PDHA1

Summary

PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1, HGNC:8806) is a protein-coding gene on chromosome Xp22.12, encoding Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial (P08559). Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex. It is haploinsufficient (ClinGen: sufficient evidence).

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5160 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 980 total — 226 pathogenic, 152 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000284

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8806
Approved symbol	PDHA1
Name	pyruvate dehydrogenase E1 subunit alpha 1
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	E1alpha
Ensembl gene	ENSG00000131828
Ensembl biotype	protein_coding
OMIM	300502
Entrez	5160

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 30 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay

ENST00000355808, ENST00000379804, ENST00000379805, ENST00000417819, ENST00000422285, ENST00000423505, ENST00000478795, ENST00000479146, ENST00000481733, ENST00000492364, ENST00000540249, ENST00000696704, ENST00000696705, ENST00000881112, ENST00000881113, ENST00000881114, ENST00000881115, ENST00000881116, ENST00000881117, ENST00000881118, ENST00000927451, ENST00000927452, ENST00000927453, ENST00000927454, ENST00000927455, ENST00000927456, ENST00000947567, ENST00000947568, ENST00000947569, ENST00000947570, ENST00000947571, ENST00000947572, ENST00000947573, ENST00000947574, ENST00000947575, ENST00000947576, ENST00000947577, ENST00000947578

RefSeq mRNA: 4 — MANE Select: NM_000284 NM_000284, NM_001173454, NM_001173455, NM_001173456

CCDS: CCDS14192, CCDS55380, CCDS55381, CCDS55382

Canonical transcript exons

ENST00000422285 — 11 exons

Exon	Start	End
ENSE00001609343	19353082	19353173
ENSE00001672419	19351281	19351407
ENSE00001678682	19355349	19355504
ENSE00001767601	19354491	19354583
ENSE00001877173	19343927	19344094
ENSE00003545396	19355686	19355757
ENSE00003586790	19349937	19350110
ENSE00003613877	19357652	19357719
ENSE00003660452	19349312	19349371
ENSE00003681497	19358916	19359024
ENSE00003968118	19359489	19361718

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.6247 / max 399.0475, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195698	55.1586	1825
209622	0.2712	142
195700	0.1950	75

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.45	gold quality
heart left ventricle	UBERON:0002084	99.33	gold quality
cardiac ventricle	UBERON:0002082	99.31	gold quality
right atrium auricular region	UBERON:0006631	99.30	gold quality
metanephros cortex	UBERON:0010533	99.28	gold quality
gastrocnemius	UBERON:0001388	99.26	gold quality
muscle of leg	UBERON:0001383	99.20	gold quality
cardiac atrium	UBERON:0002081	99.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.16	gold quality
mucosa of transverse colon	UBERON:0004991	98.98	gold quality
heart	UBERON:0000948	98.97	gold quality
transverse colon	UBERON:0001157	98.94	gold quality
rectum	UBERON:0001052	98.92	gold quality
body of pancreas	UBERON:0001150	98.90	gold quality
body of stomach	UBERON:0001161	98.90	gold quality
heart right ventricle	UBERON:0002080	98.89	gold quality
ganglionic eminence	UBERON:0004023	98.71	gold quality
minor salivary gland	UBERON:0001830	98.66	gold quality
left ventricle myocardium	UBERON:0006566	98.61	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.56	gold quality
lower esophagus	UBERON:0013473	98.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.55	gold quality
left lobe of thyroid gland	UBERON:0001120	98.50	gold quality
saliva-secreting gland	UBERON:0001044	98.49	gold quality
right lobe of thyroid gland	UBERON:0001119	98.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.38	gold quality
tendon of biceps brachii	UBERON:0008188	98.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.32	gold quality
stomach	UBERON:0000945	98.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, JUN, MYC, SP1

miRNA regulators (miRDB)

102 targeting PDHA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-1299	99.77	71.24	2389

