(PDHA1):c.*79_*90dup	PDHA1	Pathogenic	no assertion criteria provided
10893	NM_000284.4(PDHA1):c.648A>C (p.Leu216Phe)	PDHA1	Pathogenic/Likely pathogenic	no assertion criteria provided
1188095	NM_000284.4(PDHA1):c.498C>T (p.Ile166=)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1190221	NM_000284.4(PDHA1):c.787C>T (p.Arg263Ter)	PDHA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1252070	NM_000284.4(PDHA1):c.728A>G (p.Tyr243Cys)	PDHA1	Pathogenic	no assertion criteria provided
1320219	NM_000284.4(PDHA1):c.355C>T (p.Arg119Trp)	PDHA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323430	NM_000284.4(PDHA1):c.1133_1140del (p.Arg378fs)	PDHA1	Pathogenic	criteria provided, single submitter
1519076	NM_000284.4(PDHA1):c.902_907del (p.Tyr301_Thr303delinsSer)	PDHA1	Pathogenic	criteria provided, single submitter
1679534	NM_000284.4(PDHA1):c.1009-16_1010del	PDHA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2000808	NM_000284.4(PDHA1):c.653G>A (p.Cys218Tyr)	PDHA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 7 · 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
PDHA1	Definitive	X-linked	pyruvate dehydrogenase E1-alpha deficiency	8
LONP1	Supportive	X-linked	pyruvate dehydrogenase E1-alpha deficiency	10
DLST	No Known Disease Relationship	Autosomal recessive	pyruvate dehydrogenase E1-alpha deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDHA1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
DLST	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
LONP1	Orphanet:1458	CODAS syndrome
LONP1	Orphanet:2140	Congenital diaphragmatic hernia
LONP1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
ADGRG2	Orphanet:48	Congenital bilateral absence of vas deferens

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDHA1	HGNC:8806	ENSG00000131828	P08559	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	gencc,clinvar
DLST	HGNC:2911	ENSG00000119689	P36957	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	gencc
LONP1	HGNC:9479	ENSG00000196365	P36776	Lon protease homolog, mitochondrial	gencc
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	clinvar
MAP3K15	HGNC:31689	ENSG00000180815	Q6ZN16	Mitogen-activated protein kinase kinase kinase 15	clinvar
ADGRG2	HGNC:4516	ENSG00000173698	Q8IZP9	Adhesion G-protein coupled receptor G2	clinvar
PPEF1	HGNC:9243	ENSG00000086717	O14829	Serine/threonine-protein phosphatase with EF-hands 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDHA1	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.
DLST	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex.
LONP1	Lon protease homolog, mitochondrial	ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix.
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.
MAP3K15	Mitogen-activated protein kinase kinase kinase 15	Serine/threonine kinase which acts as a component of the MAP kinase signal transduction pathway.
ADGRG2	Adhesion G-protein coupled receptor G2	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.
PPEF1	Serine/threonine-protein phosphatase with EF-hands 1	May have a role in the recovery or adaptation response of photoreceptors.

Protein-family classification

Druggable: 7 · 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)	3	5.1×	0.078
Phosphatase	1	12.0×	0.201
Protease	1	5.2×	0.258
Kinase	1	4.0×	0.258
GPCR	1	3.4×	0.258

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDHA1	Enzyme (other)	yes	1.2.1.104	DH_E1, Pyrv_DH_E1_asu_subgrp-y, THDP-binding
DLST	Enzyme (other)	yes	1.2.1.105	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
LONP1	Protease	yes	3.4.21.53	Lon_prtase_N, AAA+_ATPase, ATPase_AAA_core
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
MAP3K15	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ADGRG2	GPCR	yes		GPS, GPCR_2_secretin-like, GPCR_2-like_7TM
PPEF1	Phosphatase	yes		IQ_motif_EF-hand-BS, EF_hand_dom, Calcineurin-like_PHP

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	3
right adrenal gland cortex	3
apex of heart	2
cardiac ventricle	1
heart left ventricle	1
left adrenal gland	1
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
adrenal tissue	1
caput epididymis	1
corpus epididymis	1
parotid gland	1
cortical plate	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDHA1	290	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
DLST	283	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
LONP1	275	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
MAP3K15	108	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
ADGRG2	182	broad	marker	corpus epididymis, caput epididymis, parotid gland
PPEF1	180	tissue_specific	marker	sperm, male germ cell, cortical plate

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDHA1	5,038
LONP1	4,030
DLST	3,692
PDHX	3,542
PPEF1	3,267
MAP3K15	1,104
ADGRG2	723

