Triosephosphate isomerase deficiency

Summary

Triosephosphate isomerase deficiency (MONDO:0014221) is a disease caused by TPI1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TPI1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 82
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0007009	Central nervous system degeneration	Very frequent (80-99%)
HP:0010978	Abnormality of immune system physiology	Very frequent (80-99%)
HP:0006597	Diaphragmatic paralysis	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	triosephosphate isomerase deficiency
Mondo ID	MONDO:0014221
MeSH	C566029
OMIM	615512
Orphanet	868
DOID	DOID:0050884
NCIT	C131652
SNOMED CT	234405009
UMLS	C1860808
MedGen	349893
GARD	0005287
NORD	1793
Is cancer (heuristic)	no

Also known as: hemolytic anaemia due to triosephosphate isomerase deficiency · hemolytic anemia due to triosephosphate isomerase deficiency · TPI deficiency · TPID · triose phosphate-isomerase deficiency · triosephosphate isomerase deficiency

Data availability: 82 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glucose metabolism disease › triosephosphate isomerase deficiency

Related subtypes (8): glucose intolerance, hyperinsulinism, hyperglycemia, hypoglycemia, diabetes mellitus, prediabetes syndrome, disorder of gluconeogenesis, glyceraldehyde-3-phosphate dehydrogenase 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

82 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 11 conflicting classifications of pathogenicity, 9 benign, 8 likely benign, 6 pathogenic, 4 benign/likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12468	NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)	TPI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12471	NM_000365.6(TPI1):c.125G>A (p.Cys42Tyr)	TPI1	Pathogenic	no assertion criteria provided
12472	NM_000365.6(TPI1):c.511A>G (p.Ile171Val)	TPI1	Pathogenic	no assertion criteria provided
12473	NM_000365.6(TPI1):c.436G>T (p.Glu146Ter)	TPI1	Pathogenic	no assertion criteria provided
136172	NM_000365.6(TPI1):c.722T>C (p.Phe241Ser)	TPI1	Pathogenic	no assertion criteria provided
136173	NM_000365.6(TPI1):c.32dup (p.Asn12fs)	TPI1	Pathogenic	no assertion criteria provided
4538464	TPI1, IVS3, +1, C-G	TPI1	Pathogenic	no assertion criteria provided
1698892	NM_000365.6(TPI1):c.544-1G>C	TPI1	Likely pathogenic	criteria provided, single submitter
3065734	NM_000365.6(TPI1):c.32del (p.Gly11fs)	TPI1	Likely pathogenic	criteria provided, single submitter
1330976	NM_000365.6(TPI1):c.-29C>G	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1642638	NM_000365.6(TPI1):c.458-18del	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685182	NM_000365.6(TPI1):c.463G>A (p.Val155Met)	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310358	NM_000365.6(TPI1):c.239+8C>A	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310359	NM_000365.6(TPI1):c.261C>T (p.Cys87=)	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310361	NM_000365.6(TPI1):c.543+5C>G	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719916	NM_000365.6(TPI1):c.366C>T (p.Leu122=)	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811143	NC_000012.12:g.6867505T>G	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881407	NM_000365.6(TPI1):c.192G>A (p.Ala64=)	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881844	NM_000365.6(TPI1):c.558C>T (p.His186=)	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
994232	NC_000012.12:g.6867486C>T	TPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12470	NM_000365.6(TPI1):c.721T>C (p.Phe241Leu)	TPI1	Uncertain significance	criteria provided, single submitter
1330792	NM_000365.6(TPI1):c.383T>C (p.Ile128Thr)	TPI1	Uncertain significance	criteria provided, single submitter
1432423	NM_000365.6(TPI1):c.730A>G (p.Ile244Val)	TPI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1526032	NM_000365.6(TPI1):c.694G>A (p.Val232Met)	TPI1	Uncertain significance	criteria provided, single submitter
1809736	NM_000365.6(TPI1):c.49G>A (p.Gly17Arg)	TPI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2399754	NM_000365.6(TPI1):c.434T>C (p.Phe145Ser)	TPI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437189	NM_000365.6(TPI1):c.409G>C (p.Ala137Pro)	TPI1	Uncertain significance	criteria provided, single submitter
2437190	NM_000365.6(TPI1):c.673C>A (p.Pro225Thr)	TPI1	Uncertain significance	criteria provided, single submitter
2437191	NM_000365.6(TPI1):c.453C>G (p.Ile151Met)	TPI1	Uncertain significance	criteria provided, single submitter
2437192	NM_000365.6(TPI1):c.478A>G (p.Lys160Glu)	TPI1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TPI1	Strong	Autosomal recessive	triosephosphate isomerase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPI1	Orphanet:868	Triose phosphate-isomerase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPI1	HGNC:12009	ENSG00000111669	P60174	Triosephosphate isomerase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPI1	Triosephosphate isomerase	Triosephosphate isomerase is an extremely efficient metabolic enzyme that catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde-3-phosphate (G3P) in glycolysis and gluconeogenesis.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPI1	Enzyme (other)	yes	5.3.1.1	Triosephosphate_isomerase, Aldolase_TIM, Triosephosphate_isomerase_AS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPI1	308	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPI1	510

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPI1	P60174	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gluconeogenesis	1	439.2×	0.004	TPI1
Glycolysis	1	285.5×	0.004	TPI1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
methylglyoxal biosynthetic process	1	16852.0×	4e-04	TPI1
glyceraldehyde-3-phosphate biosynthetic process	1	4213.0×	7e-04	TPI1
glycerol catabolic process	1	2407.4×	8e-04	TPI1
canonical glycolysis	1	702.2×	0.002	TPI1
glycolytic process	1	383.0×	0.003	TPI1
gluconeogenesis	1	324.1×	0.003	TPI1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TPI1	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPI1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEXAROTENE	4	TPI1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TPI1	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPI1	5.3.1.1	triose-phosphate isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
BEXAROTENE	4	TPI1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TPI1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.