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• model of the pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and binding of the E1 and E3 components (PMID:14638692)
• determinant spreading might underlie the autoimmunity against Elalpha. (PMID:14708897)
• PDHA1 gene mutations may have a role in Pyruvate dehydrogenase E1 subunit deficiency (PMID:16713755)
• Molecular genetic analysis of the X-chromosomal E1alpha subunit of PDH showed three new mutations in phylogenetically conserved areas of the protein: Glu358Lys in patient 1; Arg88Lys in patient 2 and 3 (brothers); and Leu216Ser in patient 4. (PMID:16967364)
• Short-term elevation in plasma non-esterified fatty acids at rest increases PDH-E1alpha phosphorylation, but exercise overrules this effect and phosphorylation leads to even dephosphorylation during exercise with intralipid infusion. (PMID:17065338)
• Attenuated PDHa activity contributes to the preferential oxidation of n-6 PUFA during moderate-intensity exercise. (PMID:17947500)
• Resting PDH protein content and phosphorylation on PDH-E1 alpha sites 1 and 2 were higher in vastus lateralis than in triceps and deltoid as was the activity of oxidative enzymes (PMID:17957032)
• two synonymous mutations expand the spectrum of rare PDHA1 splicing mutations, all of which are located in non canonical splice sites. (PMID:18023225)
• Our results encourage the use of amino acid supplementation to overcome the metabolic/biochemical changes induced by PDHA1 gene specific mutations associated with mild pyruvate dehydrogenase complex phenotypes. (PMID:18398624)
• In this study the phenotypes of patients with PDH deficiency have been divided into three groups of mutations. (PMID:19517265)
• AAV3-mediated transfer and expression of the pyruvate dehydrogenase E1 alpha subunit gene causes metabolic remodeling and apoptosis of human liver cancer cells. (PMID:19586787)
• PDHA1 mutations were screened in 40 patients with biochemically demonstrated pyruvate dehydrogenase complex deficiency deficiency or strong clinical suspicion and changes with probable pathological significance were found in 20. (PMID:20002461)
• Novel nonsense mutation (R263X) of the E1alpha subunit in pyruvate dehydrogenase complex deficiency (PMID:20958858)
• We document the broad variability of clinical symptoms of pdha1 deficiency disease. We proved that normal PDHc activity may not exclude the disease. (PMID:21470495)
• 4 affected female patients with PDHA1 mutations who had with severe cortical atrophy, dilated ventricles, and an incomplete corpus callosum. (PMID:21723463)
• TNFalpha can inhibit pulmonary artery smooth muscle cells pyruvate dehydrogenase activity and induce a pulmonary arterial hypertension phenotype. (PMID:21809123)
• Data show that overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner. (PMID:21852536)
• Skin fibroblast culture assay revealed PDH deficiency, confirmed by mutation analysis of the E1 alpha subunit. (PMID:21895644)
• We provide an efficient stepwise strategy for mutation screening in pyruvate dehydrogenase complex genes and expand the growing list of PDHA1 mutations analyzed at the structural level (PMID:21914562)
• Molecular analysis of PDH1A revealed a novel hemizygous c.1045G>A mutation, predicting a p.A349T missense mutation. (PMID:22142326)
• Expression of the PDHA1 gene was found in all somatic cells, whereas expression of PDHA2 gene was restricted to germ cells. The switch from X-linked to autosomic gene expression occurred in spermatocytes. (PMID:22750801)