Intra-cohort edges

A	B	Sources
DLST	PPEF1	intact
PDHA1	PDHX	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LONP1	P36776	29
PDHA1	P08559	9
PDHX	O00330	5
DLST	P36957	1
MAP3K15	Q6ZN16	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPEF1	O14829	80.64
ADGRG2	Q8IZP9	62.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 7 evidence-associated genes (5 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 5 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	2	652.6×	4e-05	PDHA1, PDHX
Regulation of pyruvate dehydrogenase (PDH) complex	2	285.5×	1e-04	PDHA1, PDHX
Signaling by Retinoic Acid	2	163.1×	3e-04	PDHA1, PDHX
Mitochondrial protein degradation	2	45.7×	0.002	PDHA1, LONP1
OADH complex synthesizes glutaryl-CoA from 2-OA	1	761.3×	0.003	DLST
OGDH complex synthesizes succinyl-CoA from 2-OG	1	571.0×	0.004	DLST
Glycine degradation	1	326.3×	0.006	DLST
Protein lipoylation	1	207.6×	0.008	DLST
Mitochondrial unfolded protein response (UPRmt)	1	120.2×	0.012	LONP1
Inactivation, recovery and regulation of the phototransduction cascade	1	63.4×	0.020	PPEF1
Cellular responses to stress	1	7.4×	0.152	LONP1
Cellular responses to stimuli	1	6.3×	0.162	LONP1
Metabolism of proteins	1	2.5×	0.344	LONP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 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	2	601.9×	1e-04	PDHA1, PDHX
tricarboxylic acid cycle	2	145.9×	0.001	PDHA1, DLST
detection of stimulus involved in sensory perception	1	1203.7×	0.005	PPEF1
oxidation-dependent protein catabolic process	1	1203.7×	0.005	LONP1
response to aluminum ion	1	802.5×	0.005	LONP1
obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine	1	802.5×	0.005	DLST
2-oxoglutarate decarboxylation to succinyl-CoA	1	802.5×	0.005	DLST
succinyl-CoA metabolic process	1	481.5×	0.008	DLST
mitochondrial protein catabolic process	1	218.9×	0.015	LONP1
2-oxoglutarate metabolic process	1	133.8×	0.021	DLST
p38MAPK cascade	1	126.7×	0.021	MAP3K15
protein quality control for misfolded or incompletely synthesized proteins	1	109.4×	0.022	LONP1
chaperone-mediated protein complex assembly	1	100.3×	0.022	LONP1
obsolete proteolysis involved in protein catabolic process	1	75.2×	0.027	LONP1
response to hormone	1	61.7×	0.031	LONP1
negative regulation of insulin receptor signaling pathway	1	53.5×	0.034	LONP1
generation of precursor metabolites and energy	1	49.1×	0.034	DLST
JNK cascade	1	38.8×	0.041	MAP3K15
glucose metabolic process	1	36.5×	0.041	PDHA1
protein dephosphorylation	1	31.7×	0.045	PPEF1
cellular response to oxidative stress	1	22.1×	0.060	LONP1
mitochondrion organization	1	21.7×	0.060	LONP1
spermatid development	1	20.8×	0.060	ADGRG2
phospholipase C-activating G protein-coupled receptor signaling pathway	1	18.8×	0.063	ADGRG2
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	16.2×	0.070	ADGRG2
response to hypoxia	1	13.7×	0.079	LONP1
cell surface receptor signaling pathway	1	9.2×	0.112	ADGRG2
G protein-coupled receptor signaling pathway	1	5.2×	0.183	ADGRG2
spermatogenesis	1	5.0×	0.183	ADGRG2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 7 of 7 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
LONP1	BORTEZOMIB
MAP3K15	RUXOLITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K15	6	4
LONP1	1	4
PDHA1	0	0
DLST	0	0
PDHX	0	0
ADGRG2	0	0
PPEF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	LONP1
RUXOLITINIB	4	MAP3K15
NINTEDANIB	4	MAP3K15
SUNITINIB	4	MAP3K15
CRIZOTINIB	4	MAP3K15
LESTAURTINIB	3	MAP3K15
SU-014813	2	MAP3K15

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
MAP3K15	81	Binding:81
LONP1	2	Binding:2
ADGRG2	2	Binding:2
PDHA1	1	Binding:1
DLST	1	Binding:1
PDHX	1	Binding:1
PPEF1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDHA1	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)
DLST	1.2.1.105	2-oxoglutarate dehydrogenase system
LONP1	3.4.21.53	Endopeptidase La
PDHX	1.2.1.104	pyruvate dehydrogenase system

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 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)
BORTEZOMIB	4	LONP1
RUXOLITINIB	4	MAP3K15
NINTEDANIB	4	MAP3K15
SUNITINIB	4	MAP3K15
CRIZOTINIB	4	MAP3K15
LESTAURTINIB	3	MAP3K15
SU-014813	2	MAP3K15

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	LONP1, MAP3K15
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	PDHA1, DLST, PDHX
D	Druggable family + AlphaFold only, no drug	2	ADGRG2, PPEF1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PDHA1	1	—
DLST	1	—
PDHX	1	—
ADGRG2	2	—
PPEF1	1	—

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