pyruvate dehydrogenase E2 deficiency

Summary

pyruvate dehydrogenase E2 deficiency (MONDO:0009502) is a disease caused by DLAT (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: DLAT (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 237
• Phenotypes (HPO): 32
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0100503	Low levels of vitamin B1	Very frequent (80-99%)
HP:0500231	Abnormal CSF pyruvate family amino acid concentration	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000546	Retinal degeneration	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002180	Neurodegeneration	Frequent (30-79%)
HP:0002268	Paroxysmal dystonia	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002454	Eye of the tiger anomaly of globus pallidus	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0005656	Positional foot deformity	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0025331	Upgaze palsy	Frequent (30-79%)
HP:0025335	Delayed ability to stand	Frequent (30-79%)
HP:0031139	Frog-leg posture	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0031960	Arm dystonia	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0007994	Peripheral visual field loss	Occasional (5-29%)
HP:0011098	Speech apraxia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase E2 deficiency
Mondo ID	MONDO:0009502
MeSH	C565448
OMIM	245348
Orphanet	79244
UMLS	C1855565
MedGen	343386
GARD	0016712
Is cancer (heuristic)	no

Also known as: dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex deficiency · dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex deficiency · PDHDD · pyruvate dehydrogenase complex component E2 deficiency · pyruvate dehydrogenase E2 deficiency

Data availability: 237 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 E2 deficiency

Related subtypes (6): pyruvate dehydrogenase E3-binding protein deficiency, pyruvate dehydrogenase E3 deficiency, pyruvate dehydrogenase E1-alpha deficiency, pyruvate dehydrogenase phosphatase deficiency, pyruvate dehydrogenase E1-beta deficiency, lipoic acid synthetase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

237 retrieved; paginated sample, class counts are floors:

106 likely benign, 84 uncertain significance, 13 benign, 13 conflicting classifications of pathogenicity, 7 likely pathogenic, 7 pathogenic, 5 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2109	NM_001931.5(DLAT):c.362_364del (p.Glu121del)	DLAT	Pathogenic	no assertion criteria provided
2196317	NM_001931.5(DLAT):c.412G>T (p.Glu138Ter)	DLAT	Pathogenic	criteria provided, multiple submitters, no conflicts
2424324	NC_000011.9:g.(?111896197)(111899689_?)del	DLAT	Pathogenic	criteria provided, single submitter
2764118	NM_001931.5(DLAT):c.802del (p.Glu268fs)	DLAT	Pathogenic	criteria provided, single submitter
2778456	NM_001931.5(DLAT):c.723dup (p.Val242fs)	DLAT	Pathogenic	criteria provided, single submitter
2793499	NM_001931.5(DLAT):c.1303C>T (p.Arg435Ter)	DLAT	Pathogenic	criteria provided, multiple submitters, no conflicts
2916183	NM_001931.5(DLAT):c.568C>T (p.Gln190Ter)	DLAT	Pathogenic	criteria provided, single submitter
432212	NM_001931.5(DLAT):c.976-1G>A	DLAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434944	NM_001931.5(DLAT):c.848_849del (p.Asp283fs)	DLAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252016	NM_001931.5(DLAT):c.975G>A (p.Pro325=)	DLAT	Likely pathogenic	criteria provided, single submitter
208790	NM_001931.5(DLAT):c.470T>G (p.Val157Gly)	DLAT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2782037	NM_001931.5(DLAT):c.381+1G>T	DLAT	Likely pathogenic	criteria provided, single submitter
3234969	NM_001931.5(DLAT):c.476del (p.Ile159fs)	DLAT	Likely pathogenic	criteria provided, single submitter
3598993	NM_001931.5(DLAT):c.1030del (p.Cys344fs)	DLAT	Likely pathogenic	criteria provided, single submitter
3598994	NM_001931.5(DLAT):c.1515-1G>T	DLAT	Likely pathogenic	criteria provided, single submitter
3912013	NM_001931.5(DLAT):c.156T>A (p.Tyr52Ter)	DLAT	Likely pathogenic	criteria provided, single submitter
1312384	NM_001931.5(DLAT):c.1382G>A (p.Arg461Gln)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1454240	NM_001931.5(DLAT):c.109C>G (p.Arg37Gly)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1661511	NM_001931.5(DLAT):c.1735A>G (p.Ile579Val)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2110	NM_001931.5(DLAT):c.1728C>A (p.Phe576Leu)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214293	NM_001931.5(DLAT):c.583C>T (p.Pro195Ser)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289331	NM_001931.5(DLAT):c.165C>G (p.Val55=)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302456	NM_001931.5(DLAT):c.946C>T (p.Pro316Ser)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302458	NM_001931.5(DLAT):c.991C>G (p.Pro331Ala)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3502227	NM_001931.5(DLAT):c.158G>T (p.Gly53Val)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3602442	NM_001931.5(DLAT):c.953_954inv (p.Val318Ala)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439604	NM_001931.5(DLAT):c.976-2del	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
596741	NM_001931.5(DLAT):c.382G>A (p.Val128Ile)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
785773	NM_001931.5(DLAT):c.1636A>G (p.Thr546Ala)	DLAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2422869	NC_000011.9:g.(?111171709)(112104278_?)dup	ALG9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
DLAT	Definitive	Autosomal recessive	pyruvate dehydrogenase E2 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLAT	Orphanet:79244	Pyruvate dehydrogenase E2 deficiency
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG

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
DLAT	HGNC:2896	ENSG00000150768	P10515	Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial	gencc,clinvar
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	clinvar
PIH1D2	HGNC:25210	ENSG00000150773	Q8WWB5	PIH1 domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLAT	Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial	The pyruvate dehydrogenase (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.
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLAT	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
PIH1D2	Other/Unknown	no		PIH1_N, PIH1D1/2/3_CS-like, PIH1/Kintoun_subfamily

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	1
heart right ventricle	1
left ventricle myocardium	1
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
left testis	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLAT	295	ubiquitous	marker	heart right ventricle, biceps brachii, left ventricle myocardium
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
PIH1D2	174	broad	marker	left testis, right testis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLAT	3,854
ALG9	1,167
PIH1D2	1,092

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLAT	P10515	13
ALG9	Q9H6U8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIH1D2	Q8WWB5	78.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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
Defective ALG9 causes CDG-1l	1	5710.0×	0.002	ALG9
PDH complex synthesizes acetyl-CoA from PYR	1	815.7×	0.008	DLAT
Protein lipoylation	1	519.1×	0.008	DLAT
Regulation of pyruvate dehydrogenase (PDH) complex	1	356.9×	0.008	DLAT
Diseases associated with N-glycosylation of proteins	1	317.2×	0.008	ALG9
Signaling by Retinoic Acid	1	203.9×	0.011	DLAT
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.018	ALG9
Diseases of glycosylation	1	65.6×	0.025	ALG9
Diseases of metabolism	1	40.2×	0.036	ALG9
Asparagine N-linked glycosylation	1	30.1×	0.043	ALG9
Post-translational protein modification	1	9.6×	0.120	ALG9
Disease	1	6.5×	0.155	ALG9
Metabolism of proteins	1	6.2×	0.155	ALG9

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
pyruvate decarboxylation to acetyl-CoA	1	702.2×	0.005	DLAT
pyruvate catabolic process	1	702.2×	0.005	DLAT
box C/D snoRNP assembly	1	561.7×	0.005	PIH1D2
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.008	ALG9
tricarboxylic acid cycle	1	170.2×	0.011	DLAT
protein N-linked glycosylation	1	87.8×	0.015	ALG9
glucose metabolic process	1	85.1×	0.015	DLAT
rRNA processing	1	47.2×	0.024	PIH1D2
protein stabilization	1	22.3×	0.044	PIH1D2

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
DLAT	0	0
ALG9	0	0
PIH1D2	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
DLAT	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DLAT	1.2.1.104, 2.3.1.12	pyruvate dehydrogenase system, dihydrolipoyllysine-residue acetyltransferase
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase

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	2	DLAT, ALG9
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PIH1D2

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)
DLAT	3	—
ALG9	0	—
PIH1D2	0	—

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