• In the presence of PPARbeta/delta, Vpr induced a 3.3-fold increase in PPAR response element-driven transcriptional activity, a 1.9-fold increase in PDK4 protein expression, and a 1.6-fold increase in the phosphorylated pyruvate dehydrogenase subunit E1alpha. (PMID:23842279)
• High HK2 expression combined with low phosphorylated PDHA1 expression in the invasive front lesions of colorectal tumors is predictive of tumor aggressiveness and survival. (PMID:25060325)
• Phosphorylation at distinct serine and tyrosine residues inhibits PDHA1 through distinct mechanisms to impact active site accessibility. (PMID:25104357)
• MPO and BPI in CD4(+)T-lymphocytes, and PDHA1 and MRPL42 in CD8(+) T-lymphocytes might be used as specific biomarkers of severe asthma progression. (PMID:26107902)
• oncoprotein HBXIP enhances glucose metabolism reprogramming through suppressing SCO2 and PDHA1 in breast cancer (PMID:26309161)
• Lack of PDHE1alpha protein expression is associated with Esophageal Squamous Cell Carcinoma. (PMID:26408721)
• Data show that metformin reduces hypoxia-inducible factor 1alpha (HIF-1alpha) gene expression and increases pyruvate dehydrogenase (PDH) expression. (PMID:27474170)
• The association of mitochondrial microphthalmia-associated transcription factor (MITF) with pyruvate dehydrogenase (PDH) emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases. (PMID:27871875)
• our results show that negative PDHA1 gene expressionis associated with significantly higher cell stemness in prostate cancer cells and reduced protein expression of this gene is associated with shorter clinical outcome in prostate cancers. (PMID:28076853)
• Findings show that serine-threonine-tyrosine kinase 1 (NOK) mediates glycolysis and nuclear pyruvate dehydrogenase complex (PDC) associated histone acetylation. (PMID:28410146)
• Case demonstrates fetal akinesia deformation sequence due to a de novo hemizygous c.498C > T splice-site mutation in the pyruvate dehydrogenase-alpha 1 (PDHA1) gene. (PMID:28495245)
• The report PDHA1 as a new component of brainstem-type Lewy bodies in idiopathic PD, DLB and PARK14, the level of PDHA1 protein being significantly decreased in the putamen and substantia nigra of patients with idiopathic Parkinson’s disease . (PMID:28564592)
• Both mitochondrial and nuclear Pyruvate dehydrogenase complex sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy. (PMID:29335542)
• our data indicate that reduced PDHA1 protein expression is associated with the poor clinical outcome of HCC. Upregulated PDHA1 gene expression can inhibit the Warburg effect and enhance the mitochondria-mediated apoptosis pathway. (PMID:29444744)
• PGC1alpha reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. (PMID:29700317)
• PDHc E1 mutation i9s associated with Pyruvate dehydrogenase complex deficiency. (PMID:29970614)
• insulin-mediated p-PDHA1 is involved in the regulation of HepG2 cell proliferation through RhoA signaling pathway. (PMID:30226812)
• PDHA1 (P = 0.025) was an independent predictor of overall survival in gastric cancer (PMID:30611622)
• LDHA/PDHA1 changes in Head and Neck Squamous Cell Carcinoma (HNSCC) resulted in a broad metabolic reprogramming while intracellular molecules including polyunsaturated fatty acids and nitrogen metabolism related metabolites underlie the malignant changes. (PMID:31100640)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdha1b	ENSDARG00000010555
danio_rerio	pdha1a	ENSDARG00000012387
mus_musculus	Pdha1	ENSMUSG00000031299
rattus_norvegicus	Pdha1	ENSRNOG00000025383
rattus_norvegicus		ENSRNOG00000084688
drosophila_melanogaster	Pdha	FBGN0028325
drosophila_melanogaster	CG7024	FBGN0029722
caenorhabditis_elegans		WBGENE00011510

Paralogs (2): PDHA2 (ENSG00000163114), BCKDHA (ENSG00000248098)

Protein

Protein identifiers

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial — P08559 (reviewed: P08559)

Alternative names: PDHE1-A type I

All UniProt accessions (7): A0A8Q3WLI8, A0A8Q3WLK5, P08559, Q5JPT9, Q5JPU0, Q5JPU1, Q5JPU2

UniProt curated annotations — full annotation on UniProt →

Function. Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex. The PDH complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). The E1 subunit catalyzes both the thiamine pyrophosphate (TPP)-dependent decarboxylation of pyruvate and the reductive acetylation of a lipoyl group covalently linked to the lipoyl-bearing domains of E2.

Subunit / interactions. Heterotetramer of two PDHA1 and two PDHB subunits. The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase (PDH) complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylation at Ser-232, Ser-293 and Ser-300 by PDK family kinases inactivates the enzyme; for this phosphorylation at a single site is sufficient. Dephosphorylation at all three sites, i.e. at Ser-232, Ser-293 and Ser-300, is required for reactivation. Acetylation alters the phosphorylation pattern. Deacetylated by SIRT3.

Disease relevance. Pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170] An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Pyruvate dehydrogenase activity is inhibited by phosphorylation of PDHA1; it is reactivated by dephosphorylation.

Isoforms (4)

UniProt ID	Names	Canonical?
P08559-1	1	yes
P08559-2	2
P08559-3	3
P08559-4	4

RefSeq proteins (4): NP_000275, NP_001166925, NP_001166926, NP_001166927 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001017	DH_E1	Domain
IPR017597	Pyrv_DH_E1_asu_subgrp-y	Family
IPR029061	THDP-binding	Homologous_superfamily
IPR050642	PDH_E1_Alpha_Subunit	Family

Pfam: PF00676

Enzyme classification (BRENDA):

• EC 1.2.1.104 — pyruvate dehydrogenase system (BRENDA: 46 organisms, 32 substrates, 100 inhibitors, 83 Km, 12 kcat entries)
• EC 1.2.4.1 — pyruvate dehydrogenase (acetyl-transferring) (BRENDA: 29 organisms, 58 substrates, 114 inhibitors, 56 Km, 45 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PYRUVATE	0.0002–1	44
PYRUVATE	0.0011–1.7	32
NAD+	0.01–0.27	14
THIAMINE DIPHOSPHATE	0.0006–0.065	14
COA	0.0005–0.61	12
THIAMINE DIPHOSPHATE	0.0016–0.05	3
LIPOYL DOMAIN	0.024–0.027	2
2-OXOBUTANOATE	1.35	1
2-OXOBUTYRATE	1.66	1
2-OXOISOVALERATE	1.27	1
COENZYME A	0.003	1
HYDROXYETHYL THIAMINE DIPHOSPHATE	0.0082	1
LIPOYL DOMAIN	0.02	1
N-ACETYL-GDLLAEIETDK(LIPOYL)-ATIG-AMIDE	15	1
N-TERMINAL LIPOYL DOMAIN	0.052	1

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + pyruvate + H(+) = N(6)-[(R)-S(8)-acetyldihydrolipoyl]-L-lysyl-[protein] + CO2 (RHEA:19189)

UniProt features (112 total): sequence variant 27, binding site 23, helix 15, modified residue 15, strand 14, sequence conflict 5, turn 4, mutagenesis site 4, splice variant 3, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2OZL	X-RAY DIFFRACTION	1.9
1NI4	X-RAY DIFFRACTION	1.95
3EXE	X-RAY DIFFRACTION	1.98
3EXI	X-RAY DIFFRACTION	2.2
3EXH	X-RAY DIFFRACTION	2.44
6CER	X-RAY DIFFRACTION	2.69
6CFO	X-RAY DIFFRACTION	2.7
3EXF	X-RAY DIFFRACTION	3
3EXG	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08559-F1	94.77	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (23): 167; 167; 196; 196; 196; 197; 197; 198; 198; 225; 92; 225 …

Post-translational modifications (15): 63, 63, 232, 244, 244, 277, 293, 295, 300, 301, 313, 313, 321, 336, 385

Mutagenesis-validated functional residues (4):

Position	Phenotype
232	abolishes inactivation by phosphorylation; when associated with a-293 and a-300.
293	reduces enzyme activity. abolishes inactivation by phosphorylation; when associated with a-232 and a-300.
293	interferes with substrate binding.
300	abolishes inactivation by phosphorylation; when associated with a-232 and a-293.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9861559	PDH complex synthesizes acetyl-CoA from PYR

MSigDB gene sets: 365 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, GOBP_AMIDE_BIOSYNTHETIC_PROCESS

GO Biological Process (3): glucose metabolic process (GO:0006006), pyruvate decarboxylation to acetyl-CoA (GO:0006086), tricarboxylic acid cycle (GO:0006099)

GO Molecular Function (5): pyruvate dehydrogenase (acetyl-transferring) activity (GO:0004739), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor (GO:0016624)

GO Cellular Component (7): nucleus (GO:0005634), nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), pyruvate dehydrogenase complex (GO:0045254), intracellular membrane-bounded organelle (GO:0043231), oxidoreductase complex (GO:1990204)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Metabolism of proteins	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic respiration	2
intracellular membrane-bounded organelle	2
hexose metabolic process	1
dihydrolipoyl dehydrogenase (NADH) activity	1
pyruvate dehydrogenase (acetyl-transferring) activity	1
dihydrolipoyllysine-residue acetyltransferase activity	1
acetyl-CoA biosynthetic process	1
pyruvate metabolic process	1
primary metabolic process	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor	1
cation binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
acetyltransferase complex	1
intracellular anatomical structure	1
membrane-bounded organelle	1
intracellular organelle	1
catalytic complex	1

Protein interactions and networks

STRING

3990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDHA1	PDHB	P11177	999
PDHA1	DLD	P09622	991
PDHA1	PDHX	O00330	988
PDHA1	DLAT	P10515	985
PDHA1	PDK3	Q15120	881
PDHA1	PDP2	Q9P2J9	815
PDHA1	SDHA	P31040	783
PDHA1	NDUFV1	P49821	772
PDHA1	SMPX	Q9UHP9	763
PDHA1	MDH2	P40926	761
PDHA1	PDP1	Q9P0J1	732
PDHA1	PDK1	Q15118	715
PDHA1	GLUD1	P00367	706
PDHA1	OGDH	Q02218	685
PDHA1	ITGB1BP2	Q9UKP3	683

IntAct

101 interactions, top by confidence:

A	B	Type	Score
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PDHB	PDHA1	psi-mi:“MI:0407”(direct interaction)	0.690
STAT5A	PDHA1	psi-mi:“MI:0914”(association)	0.640
PDK1	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.570
PDK3	PDHX	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
STAT5A	PDHX	psi-mi:“MI:0914”(association)	0.530
CFTR	PDHA1	psi-mi:“MI:0915”(physical association)	0.520
PDHA1	IMMT	psi-mi:“MI:0915”(physical association)	0.500
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
PDHA1	AKT2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDK2	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDK3	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDK4	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDP1	PDHA1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
STAT5B	PDHX	psi-mi:“MI:0914”(association)	0.350
STAT5A	R3HDM2	psi-mi:“MI:0914”(association)	0.350
HDAC6	GLOD5	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
ORF70	PDHX	psi-mi:“MI:0914”(association)	0.350
COQ2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350

BioGRID (947): PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), ATP1B1 (Co-fractionation), DLAT (Co-fractionation), PDHA1 (Co-fractionation), PDHA1 (Co-fractionation), PDHA1 (Co-fractionation), PDHA1 (Co-fractionation), PDHA1 (Co-fractionation), PDHA1 (Co-fractionation)

ESM2 similar proteins: A0A2I2F2I5, A5A6L0, A7MB35, G0SHF3, O13366, O33112, O60028, P07342, P08559, P09114, P09342, P0A623, P0AEP7, P0AEP8, P0DN31, P14874, P16387, P17597, P25374, P26267, P26268, P26284, P27818, P27819, P29804, P33280, P35486, P36620, P42463, P52899, P52901, P52903, P87185, P87187, P9WG40, P9WG41, Q10489, Q12611, Q41768, Q41769

Diamond homologs: A5A6L0, A7MB35, G0SHF3, O13366, O24457, O31404, O66112, P08559, P09060, P16387, P21881, P26267, P26268, P26284, P27745, P29803, P29804, P35485, P35486, P35487, P37940, P51267, P52899, P52900, P52901, P52902, P52903, P60089, P60090, P9WIS2, P9WIS3, Q06437, Q10489, Q1RJX4, Q1XDM0, Q4MTG0, Q4UKQ6, Q54C70, Q5HGZ1, Q5R490

SIGNOR signaling

36 interactions.

A	Effect	B	Mechanism
PDK2	down-regulates	PDHA1	phosphorylation
PDK4	down-regulates	PDHA1	phosphorylation
PDP1	“up-regulates activity”	PDHA1	dephosphorylation
PDP2	“up-regulates activity”	PDHA1	dephosphorylation
PDHA1	“form complex”	PDH	binding
SIRT3	“down-regulates activity”	PDHA1	deacetylation
SRC	“down-regulates activity”	PDHA1	phosphorylation
PDK1	“down-regulates activity”	PDHA1	phosphorylation
PDK2	“down-regulates activity”	PDHA1	phosphorylation
PDK3	“down-regulates activity”	PDHA1	phosphorylation
PDK4	“down-regulates activity”	PDHA1	phosphorylation
ACAT1	“down-regulates activity”	PDHA1	acetylation
AMPK	“up-regulates activity”	PDHA1	phosphorylation
PRKAA1	“up-regulates activity”	PDHA1	phosphorylation
PRKAA2	“up-regulates activity”	PDHA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 101 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of pyruvate dehydrogenase (PDH) complex	8	75.1×	2e-11
Signaling by Retinoic Acid	7	37.6×	1e-07
Signaling by FGFR1 in disease	5	19.3×	9e-04
Transcriptional regulation of white adipocyte differentiation	5	8.5×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
insulin receptor signaling pathway	7	18.1×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

980 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	226
Likely pathogenic	152
Uncertain significance	145
Likely benign	229
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028668	NM_000284.4(PDHA1):c.899+2T>A	Pathogenic
10871	NM_000284.4(PDHA1):c.1167_1170del (p.Ser390fs)	Pathogenic
10872	NM_000284.4(PDHA1):c.934_940del (p.Ser312fs)	Pathogenic
10874	NM_000284.4(PDHA1):c.938_940del (p.Lys313del)	Pathogenic
10875	NM_000284.4(PDHA1):c.1159_1160del (p.Lys387fs)	Pathogenic
10876	NM_000284.4(PDHA1):c.1073_1092del (p.Glu358fs)	Pathogenic
10878	NM_000284.4(PDHA1):c.787C>G (p.Arg263Gly)	Pathogenic
10879	NM_000284.4(PDHA1):c.904C>T (p.Arg302Cys)	Pathogenic
10880	NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)	Pathogenic
10881	NM_000284.4(PDHA1):c.773A>C (p.Asp258Ala)	Pathogenic
10883	NM_000284.4(PDHA1):c.727T>A (p.Tyr243Asn)	Pathogenic
10886	NM_000284.4(PDHA1):c.861_862insT (p.Arg288fs)	Pathogenic
10888	NM_000284.4(PDHA1):c.991_1003dup (p.Leu335fs)	Pathogenic
10889	NM_000284.4(PDHA1):c.1074_1109dup (p.Pro359_Ser370dup)	Pathogenic
10890	NM_000284.4(PDHA1):c.863G>A (p.Arg288His)	Pathogenic
10891	NM_000284.4(PDHA1):c.*79_*90dup	Pathogenic
1188095	NM_000284.4(PDHA1):c.498C>T (p.Ile166=)	Pathogenic
1190221	NM_000284.4(PDHA1):c.787C>T (p.Arg263Ter)	Pathogenic
1201931	NM_000284.4(PDHA1):c.900-1_902dup	Pathogenic
1220221	NM_000284.4(PDHA1):c.1162_*1del (p.Ser388fs)	Pathogenic
1252070	NM_000284.4(PDHA1):c.728A>G (p.Tyr243Cys)	Pathogenic
1323430	NM_000284.4(PDHA1):c.1133_1140del (p.Arg378fs)	Pathogenic
1519076	NM_000284.4(PDHA1):c.902_907del (p.Tyr301_Thr303delinsSer)	Pathogenic
2000808	NM_000284.4(PDHA1):c.653G>A (p.Cys218Tyr)	Pathogenic
2092211	NM_000284.4(PDHA1):c.956_959dup (p.Lys321fs)	Pathogenic
2119720	NM_000284.4(PDHA1):c.688_700del (p.Gly230fs)	Pathogenic
2121087	NM_000284.4(PDHA1):c.1043_1053del (p.Asp348fs)	Pathogenic
214935	NM_000284.4(PDHA1):c.910C>T (p.Arg304Ter)	Pathogenic
214936	NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)	Pathogenic
214939	NM_000284.4(PDHA1):c.292-1G>A	Pathogenic

SpliceAI

1739 predictions. Top by Δscore:

Variant	Effect	Δscore
X:19344043:G:GT	donor_gain	1.0000
X:19344091:GCCG:G	donor_gain	1.0000
X:19344092:CCGGT:C	donor_loss	1.0000
X:19344093:CGGT:C	donor_loss	1.0000
X:19344094:GGTGA:G	donor_loss	1.0000
X:19344095:G:GG	donor_gain	1.0000
X:19349307:TTAA:T	acceptor_loss	1.0000
X:19349308:TAA:T	acceptor_loss	1.0000
X:19349309:A:AG	acceptor_gain	1.0000
X:19349309:AAG:A	acceptor_gain	1.0000
X:19349309:AAGG:A	acceptor_loss	1.0000
X:19349310:A:G	acceptor_gain	1.0000
X:19349311:G:GA	acceptor_loss	1.0000
X:19349311:G:GG	acceptor_gain	1.0000
X:19349930:A:AG	acceptor_gain	1.0000
X:19349932:TTCA:T	acceptor_loss	1.0000
X:19349935:A:AG	acceptor_gain	1.0000
X:19349936:G:GT	acceptor_gain	1.0000
X:19349936:GA:G	acceptor_gain	1.0000
X:19349936:GAA:G	acceptor_gain	1.0000
X:19349936:GAAA:G	acceptor_gain	1.0000
X:19349936:GAAAT:G	acceptor_gain	1.0000
X:19350059:GCT:G	donor_gain	1.0000
X:19350107:TCAG:T	donor_loss	1.0000
X:19350109:AGGT:A	donor_loss	1.0000
X:19350110:GGTG:G	donor_loss	1.0000
X:19350111:G:C	donor_loss	1.0000
X:19350112:T:A	donor_loss	1.0000
X:19351274:A:AG	acceptor_gain	1.0000
X:19351277:A:AG	acceptor_gain	1.0000

AlphaMissense

2561 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:19350033:C:A	R72S	1.000
X:19350034:G:C	R72P	1.000
X:19350037:G:C	R73P	1.000
X:19350051:G:C	A78P	1.000
X:19350061:T:C	L81P	1.000
X:19350084:G:C	G89R	1.000
X:19350085:G:A	G89D	1.000
X:19350087:T:A	F90I	1.000
X:19350087:T:C	F90L	1.000
X:19350087:T:G	F90V	1.000
X:19350088:T:G	F90C	1.000
X:19350089:C:A	F90L	1.000
X:19350089:C:G	F90L	1.000
X:19350090:T:C	C91R	1.000
X:19350091:G:A	C91Y	1.000
X:19350092:T:G	C91W	1.000
X:19350093:C:A	H92N	1.000
X:19350093:C:G	H92D	1.000
X:19350094:A:G	H92R	1.000
X:19350095:C:A	H92Q	1.000
X:19350095:C:G	H92Q	1.000
X:19350105:G:C	G96R	1.000
X:19350105:G:T	G96C	1.000
X:19350106:G:A	G96D	1.000
X:19350106:G:T	G96V	1.000
X:19351402:T:C	L138P	1.000
X:19353112:G:A	G150E	1.000
X:19353115:G:A	G151E	1.000
X:19353148:G:A	G162E	1.000
X:19353156:G:C	G165R	1.000

dbSNP variants (sampled 300 via entrez): RS1000013914 (X:19353933 T>G), RS1000146124 (X:19353510 G>A,T), RS1000523769 (X:19345203 C>A,T), RS1000527694 (X:19344199 C>T), RS1000596812 (X:19343210 C>T), RS1000675859 (X:19353826 G>C), RS1000809999 (X:19360641 G>A,C), RS1001062781 (X:19344701 C>T), RS1001802005 (X:19343622 C>A), RS1001944839 (X:19352374 A>C), RS1002356738 (X:19351134 A>C,G), RS1002526264 (X:19347621 G>A), RS1002557265 (X:19347237 C>G), RS1002885901 (X:19357213 T>C), RS1003026438 (X:19346089 G>A)

Disease associations

OMIM: gene MIM:300502 | disease phenotypes: MIM:312170

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate dehydrogenase E1-alpha deficiency	Definitive	X-linked
Leigh syndrome	Definitive	X-linked
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	XL
Leigh syndrome	Definitive	XL

Mondo (5): pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717), pyruvate dehydrogenase deficiency (MONDO:0019169), intellectual disability (MONDO:0001071), Leigh syndrome (MONDO:0009723), (MONDO:0016815)

Orphanet (3): Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243), Pyruvate dehydrogenase deficiency (Orphanet:765), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000431	Wide nasal bridge
HP:0000454	Flared nostrils
HP:0000463	Anteverted nares
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000618	Blindness
HP:0000707	Abnormality of the nervous system
HP:0000954	Single transverse palmar crease
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001338	Partial agenesis of the corpus callosum
HP:0001371	Flexion contracture
HP:0001423	X-linked dominant inheritance
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001629	Ventricular septal defect
HP:0001761	Pes cavus
HP:0001883	Talipes

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_309	Metabolite levels	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010430	triacylglycerol 56:3 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2092 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.04	Kd	92.05	nM	CHEMBL3752910
6.99	ED50	101.3	nM	CHEMBL3752910
6.35	Kd	447.3	nM	CHEMBL5653589
6.31	ED50	492.4	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148959: Binding affinity to human PDHA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0921	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148959: Binding affinity to human PDHA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.4473	uM

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	3
Valproic Acid	affects expression, increases expression	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Dichloroacetic Acid	decreases phosphorylation, decreases reaction	2
VER-246608	decreases phosphorylation	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
kojic acid	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
methylparaben	increases expression	1
2,6-dichloro-4-nitrophenol	decreases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases abundance, increases expression	1
perfluorooctanoic acid	increases expression	1
quinoline	increases expression	1
epigallocatechin gallate	decreases expression, decreases reaction	1
brequinar	decreases expression	1
dinophysistoxin 1	affects expression	1
di-n-butylphosphoric acid	affects expression	1
JP8 aviation fuel	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
AZD 7545	decreases phosphorylation	1
picoxystrobin	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652001	Binding	Binding affinity to human PDHA1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 finite cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5M50	GM12212	Finite cell line	Male
CVCL_B2AC	Abcam HeLa PDHA1 KO	Cancer cell line	Female
CVCL_D9MH	Ubigene HEK293 PDHA1 KO	Transformed cell line	Female
CVCL_E0JU	Ubigene HeLa PDHA1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

216 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02616484	PHASE3	ACTIVE_NOT_RECRUITING	Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT03734263	PHASE2	COMPLETED	Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT06340685	PHASE1	RECRUITING	Triheptanoin for Children With Primary-Specific Pyruvate Dehydrogenase Complex (PDC) Deficiency
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT06931262	Not specified	AVAILABLE	Expanded Access Treatment Protocol With DCA for Patients With PDCD
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder