Triosephosphate Isomerase Deficiency

Mendelian MONDO:0014221 Pathograph 28 Show in embeddings browser Inborn Error of Metabolism

Triosephosphate isomerase deficiency is an autosomal-recessive multisystem glycolytic disorder caused by biallelic pathogenic variants in TPI1. Its classical clinical combination is congenital or early-onset chronic hemolytic anemia with variably progressive neurologic and neuromuscular dysfunction; hypotonia, muscle weakness and wasting, movement abnormalities, recurrent infections, respiratory failure, and occasional cardiomyopathy broaden the phenotype. The recurrent p.Glu105Asp variant (historically called E104D when the initiator methionine was omitted) disrupts dimer stability despite retaining near-normal catalytic activity in purified protein. Other alleles can impair catalysis, stability, or both. Human-cell and animal studies therefore support variant-specific protein instability and tissue-dependent TPI abundance as important determinants, while low catalytic activity alone is insufficient to produce disease in a mouse model. Erythrocyte DHAP accumulation and methylglyoxal/glycation-redox abnormalities are measured in affected people, but their causal contribution to neurodegeneration remains unresolved. There is no proven disease-modifying therapy; management is supportive and tailored to hematologic, respiratory, nutritional, and neuromuscular needs.

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1
Mappings
1
Inheritance
12
Pathophys.
11
Phenotypes
2
Hypotheses
2
Gaps
28
Pathograph
1
Genes
1
Medical Actions
4
Models
19
References
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Classifications

ICIMD (Inherited Metabolic Disorders)
glycolysis
🔗

Mappings

MONDO
MONDO:0014221 triosephosphate isomerase deficiency
skos:exactMatch MONDO
MONDO:0014221 is the exact disease concept and carries the corresponding OMIM:615512 and Orphanet ORPHA:868 cross-references.
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:40897044 SUPPORT Other
"TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1."
Explicitly establishes autosomal-recessive inheritance.
◈

Mechanistic Hypotheses

2
Variant-specific stability and tissue-abundance model
tpi_stability_tissue_abundance_model EMERGING
Evidence balance 2 support
Pathogenicity and clinical severity depend more strongly on mutant-protein instability and tissue-dependent steady-state TPI abundance than on reduced catalytic activity alone. This model is supported by human structural and fibroblast data and by a stable low-activity mouse that does not develop the disease, but the tissue-specific bridge to human neuromuscular injury is not fully resolved.
Pathograph links
Variant-Specific TPI1 Dysfunction -> Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance DIRECT Destabilizing variants reduce dimer formation or accelerate protein turnover, lowering steady-state TPI abundance in a tissue- and allele-dependent manner.
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance -> Progressive Central and Neuromuscular Dysfunction INDIRECT UNKNOWN INTERMEDIATES Low or unstable TPI protein is associated with the severe neuromuscular phenotype, but the intervening human neural, synaptic, and muscle events are not established.
Show evidence (2 references)
PMID:31111503 SUPPORT Model Organism
"Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency."
The stable I170V mouse separates catalytic loss from instability and falsifies a simple low-activity-only mechanism.
PMID:35315486 SUPPORT In Vitro
"These data suggest that impaired stability, and not catalytic activity, is a better predictor of TPI Df severity."
Human variant and patient-fibroblast data support the stability/abundance model while retaining it as a predictor rather than a complete mechanism.
DHAP-methylglyoxal/glycation-redox neurotoxicity model
tpi_methylglyoxal_glycation_stress_model ALTERNATIVE
Evidence balance 1 support
Accumulated DHAP can form methylglyoxal, advanced glycation products, and oxidative or nitrosative stress. These abnormalities are demonstrated in blood from one phenotypically discordant family, but a causal neural-tissue pathway has not been shown.
Pathograph links
Erythrocyte Triose-Phosphate Imbalance and Reduced Integrity -> Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress INDIRECT UNKNOWN INTERMEDIATES Blood and erythrocyte DHAP-associated methylglyoxal and glycation-redox stress form a candidate neurotoxic arm, but the systemic-to-neural bridge is unobserved and human measurements currently come from blood and urine.
Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress -> Progressive Central and Neuromuscular Dysfunction INDIRECT UNKNOWN INTERMEDIATES Methylglyoxal/glycation-redox stress may contribute to neurologic disease, but the intervening human neural mechanism is unknown.
Show evidence (1 reference)
PMID:14559119 SUPPORT Human Clinical
"The increased derangement of MG metabolism and associated glycation, oxidative and nitrosative stress in the propositus may be linked to neurodegenerative process in triosephosphate isomerase deficiency."
The source itself uses associative language, so it supports an alternative hypothesis rather than an established causal arm.
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Discussions and Knowledge Gaps

2
Which variant- and tissue-dependent event is causally necessary for human neurologic and neuromuscular disease: loss of stable TPI protein, DHAP-methylglyoxal/glycation-redox stress, proteostasis/aggregation, synaptic or neuromuscular-junction dysfunction, or a combination?
KNOWLEDGE GAP OPEN gap_tpi_human_neuromuscular_causal_bridge
Attached to
pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress pathophysiology#Progressive Central and Neuromuscular Dysfunction
Genotype-matched brothers can differ neurologically; a stable low-activity mouse remains well; methylglyoxal evidence is associative and blood-based; and the positive mouse reveals several candidate tissue lesions. Resolving causal necessity is essential for choosing between protein stabilization, metabolic detoxification, and neural or muscle-directed therapies.
Proposed experiments
Isogenic human motor-unit mechanism dissection
tpi_isogenic_human_motor_unit_mechanism_dissection
Generate genotype-corrected and p.Glu105Asp/null isogenic human iPSC motor neurons co-cultured with skeletal muscle. Independently restore TPI protein stability or modulate methylglyoxal detoxification, then measure TPI abundance and turnover, DHAP/MG/AGE-redox markers, neuronal survival, synaptic release, NMJ transmission, and muscle contraction over time.
Readouts
TPI abundance, turnover, and tissue threshold
pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
Methylglyoxal/glycation-redox burden
pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
Motor-neuron, NMJ, and muscle functional rescue
pathophysiology#Progressive Central and Neuromuscular Dysfunction
Decision criterion
A perturbation that rescues neural/NMJ/muscle function while selectively normalizing one candidate arm would support causal necessity; dissociation of biomarkers from functional rescue would argue against that arm as the primary driver.
Would support
pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress pathophysiology#Progressive Central and Neuromuscular Dysfunction
Show evidence (3 references)
PMID:17424909 SUPPORT Other
"Two germ-line identical Hungarian compound heterozygote brothers with distinct phenotypes question the exclusive role of the inherited mutations in the etiology of neurodegeneration."
Human phenotypic discordance shows that genotype alone does not resolve the neural mechanism.
PMID:12023819 SUPPORT Other
"the mutations of TPI explain in themselves neither the severe decrease in the enzyme activity characteristic of TPI deficiency nor the enhanced ability of the mutant enzyme from haemolysate of the propositus to associate with subcellular particles."
The misfolding literature itself identifies unexplained steps beyond the variants.
PMID:40897044 SUPPORT Other
"Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear."
A current review explicitly identifies the exact pathomechanism as unresolved.
How faithfully do the E105D/null mouse, sugarkill fly, stable low-activity mouse, and patient fibroblast reproduce the cell-type-specific mechanisms of human embryonic and childhood motor-system disease?
HUMAN MODEL MISMATCH OPEN mismatch_tpi_models_to_human_motor_system
Attached to
animal_models#Tpi1 p.Glu105Asp/null mouse animal_models#Stable low-activity Tpi1 p.Ile170Val mouse animal_models#sugarkill TPI-mutant fly experimental_models#TPI p.Gln181Pro/p.Glu105Asp patient-fibroblast stability model pathophysiology#Progressive Central and Neuromuscular Dysfunction
The positive mouse has a compressed lethal course and a compound genotype, the negative mouse deliberately lacks the stability defect, the fly lacks mammalian erythrocyte and respiratory physiology, and fibroblasts do not model motor neurons or muscle. Cross-model agreement generates candidates but cannot by itself establish the corresponding human cellular mechanism.
Proposed experiments
Cross-model human neural concordance study
tpi_cross_model_human_neural_concordance
Compare matched longitudinal proteomic, metabolomic, and functional signatures across human isogenic motor neurons/muscle, E105D/null mouse brain-spinal cord-NMJ-muscle, stable I170V mouse, and sugarkill fly, using prespecified orthologous endpoints and genotype rescue controls.
Readouts
Cross-species concordance of neural, NMJ, and muscle signatures
pathophysiology#Progressive Central and Neuromuscular Dysfunction
Decision criterion
Reproducible directionally concordant signatures that normalize after genotype correction in human cells would increase model fidelity; model-specific signatures absent from human cells would constrain extrapolation.
Would support
pathophysiology#Progressive Central and Neuromuscular Dysfunction
Show evidence (2 references)
PMID:39127839 SUPPORT Model Organism
"An additional limitation is the lack of spinal cord analysis. It is possible that there are structural defects and denervation occurring between upper and lower motor neurons within the spinal cord, that these studies would have missed."
The positive mouse study explicitly identifies an unexamined motor-system compartment.
PMID:35315486 SUPPORT In Vitro
"Additionally, the patient fibroblast studies presented here are important, but studies with nervous tissues are needed to better elucidate the basis of the apparent genetic complementation."
The human-cell study explicitly limits fibroblast-to-neural extrapolation.
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Pathophysiology

12
Variant-Specific TPI1 Dysfunction
Biallelic pathogenic TPI1 variants impair the steady-state function of triosephosphate isomerase through variant-specific combinations of altered catalysis, dimer formation, thermal stability, and protein turnover. The common p.Glu105Asp variant is structurally destabilizing even though purified mutant enzyme can retain normal catalytic activity; reduced enzyme activity alone is therefore not treated as the complete disease mechanism.
Variant-specific stability and tissue-abundance model
TPI1 hgnc:12009 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TPI1 (hgnc:12009). hgnc:12009 is a gene from the HUGO Gene Nomenclature Committee.
triose-phosphate isomerase activity GO:0004807 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased triose-phosphate isomerase activity (GO:0004807). GO:0004807 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance Destabilizing variants reduce dimer formation or accelerate protein turnover, lowering steady-state TPI abundance in a tissue- and allele-dependent manner. Variant-specific stability and tissue-abundance model
Erythrocyte Triose-Phosphate Imbalance and Reduced Integrity Reduced TPI function in patient erythrocytes produces marked DHAP accumulation and altered glycolytic steady state without a generalized collapse of cellular energy charge.
Recurrent Infection Susceptibility Recurrent infections are a reproducible clinical association, but whether they arise from anemia, immune-cell TPI biology, respiratory weakness, or another route is unknown.
Variable Cardiac Involvement Cardiomyopathy is reported in the clinical spectrum, but its route from TPI1 dysfunction and its genotype dependence remain unresolved.
Show evidence (3 references)
PMID:40897044 SUPPORT Other
"TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1."
Establishes the biallelic TPI1 disease trigger and exact disease identity.
PMID:18562316 SUPPORT In Vitro
"Here, we show that the purified, recombinant mutant enzyme E104D, while exhibiting normal catalytic activity, shows impairments in the formation of active dimers and low thermostability and monomerizes under conditions in which the wild type retains its dimeric form."
Direct structural and biochemical evidence shows why the common allele cannot be represented as a simple catalytic null.
PMID:19786097 SUPPORT Other
"the mutations result in decrease in the catalytic activity and/or the dissociation of the dimers into inactive monomers"
The review supports the variant-dependent combination of reduced catalysis and dimer disruption represented at the root.
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
Destabilizing variants reduce formation or persistence of functional TPI dimers and can lower steady-state protein abundance. Patient fibroblasts and structurally matched models support this lesion, while a stable catalytic mutant with similarly low activity does not produce disease. Tissue-specific abundance is therefore a leading, but incomplete, explanation for clinical severity.
Variant-specific stability and tissue-abundance model
TPI1 hgnc:12009 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TPI1 (hgnc:12009). hgnc:12009 is a gene from the HUGO Gene Nomenclature Committee.
protein stabilization GO:0050821 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein stabilization (GO:0050821). GO:0050821 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
TPI p.Gln181Pro/p.Glu105Asp patient-fibroblast stability model PRIMARY CELL CULTURE Patient fibroblasts reproduce reduced steady-state TPI protein abundance.
Animal models
Tpi1 p.Glu105Asp/null mouse Mus musculus recapitulates The model reproduces severe loss of steady-state TPI protein.
Stable low-activity Tpi1 p.Ile170Val mouse Mus musculus fails to recapitulate The catalytic variant deliberately preserves protein stability and lacks tissue-selective loss.
Downstream
Progressive Central and Neuromuscular Dysfunction Low or unstable TPI protein is associated with the severe neuromuscular phenotype, but the intervening human neural, synaptic, and muscle events are not established. Variant-specific stability and tissue-abundance model
Show evidence (3 references)
PMID:35315486 SUPPORT In Vitro
"Western blots using patient fibroblasts demonstrated reduced TPI in patient cells compared with wild-type levels"
Patient-derived cells directly demonstrate reduced steady-state TPI abundance.
PMID:41153421 SUPPORT In Vitro
"Thus, since there is an ~90% decrease in TPI protein relative to control fibroblasts, these data demonstrate that the novel TPIR5G mutant protein has pathogenic consequences that significantly decrease either its expression or stability, lowering steady-state protein levels."
A second patient genotype couples near-normal purified catalytic activity to markedly reduced steady-state TPI abundance in patient fibroblasts.
PMID:31111503 SUPPORT Model Organism
"Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency."
The negative mouse model distinguishes instability/tissue abundance from catalytic loss alone.
Erythrocyte Triose-Phosphate Imbalance and Reduced Integrity
Patient erythrocytes with deficient TPI have markedly increased DHAP and an altered glycolytic steady state. Compensatory kinase activity can preserve the modeled energy state, so this node represents substrate imbalance and vulnerable red-cell integrity rather than an unsupported global ATP failure.
DHAP-methylglyoxal/glycation-redox neurotoxicity model
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↕ DYSREGULATED glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Erythrocyte Glycation and Oxidative Injury Accumulated DHAP can degrade to methylglyoxal, with measured blood and erythrocyte glycation and oxidative-stress markers.
Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress Blood and erythrocyte DHAP-associated methylglyoxal and glycation-redox stress form a candidate neurotoxic arm, but the systemic-to-neural bridge is unobserved and human measurements currently come from blood and urine. DHAP-methylglyoxal/glycation-redox neurotoxicity model
Show evidence (1 reference)
PMID:16086671 SUPPORT Human Clinical
"Although the rapid equilibration of triosephosphates is not achieved, the energy state of the cells is not 'sick' due to the activation of key regulatory enzymes."
Patient erythrocyte analysis supports disturbed triose-phosphate balance while bounding the prior energy-failure interpretation.
Erythrocyte Glycation and Oxidative Injury
In an affected family, erythrocyte methylglyoxal and glyoxalase activity, circulating D-lactate, hemoglobin-derived AGEs, and oxidative/nitrosative markers were increased. These measurements establish a red-cell stress state; they do not by themselves prove the mechanism of hemolysis.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED methylglyoxal biosynthetic process GO:0019242 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased methylglyoxal biosynthetic process (GO:0019242). GO:0019242 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Premature Erythrocyte Destruction Glycation and oxidative injury plausibly mark vulnerable erythrocytes for premature removal, but the specific intravascular versus macrophage-mediated clearance route has not been directly demonstrated in TPI deficiency.
Show evidence (1 reference)
PMID:14559119 SUPPORT Human Clinical
"The concentration of MG and activity of glyoxalase I in red blood cells (RBCs) were increased, and the concentrations of D-lactate in blood plasma and D-lactate urinary excretion were also increased markedly in the propositus."
Direct human measurements establish abnormal methylglyoxal metabolism.
Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
DHAP-derived methylglyoxal, advanced glycation products, and associated oxidative or nitrosative stress are a candidate route to neurologic disease. The human evidence consists of blood, erythrocyte, and urine measurements in one phenotypically discordant family; neural-tissue exposure and causal sufficiency have not been demonstrated.
DHAP-methylglyoxal/glycation-redox neurotoxicity model
methylglyoxal biosynthetic process GO:0019242 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased methylglyoxal biosynthetic process (GO:0019242). GO:0019242 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Central and Neuromuscular Dysfunction Methylglyoxal/glycation-redox stress may contribute to neurologic disease, but the intervening human neural mechanism is unknown. DHAP-methylglyoxal/glycation-redox neurotoxicity model
Show evidence (1 reference)
PMID:14559119 SUPPORT Human Clinical
"The increased derangement of MG metabolism and associated glycation, oxidative and nitrosative stress in the propositus may be linked to neurodegenerative process in triosephosphate isomerase deficiency."
The source reports association in one family and explicitly stops short of a causal claim.
Premature Erythrocyte Destruction
TPI deficiency produces hereditary hemolysis, which by definition reflects premature erythrocyte destruction. The disease-specific proportions of intravascular and extravascular destruction have not been resolved.
erythrocyte clearance GO:0034102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythrocyte clearance (GO:0034102). GO:0034102 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Shortened Erythrocyte Lifespan and Compensatory Erythropoiesis Premature destruction shortens red-cell survival and elicits a reticulocyte response.
Show evidence (1 reference)
PMID:15202694 SUPPORT Other
"Premature destruction of erythrocytes occurs intravascularly or extravascularly."
Defines the conserved destruction routes while the TPI-specific route is explicitly left unresolved.
Shortened Erythrocyte Lifespan and Compensatory Erythropoiesis
Accelerated erythrocyte loss triggers compensatory erythropoiesis and reticulocytosis, but production cannot fully maintain hemoglobin in affected infants and children.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
erythrocyte homeostasis GO:0034101 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal erythrocyte homeostasis (GO:0034101). GO:0034101 is a biological process from the Gene Ontology. ⚠ ABNORMAL erythropoiesis GO:0030218 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythropoiesis, annotated with erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Chronic Hemolytic Anemia Ongoing erythrocyte loss exceeding replacement produces chronic hemolytic anemia.
Show evidence (1 reference)
PMID:37323194 SUPPORT Human Clinical
"The reticulocyte count was elevated to 13%, and the direct Coombs test was negative."
An affected child had the expected compensatory reticulocyte response during nonimmune hemolysis.
Chronic Hemolytic Anemia
Chronic nonspherocytic hemolytic anemia, often beginning with neonatal jaundice or anemia in early infancy, is a common classical manifestation.
erythrocyte homeostasis GO:0034101 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal erythrocyte homeostasis (GO:0034101). GO:0034101 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Tpi1 p.Glu105Asp/null mouse Mus musculus recapitulates The mouse reproduces anemia and splenic pathology.
Downstream
Chronic hemolytic anemia The terminal hematologic state is the corresponding clinical phenotype.
Jaundice Hemoglobin breakdown during hemolysis produces neonatal or recurrent jaundice.
Show evidence (2 references)
PMID:40897044 SUPPORT Other
"In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding."
Establishes severe hemolytic anemia as a core clinical manifestation.
PMID:41153421 SUPPORT Human Clinical
"The TPIR5G/f.s.allelic combination results in TPI Df with locomotor and neurologic symptoms but lacking anemia."
An attenuated genotype without anemia bounds this node to a common classical manifestation rather than a universal defining feature.
Progressive Central and Neuromuscular Dysfunction
Progressive neurologic and neuromuscular disease can include developmental regression, hypotonia, weakness, dystonia, tremor, muscle wasting, central and peripheral motor-system abnormalities, and severe disability. Human reports establish the phenotype, while mouse findings in brain, neuromuscular junction, and muscle generate testable—but not yet human-proven—intermediates.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Animal models
Tpi1 p.Glu105Asp/null mouse Mus musculus recapitulates The mouse reproduces progressive motor dysfunction and candidate pathology in brain, NMJ, and muscle.
Stable low-activity Tpi1 p.Ile170Val mouse Mus musculus fails to recapitulate The mice lack the neurologic and neuromuscular phenotype despite severe catalytic reduction.
sugarkill TPI-mutant fly Drosophila melanogaster recapitulates The fly reproduces progressive locomotor and neural degeneration phenotypes.
Downstream
Progressive neurologic deterioration The mechanistic state manifests clinically as progressive neurologic deterioration.
Progressive muscle weakness Neuromuscular deterioration produces progressive loss of strength.
Hypotonia Axial and peripheral hypotonia are early neuromuscular manifestations.
Dystonia Dystonic posturing occurs within the variable movement-disorder phenotype.
Tremor Tremor is part of the movement phenotype in some allelic presentations.
Skeletal muscle atrophy Progressive neuromuscular dysfunction can culminate in loss of muscle bulk and atrophy.
Respiratory Muscle and Diaphragm Dysfunction Neuromuscular weakness can involve the diaphragm and respiratory musculature.
Show evidence (2 references)
PMID:37323194 SUPPORT Human Clinical
"He became ventilator- and wheelchair-dependent with progressive muscle weakness."
Directly documents progressive severe neuromuscular disease in an affected child.
PMID:39127839 SUPPORT Model Organism
"We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size."
The genotype-matched mouse identifies candidate tissue-level contributors without proving that each operates identically in humans.
Respiratory Muscle and Diaphragm Dysfunction
Diaphragmatic hypomotility, paralysis, or broader respiratory muscle weakness can cause progressive ventilatory dependence and respiratory failure.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Respiratory failure Severe diaphragm and respiratory muscle dysfunction produces respiratory failure.
Show evidence (1 reference)
PMID:40981120 SUPPORT Human Clinical
"An abdominal ultrasound showed bilateral diaphragmatic hypomotility."
Provides a direct structural-functional respiratory-muscle finding.
Recurrent Infection Susceptibility
Recurrent bacterial and respiratory infections occur in the clinical spectrum. The responsible immune, hematologic, respiratory, or mixed mechanism is not known and is not inferred here.
Downstream
Recurrent bacterial infections The susceptibility state manifests as recurrent bacterial infections.
Show evidence (1 reference)
PMID:21215915 SUPPORT Human Clinical
"characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections"
Lists recurrent bacterial infections within the defining clinical spectrum.
Variable Cardiac Involvement
Cardiomyopathy occurs in a subset of reported patients. A genotype-matched mouse develops hypertrophic and functional cardiac changes, but the human causal intermediates and penetrance are unresolved.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Cardiomyopathy Variable cardiac involvement can manifest clinically as cardiomyopathy.
Show evidence (1 reference)
PMID:39127839 SUPPORT Other
"Other, less frequent symptoms include cardiomyopathy and seizures"
The clinical literature synthesis bounds cardiomyopathy as less frequent.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Triosephosphate Isomerase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 1
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37323194 SUPPORT Other
"Chronic haemolytic anaemia, increased susceptibility to infections, cardiomyopathy, neurodegeneration, and death in early childhood are the clinical findings of triosephosphate isomerase (TPI) deficiency, which is an ultra-rare disorder."
Supports cardiomyopathy as part of the variable spectrum.
Digestive 1
Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37323194 SUPPORT Human Clinical
"On the second day after birth, the newborn was admitted to the neonatal unit with jaundice."
Documents neonatal jaundice in a confirmed case.
Musculoskeletal 3
Progressive muscle weakness HP:0003323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive muscle weakness (HP:0003323), qualified as course progressive. HP:0003323 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37323194 SUPPORT Human Clinical
"He became ventilator- and wheelchair-dependent with progressive muscle weakness."
Directly documents progressive weakness.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40981120 SUPPORT Human Clinical
"Neurological findings were significant for axial and peripheral hypotonia, with symmetrical distal brachial predominance paresis."
Directly supports hypotonia.
Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37323194 SUPPORT Human Clinical
"Decreased deep tendon reflexes, muscle atrophy, and hyperelasticity of the joints were detected in the extremities."
Directly supports muscle atrophy.
Nervous System 3
Progressive neurologic deterioration HP:0002344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive neurologic deterioration (HP:0002344), qualified as course progressive. HP:0002344 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37323194 SUPPORT Other
"Chronic haemolytic anaemia, recurrent infections, cardiomyopathy, developmental delay, and progressive neurologic deterioration are variably combined in the different phenotypes in patients with TPI deficiency."
Supports progressive neurologic deterioration while retaining variability.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35315486 SUPPORT Human Clinical
"Dystonia and tightness of her left side, as well as a tremor in her hands, were observed around the same time."
Documents dystonia in a molecularly characterized person.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35315486 SUPPORT Human Clinical
"Dystonia and tightness of her left side, as well as a tremor in her hands, were observed around the same time."
Documents tremor in a molecularly characterized person.
Respiratory 1
Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40981120 SUPPORT Human Clinical
"Case Presentation: We describe the case of an infant diagnosed with TPI deficiency in the context of haemolytic anaemia with progressive neurological deterioration and respiratory failure."
Directly supports respiratory failure.
Other 2
Chronic hemolytic anemia HP:0004870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic hemolytic anemia (HP:0004870), qualified as temporality chronic. HP:0004870 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:40897044 SUPPORT Other
"In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding."
Supports the core anemia phenotype.
PMID:41153421 SUPPORT Human Clinical
"The TPIR5G/f.s.allelic combination results in TPI Df with locomotor and neurologic symptoms but lacking anemia."
Documents that the phenotype is not universal across the allelic spectrum.
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718), qualified as temporality recurrent. HP:0002718 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:21215915 SUPPORT Human Clinical
"characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections"
Directly supports recurrent bacterial infections.
🧬

Genetic Associations

1
Biallelic TPI1 pathogenic variants
Gene: TPI1 hgnc:12009 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TPI1 (hgnc:12009). hgnc:12009 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:35315486 SUPPORT Other
"Note: The classical convention for numbering TPI amino acids does not include the start methionine. Thus, E105D is also known as E104D in some previously published papers."
Resolves current versus historical numbering of the common allele.
PMID:10916682 SUPPORT Other
"All kindreds that have been studied with the predominant Glu104Asp mutation are linked by a common haplotype, indicating descent from a common ancestor."
Documents the founder haplotype of the common historically numbered allele.
💊

Medical Actions

1
Supportive Multidisciplinary Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No proven disease-modifying therapy is available. Care is individualized and may include transfusion support for severe anemia, respiratory support, feeding assistance, and physical, occupational, or speech rehabilitation. Experimental enzyme replacement, gene therapy, bone-marrow transplantation, metabolic diets, and small-molecule stabilizers are not represented as established human treatments.
Show evidence (4 references)
PMID:40981120 SUPPORT Human Clinical
"As a severe paediatric condition without specific treatment, TPI deficiency requires primarily supportive care, such as feeding by nasogastric tube or gastrostomy and respiratory support."
Directly supports supportive feeding and respiratory management.
PMID:40981120 SUPPORT Human Clinical
"Her medical history is significant for neonatal jaundice, needing phototherapy and a prior hospital admission at 2 months of age due to Respiratory Syncytial Virus (RSV) bronchiolitis and anaemia (haemoglobin 6.5 g/dL), requiring blood transfusion support."
Documents transfusion support for severe anemia in an affected infant.
PMID:40981120 SUPPORT Human Clinical
"She has maintained physical medicine and rehabilitation therapy (3 times per week), which has been integral in addressing her motor and developmental needs. She also has Speech Therapy once weekly and Occupational Therapy once weekly."
Documents ongoing multidisciplinary rehabilitation in an affected child.
+ 1 more reference
🔬

Biochemical Markers

2
Erythrocyte triosephosphate isomerase activity (Decreased)
Show evidence (1 reference)
PMID:11196750 SUPPORT Human Clinical
"A search for a red cell enzyme deficiency revealed that the red cell triosephosphate isomerase (TPI) activity was low."
Directly supports the characteristic enzyme-assay abnormality.
Erythrocyte dihydroxyacetone phosphate (Increased)
Show evidence (1 reference)
PMID:16086671 SUPPORT Human Clinical
"Our results showed that the flux was 2.5-fold higher and the concentration of DHAP (dihydroxyacetone phosphate) and fructose 1,6-bisphosphate increased 40- and 5-fold respectively in the erythrocytes of the patient compared with the control."
Directly supports marked erythrocyte DHAP elevation.
🔬

Diagnosis

2
Erythrocyte TPI enzyme activity assay
Reduced erythrocyte TPI activity supports the biochemical diagnosis in a compatible congenital nonspherocytic hemolytic anemia. Interpretation must account for recent red-cell transfusion, which can raise measured activity toward normal; molecular confirmation is therefore important.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Markers: Erythrocyte triosephosphate isomerase activity
Results: Reduced erythrocyte TPI activity supports TPI deficiency.
Show evidence (2 references)
PMID:11196750 SUPPORT Human Clinical
"A search for a red cell enzyme deficiency revealed that the red cell triosephosphate isomerase (TPI) activity was low."
Demonstrates biochemical detection of reduced red-cell TPI activity.
PMID:37323194 SUPPORT Other
"It should also be noted that in patients who are frequently transfused with erythrocyte suspensions, the TPI activity might be within the normal range."
Defines the important transfusion-related false-negative limitation.
Molecular confirmation of biallelic TPI1 variants
Identification of two pathogenic or likely pathogenic TPI1 variants in trans confirms the molecular diagnosis and can resolve cases in which enzyme testing is unavailable or confounded by transfusion.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Markers: Biallelic pathogenic or likely pathogenic TPI1 variants
Results: Pathogenic or likely pathogenic TPI1 variants on both alleles support the diagnosis.
Show evidence (1 reference)
PMID:40981120 SUPPORT Human Clinical
"Therefore, trio whole-exome sequencing (WES) was performed, including analysis of the mitochondrial genome, revealing two heterozygous missense variants in the TPI1 gene, in trans, both classified as likely pathogenic"
Directly documents molecular confirmation with two variants in trans.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The exact incidence is unknown; a 2023 review reported fewer than 50 clinically affected people in the literature and described the disorder as ultra-rare. Underdiagnosis is plausible because erythrocyte TPI activity is not routinely assayed and can be confounded by transfusion.
Show evidence (1 reference)
PMID:37323194 SUPPORT Other
"Fewer than 50 clinically affected patients have been described in the literature to date."
Supports the literature-case scale underlying the ultra-rare classification.
🧫

Experimental Models

1
TPI p.Gln181Pro/p.Glu105Asp patient-fibroblast stability model PRIMARY_CELL_CULTURE
Primary fibroblasts from compound-heterozygous affected siblings and carrier parents were used to measure steady-state TPI protein and pharmacologic stabilization. The model directly addresses human protein abundance but not disease-relevant neural, muscle, or erythrocyte physiology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary skin fibroblasts from affected siblings and carrier parents
Culture
Fibroblast monolayer with immunoblot measurement of TPI abundance
Publication
PMID:35315486
Pathograph links
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance recapitulates fidelity: moderate Patient fibroblasts reproduce reduced steady-state TPI protein abundance.
Limitations: Fibroblast abundance does not establish TPI turnover or thresholds in human motor neurons, muscle, or erythrocytes.
Show evidence (1 reference)
PMID:35315486 SUPPORT In Vitro
"Both patients exhibited ∼40% of normal TPI levels."
Quantifies reduced steady-state TPI in patient fibroblasts.
Show evidence (1 reference)
PMID:35315486 SUPPORT In Vitro
"Patient fibroblasts were obtained from both the patients and parents, and the TPI locus was PCR amplified and coding regions were sequenced."
Defines the genotype-confirmed primary-cell model.
🐁

Animal Models

3
Tpi1 p.Glu105Asp/null mouse
This mammalian model carries the common human disease allele in trans with a null allele. It has markedly reduced TPI protein, shortened survival, hemolytic anemia, splenic pathology, and progressive neuromuscular dysfunction; later work identified brain, neuromuscular-junction, muscle, cardiac, and vascular abnormalities.
Species
Mus musculus
Genotype
Compound heterozygous Tpi1 E105D and frameshift-null alleles
Genes
TPI1 hgnc:12009 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TPI1 (hgnc:12009). hgnc:12009 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:36405628
Pathograph links
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance recapitulates fidelity: moderate The model reproduces severe loss of steady-state TPI protein.
Limitations: The compound E105D/null genotype is not identical to common human E105D homozygosity, and mouse tissue thresholds may differ from humans.
Show evidence (1 reference)
PMID:36405628 SUPPORT Model Organism
"There is a ∼95% reduction in TPI protein levels in Tpi1 E105D/null animals compared to wild-type littermates, consistent with decreased TPI protein stability"
Directly supports severe protein loss in the model.
Chronic Hemolytic Anemia recapitulates fidelity: moderate The mouse reproduces anemia and splenic pathology.
Limitations: The exact erythrocyte-destruction route was not resolved by the cited summary.
Show evidence (1 reference)
PMID:36405628 SUPPORT Model Organism
"hemolytic anemia, pathological changes in spleen, and decreased body weight"
Directly supports the hematologic phenotype.
Progressive Central and Neuromuscular Dysfunction recapitulates fidelity: moderate The mouse reproduces progressive motor dysfunction and candidate pathology in brain, NMJ, and muscle.
Limitations: The roughly 40-day mouse course is compressed relative to human disease; spinal cord and demyelination were not assessed, and several findings were sex-dependent or late-stage.
Readouts
Brain, neuromuscular-junction, and muscle pathology
Interpretation: Neurodegeneration, altered NMJ transmission, and reduced muscle-fiber size jointly report the modeled neuromuscular state.
Show evidence (1 reference)
PMID:39127839 SUPPORT Model Organism
"We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size."
Defines the model's major neuromuscular readouts.
Show evidence (1 reference)
PMID:39127839 SUPPORT Model Organism
"We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size."
Directly supports modeled neuromuscular pathology.
Show evidence (1 reference)
PMID:36405628 SUPPORT Model Organism
"Tpi1 E105D/null mice experience a markedly shortened lifespan, postural abnormalities consistent with extensive neuromuscular dysfunction, hemolytic anemia, pathological changes in spleen, and decreased body weight."
Summarizes the model's disease-relevant phenotype.
Stable low-activity Tpi1 p.Ile170Val mouse
This critical negative model retains approximately 13-15% TPI activity across tissues but preserves dimer stability and protein abundance. Despite altered metabolites, it does not develop anemia, neurologic, neuromuscular, immune, respiratory, or cardiac disease, demonstrating that low catalysis alone is insufficient.
Species
Mus musculus
Genotype
Homozygous Tpi1 I170V catalytic-site variant on a C57BL/6J background
Genes
TPI1 hgnc:12009 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TPI1 (hgnc:12009). hgnc:12009 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:31111503
Pathograph links
Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance fails to recapitulate fidelity: low The catalytic variant deliberately preserves protein stability and lacks tissue-selective loss.
Limitations: It is a falsification model for low catalytic activity, not a genetic model of the common destabilizing human allele.
Show evidence (1 reference)
PMID:31111503 SUPPORT Model Organism
"While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation."
Directly establishes the intended stability/activity separation.
Progressive Central and Neuromuscular Dysfunction fails to recapitulate fidelity: low The mice lack the neurologic and neuromuscular phenotype despite severe catalytic reduction.
Limitations: This stable catalytic-site allele is not a genetic match for destabilizing human alleles, so its negative phenotype isolates catalytic insufficiency but does not test the full human disease genotype.
Show evidence (1 reference)
PMID:31111503 SUPPORT Model Organism
"TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency."
Directly supports failure to reproduce disease pathology.
Show evidence (1 reference)
PMID:31111503 SUPPORT Model Organism
"TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues"
Establishes the strong, tissue-consistent catalytic reduction.
sugarkill TPI-mutant fly
The invertebrate model has reduced longevity, progressive locomotor decline, and neural degeneration without a detectable bioenergetic deficit. It is informative for neural phenotypes but does not reproduce the human hematologic or mammalian respiratory context.
Species
Drosophila melanogaster
Genotype
Recessive missense mutation in the TPI-encoding sugarkill (sgk) gene
Publication
PMID:16980388
Pathograph links
Progressive Central and Neuromuscular Dysfunction recapitulates fidelity: low The fly reproduces progressive locomotor and neural degeneration phenotypes.
Limitations: Invertebrate anatomy, lifespan, and oxygen transport limit extrapolation to human motor systems, erythrocytes, and respiratory failure.
Show evidence (1 reference)
PMID:16980388 SUPPORT Model Organism
"Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration."
Directly supports the modeled neurologic phenotype.
Show evidence (1 reference)
PMID:16980388 SUPPORT Model Organism
"Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment."
Supports use of the model to test mechanisms beyond simple energy failure.
{ }

Source YAML

click to show 
name: Triosephosphate Isomerase Deficiency
category: Mendelian
creation_date: "2026-07-08T00:00:00Z"
synonyms:
- TPI deficiency
- TPI Df
- TPID
- Triose phosphate-isomerase deficiency
- Hemolytic anemia due to triosephosphate isomerase deficiency
- TPI1-related triosephosphate isomerase deficiency
description: >-
  Triosephosphate isomerase deficiency is an autosomal-recessive multisystem
  glycolytic disorder caused by biallelic pathogenic variants in TPI1. Its
  classical clinical combination is congenital or early-onset chronic hemolytic
  anemia with variably progressive neurologic and neuromuscular dysfunction;
  hypotonia, muscle weakness and wasting, movement abnormalities, recurrent
  infections, respiratory failure, and occasional cardiomyopathy broaden the
  phenotype. The recurrent p.Glu105Asp variant (historically called E104D when
  the initiator methionine was omitted) disrupts dimer stability despite
  retaining near-normal catalytic activity in purified protein. Other alleles
  can impair catalysis, stability, or both. Human-cell and animal studies
  therefore support variant-specific protein instability and tissue-dependent
  TPI abundance as important determinants, while low catalytic activity alone is
  insufficient to produce disease in a mouse model. Erythrocyte DHAP
  accumulation and methylglyoxal/glycation-redox abnormalities are measured in
  affected people, but their causal contribution to neurodegeneration remains
  unresolved. There is no proven disease-modifying therapy; management is
  supportive and tailored to hematologic, respiratory, nutritional, and
  neuromuscular needs.
disease_term:
  preferred_term: triosephosphate isomerase deficiency
  term:
    id: MONDO:0014221
    label: triosephosphate isomerase deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014221
      label: triosephosphate isomerase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0014221 is the exact disease concept and carries the corresponding
      OMIM:615512 and Orphanet ORPHA:868 cross-references.
classifications:
  icimd_category:
  - classification_value: glycolysis
    notes: >-
      IEMbase/ICIMD places TPI1-related triosephosphate isomerase deficiency
      under disorders of glycolysis within disorders of carbohydrate metabolism
      (WP-007 package, classification code 3.3.09.01).
parents:
- Inborn Error of Metabolism
mechanistic_hypotheses:
- hypothesis_group_id: tpi_stability_tissue_abundance_model
  hypothesis_label: Variant-specific stability and tissue-abundance model
  status: EMERGING
  description: >-
    Pathogenicity and clinical severity depend more strongly on mutant-protein
    instability and tissue-dependent steady-state TPI abundance than on reduced
    catalytic activity alone. This model is supported by human structural and
    fibroblast data and by a stable low-activity mouse that does not develop the
    disease, but the tissue-specific bridge to human neuromuscular injury is not
    fully resolved.
  evidence:
  - reference: PMID:31111503
    reference_title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, without the stability defect that affects TPI activity in a
      tissue-specific manner, a strong decline in TPI catalytic activity is not
      sufficient to explain the pathological onset of TPI deficiency.
    explanation: >-
      The stable I170V mouse separates catalytic loss from instability and
      falsifies a simple low-activity-only mechanism.
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data suggest that impaired stability, and not catalytic activity, is
      a better predictor of TPI Df severity.
    explanation: >-
      Human variant and patient-fibroblast data support the stability/abundance
      model while retaining it as a predictor rather than a complete mechanism.
- hypothesis_group_id: tpi_methylglyoxal_glycation_stress_model
  hypothesis_label: DHAP-methylglyoxal/glycation-redox neurotoxicity model
  status: ALTERNATIVE
  description: >-
    Accumulated DHAP can form methylglyoxal, advanced glycation products, and
    oxidative or nitrosative stress. These abnormalities are demonstrated in
    blood from one phenotypically discordant family, but a causal neural-tissue
    pathway has not been shown.
  evidence:
  - reference: PMID:14559119
    reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increased derangement of MG metabolism and associated glycation,
      oxidative and nitrosative stress in the propositus may be linked to
      neurodegenerative process in triosephosphate isomerase deficiency.
    explanation: >-
      The source itself uses associative language, so it supports an alternative
      hypothesis rather than an established causal arm.
pathophysiology:
- name: Variant-Specific TPI1 Dysfunction
  description: >-
    Biallelic pathogenic TPI1 variants impair the steady-state function of
    triosephosphate isomerase through variant-specific combinations of altered
    catalysis, dimer formation, thermal stability, and protein turnover. The
    common p.Glu105Asp variant is structurally destabilizing even though purified
    mutant enzyme can retain normal catalytic activity; reduced enzyme activity
    alone is therefore not treated as the complete disease mechanism.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: TPI1
    term:
      id: hgnc:12009
      label: TPI1
  molecular_functions:
  - preferred_term: triose-phosphate isomerase activity
    term:
      id: GO:0004807
      label: triose-phosphate isomerase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due
      to biallelic pathogenic variants in TPI1.
    explanation: Establishes the biallelic TPI1 disease trigger and exact disease identity.
  - reference: PMID:18562316
    reference_title: "Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that the purified, recombinant mutant enzyme E104D, while
      exhibiting normal catalytic activity, shows impairments in the formation
      of active dimers and low thermostability and monomerizes under conditions
      in which the wild type retains its dimeric form.
    explanation: >-
      Direct structural and biochemical evidence shows why the common allele
      cannot be represented as a simple catalytic null.
  - reference: PMID:19786097
    reference_title: "Triosephosphate isomerase deficiency: new insights into an enigmatic disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the mutations result in decrease in the catalytic activity and/or the
      dissociation of the dimers into inactive monomers
    explanation: >-
      The review supports the variant-dependent combination of reduced catalysis
      and dimer disruption represented at the root.
  downstream:
  - target: Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpi_stability_tissue_abundance_model
    description: >-
      Destabilizing variants reduce dimer formation or accelerate protein
      turnover, lowering steady-state TPI abundance in a tissue- and
      allele-dependent manner.
    evidence:
    - reference: PMID:18562316
      reference_title: "Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that the purified, recombinant mutant enzyme E104D, while
        exhibiting normal catalytic activity, shows impairments in the formation
        of active dimers and low thermostability and monomerizes under conditions
        in which the wild type retains its dimeric form.
      explanation: The common variant directly impairs dimer formation and stability.
  - target: Erythrocyte Triose-Phosphate Imbalance and Reduced Integrity
    causal_link_type: DIRECT
    description: >-
      Reduced TPI function in patient erythrocytes produces marked DHAP
      accumulation and altered glycolytic steady state without a generalized
      collapse of cellular energy charge.
    evidence:
    - reference: PMID:16086671
      reference_title: "Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results showed that the flux was 2.5-fold higher and the
        concentration of DHAP (dihydroxyacetone phosphate) and fructose
        1,6-bisphosphate increased 40- and 5-fold respectively in the
        erythrocytes of the patient compared with the control.
      explanation: >-
        Patient erythrocyte modeling directly supports the disease-specific
        metabolic imbalance and corrects the prior claim of reduced glycolytic flux.
  - target: Recurrent Infection Susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent infections are a reproducible clinical association, but whether
      they arise from anemia, immune-cell TPI biology, respiratory weakness, or
      another route is unknown.
    evidence:
    - reference: PMID:39127839
      reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Often, patients experience recurrent infections throughout their
        lifespan, the basis of which is unknown but may be related to the severe
        anemia patients experience
      explanation: >-
        The source supports the clinical association and explicitly identifies
        its causal basis as unresolved.
  - target: Variable Cardiac Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cardiomyopathy is reported in the clinical spectrum, but its route from
      TPI1 dysfunction and its genotype dependence remain unresolved.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Chronic haemolytic anaemia, increased susceptibility to infections,
        cardiomyopathy, neurodegeneration, and death in early childhood are the
        clinical findings of triosephosphate isomerase (TPI) deficiency, which is
        an ultra-rare disorder.
      explanation: >-
        The clinical review includes cardiomyopathy in the spectrum but does not
        resolve a causal pathway or imply that it is universal.
- name: Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
  description: >-
    Destabilizing variants reduce formation or persistence of functional TPI
    dimers and can lower steady-state protein abundance. Patient fibroblasts and
    structurally matched models support this lesion, while a stable catalytic
    mutant with similarly low activity does not produce disease. Tissue-specific
    abundance is therefore a leading, but incomplete, explanation for clinical
    severity.
  role: central_effector
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: TPI1
    term:
      id: hgnc:12009
      label: TPI1
  biological_processes:
  - preferred_term: protein stabilization
    term:
      id: GO:0050821
      label: protein stabilization
    modifier: DECREASED
  evidence:
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blots using patient fibroblasts demonstrated reduced TPI in patient
      cells compared with wild-type levels
    explanation: Patient-derived cells directly demonstrate reduced steady-state TPI abundance.
  - reference: PMID:41153421
    reference_title: "Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1(R5G)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, since there is an ~90% decrease in TPI protein relative to control
      fibroblasts, these data demonstrate that the novel TPIR5G mutant protein
      has pathogenic consequences that significantly decrease either its
      expression or stability, lowering steady-state protein levels.
    explanation: >-
      A second patient genotype couples near-normal purified catalytic activity
      to markedly reduced steady-state TPI abundance in patient fibroblasts.
  - reference: PMID:31111503
    reference_title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, without the stability defect that affects TPI activity in a
      tissue-specific manner, a strong decline in TPI catalytic activity is not
      sufficient to explain the pathological onset of TPI deficiency.
    explanation: >-
      The negative mouse model distinguishes instability/tissue abundance from
      catalytic loss alone.
  downstream:
  - target: Progressive Central and Neuromuscular Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tpi_stability_tissue_abundance_model
    description: >-
      Low or unstable TPI protein is associated with the severe neuromuscular
      phenotype, but the intervening human neural, synaptic, and muscle events
      are not established.
    evidence:
    - reference: PMID:40897044
      reference_title: "TPI deficiency: A case report and review of the literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the
        life-limiting neuromuscular phenotype seen in humans, but the exact
        pathomechanism remains unclear.
      explanation: >-
        Genotype-matched disease and model phenotypes support the association
        while the source explicitly leaves the mechanistic bridge unresolved.
- name: Erythrocyte Triose-Phosphate Imbalance and Reduced Integrity
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
  description: >-
    Patient erythrocytes with deficient TPI have markedly increased DHAP and an
    altered glycolytic steady state. Compensatory kinase activity can preserve
    the modeled energy state, so this node represents substrate imbalance and
    vulnerable red-cell integrity rather than an unsupported global ATP failure.
  role: trigger
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: DYSREGULATED
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16086671
    reference_title: "Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the rapid equilibration of triosephosphates is not achieved, the
      energy state of the cells is not 'sick' due to the activation of key
      regulatory enzymes.
    explanation: >-
      Patient erythrocyte analysis supports disturbed triose-phosphate balance
      while bounding the prior energy-failure interpretation.
  downstream:
  - target: Erythrocyte Glycation and Oxidative Injury
    causal_link_type: DIRECT
    description: >-
      Accumulated DHAP can degrade to methylglyoxal, with measured blood and
      erythrocyte glycation and oxidative-stress markers.
    evidence:
    - reference: PMID:14559119
      reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DHAP degrades spontaneously to methylglyoxal (MG)--a potent precursor of
        advanced glycation endproducts (AGEs).
      explanation: Establishes the direct chemical link from accumulated DHAP to methylglyoxal and AGEs.
  - target: Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tpi_methylglyoxal_glycation_stress_model
    description: >-
      Blood and erythrocyte DHAP-associated methylglyoxal and glycation-redox
      stress form a candidate neurotoxic arm, but the systemic-to-neural bridge
      is unobserved and human measurements currently come from blood and urine.
    evidence:
    - reference: PMID:14559119
      reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DHAP degrades spontaneously to methylglyoxal (MG)--a potent precursor of
        advanced glycation endproducts (AGEs).
      explanation: >-
        The chemistry is direct, while extension from measured blood markers to
        a human neural-tissue mechanism remains hypothetical.
- name: Erythrocyte Glycation and Oxidative Injury
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Oxidative and Membrane Injury"
  description: >-
    In an affected family, erythrocyte methylglyoxal and glyoxalase activity,
    circulating D-lactate, hemoglobin-derived AGEs, and oxidative/nitrosative
    markers were increased. These measurements establish a red-cell stress state;
    they do not by themselves prove the mechanism of hemolysis.
  role: amplifier
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: methylglyoxal biosynthetic process
    term:
      id: GO:0019242
      label: methylglyoxal biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:14559119
    reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The concentration of MG and activity of glyoxalase I in red blood cells
      (RBCs) were increased, and the concentrations of D-lactate in blood plasma
      and D-lactate urinary excretion were also increased markedly in the propositus.
    explanation: Direct human measurements establish abnormal methylglyoxal metabolism.
  downstream:
  - target: Premature Erythrocyte Destruction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Glycation and oxidative injury plausibly mark vulnerable erythrocytes for
      premature removal, but the specific intravascular versus macrophage-mediated
      clearance route has not been directly demonstrated in TPI deficiency.
    evidence:
    - reference: PMID:14559119
      reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There were concomitant increases in MG-derived AGEs and the oxidative
        marker dityrosine in hemoglobin.
      explanation: >-
        Demonstrates erythrocyte protein injury upstream of hemolysis but not the
        exact clearance mechanism, hence partial support.
- name: Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
  description: >-
    DHAP-derived methylglyoxal, advanced glycation products, and associated
    oxidative or nitrosative stress are a candidate route to neurologic disease.
    The human evidence consists of blood, erythrocyte, and urine measurements in
    one phenotypically discordant family; neural-tissue exposure and causal
    sufficiency have not been demonstrated.
  role: candidate_effector
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: methylglyoxal biosynthetic process
    term:
      id: GO:0019242
      label: methylglyoxal biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:14559119
    reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increased derangement of MG metabolism and associated glycation,
      oxidative and nitrosative stress in the propositus may be linked to
      neurodegenerative process in triosephosphate isomerase deficiency.
    explanation: >-
      The source reports association in one family and explicitly stops short
      of a causal claim.
  downstream:
  - target: Progressive Central and Neuromuscular Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tpi_methylglyoxal_glycation_stress_model
    description: >-
      Methylglyoxal/glycation-redox stress may contribute to neurologic disease,
      but the intervening human neural mechanism is unknown.
    evidence:
    - reference: PMID:14559119
      reference_title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The increased derangement of MG metabolism and associated glycation,
        oxidative and nitrosative stress in the propositus may be linked to
        neurodegenerative process in triosephosphate isomerase deficiency.
      explanation: >-
        The source's associative wording justifies an explicitly hypothetical,
        unknown-intermediate edge.
- name: Premature Erythrocyte Destruction
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >-
    TPI deficiency produces hereditary hemolysis, which by definition reflects
    premature erythrocyte destruction. The disease-specific proportions of
    intravascular and extravascular destruction have not been resolved.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  evidence:
  - reference: PMID:15202694
    reference_title: Hemolytic anemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Premature destruction of erythrocytes occurs intravascularly or extravascularly.
    explanation: >-
      Defines the conserved destruction routes while the TPI-specific route is
      explicitly left unresolved.
  downstream:
  - target: Shortened Erythrocyte Lifespan and Compensatory Erythropoiesis
    causal_link_type: DIRECT
    description: Premature destruction shortens red-cell survival and elicits a reticulocyte response.
    evidence:
    - reference: PMID:15202694
      reference_title: Hemolytic anemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hemolysis presents as acute or chronic anemia, reticulocytosis, or jaundice.
      explanation: Establishes the conserved link from erythrocyte destruction to compensatory reticulocytosis.
- name: Shortened Erythrocyte Lifespan and Compensatory Erythropoiesis
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Shortened Erythrocyte Lifespan and Erythropoietic Strain"
  description: >-
    Accelerated erythrocyte loss triggers compensatory erythropoiesis and
    reticulocytosis, but production cannot fully maintain hemoglobin in affected
    infants and children.
  role: effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: ABNORMAL
  - preferred_term: erythropoiesis
    term:
      id: GO:0030218
      label: erythrocyte differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The reticulocyte count was elevated to 13%, and the direct Coombs test was negative.
    explanation: An affected child had the expected compensatory reticulocyte response during nonimmune hemolysis.
  downstream:
  - target: Chronic Hemolytic Anemia
    causal_link_type: DIRECT
    description: Ongoing erythrocyte loss exceeding replacement produces chronic hemolytic anemia.
    evidence:
    - reference: PMID:15202694
      reference_title: Hemolytic anemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hemolysis presents as acute or chronic anemia, reticulocytosis, or jaundice.
      explanation: Supports anemia as the clinical consequence of ongoing hemolysis.
- name: Chronic Hemolytic Anemia
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Hemolytic Anemia"
  description: >-
    Chronic nonspherocytic hemolytic anemia, often beginning with neonatal
    jaundice or anemia in early infancy, is a common classical manifestation.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding.
    explanation: Establishes severe hemolytic anemia as a core clinical manifestation.
  - reference: PMID:41153421
    reference_title: "Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1(R5G)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TPIR5G/f.s.allelic combination results in TPI Df with locomotor and
      neurologic symptoms but lacking anemia.
    explanation: >-
      An attenuated genotype without anemia bounds this node to a common
      classical manifestation rather than a universal defining feature.
  downstream:
  - target: Chronic hemolytic anemia
    causal_link_type: DIRECT
    description: The terminal hematologic state is the corresponding clinical phenotype.
    evidence:
    - reference: PMID:40897044
      reference_title: "TPI deficiency: A case report and review of the literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding.
      explanation: Directly supports the phenotype link.
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hemoglobin breakdown with bilirubin production
    description: Hemoglobin breakdown during hemolysis produces neonatal or recurrent jaundice.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        On the second day after birth, the newborn was admitted to the neonatal unit with jaundice.
      explanation: Documents neonatal jaundice in a molecularly confirmed affected child.
- name: Progressive Central and Neuromuscular Dysfunction
  description: >-
    Progressive neurologic and neuromuscular disease can include developmental
    regression, hypotonia, weakness, dystonia, tremor, muscle wasting, central
    and peripheral motor-system abnormalities, and severe disability. Human
    reports establish the phenotype, while mouse findings in brain, neuromuscular
    junction, and muscle generate testable—but not yet human-proven—intermediates.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He became ventilator- and wheelchair-dependent with progressive muscle weakness.
    explanation: Directly documents progressive severe neuromuscular disease in an affected child.
  - reference: PMID:39127839
    reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We identified several contributors to neuromuscular symptoms, including
      neurodegeneration in the brain, alterations in neurotransmission at the
      neuromuscular junction, and reduced muscle fiber size.
    explanation: >-
      The genotype-matched mouse identifies candidate tissue-level contributors
      without proving that each operates identically in humans.
  downstream:
  - target: Progressive neurologic deterioration
    causal_link_type: DIRECT
    description: The mechanistic state manifests clinically as progressive neurologic deterioration.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Chronic haemolytic anaemia, recurrent infections, cardiomyopathy,
        developmental delay, and progressive neurologic deterioration are
        variably combined in the different phenotypes in patients with TPI deficiency.
      explanation: Supports the progressive neurologic phenotype while retaining variability.
  - target: Progressive muscle weakness
    causal_link_type: DIRECT
    description: Neuromuscular deterioration produces progressive loss of strength.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He became ventilator- and wheelchair-dependent with progressive muscle weakness.
      explanation: Directly supports progressive muscle weakness.
  - target: Hypotonia
    causal_link_type: DIRECT
    description: Axial and peripheral hypotonia are early neuromuscular manifestations.
    evidence:
    - reference: PMID:40981120
      reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurological findings were significant for axial and peripheral hypotonia,
        with symmetrical distal brachial predominance paresis.
      explanation: Directly documents axial and peripheral hypotonia.
  - target: Dystonia
    causal_link_type: DIRECT
    description: Dystonic posturing occurs within the variable movement-disorder phenotype.
    evidence:
    - reference: PMID:35315486
      reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dystonia and tightness of her left side, as well as a tremor in her hands,
        were observed around the same time.
      explanation: Directly documents dystonia in a molecularly characterized affected person.
  - target: Tremor
    causal_link_type: DIRECT
    description: Tremor is part of the movement phenotype in some allelic presentations.
    evidence:
    - reference: PMID:35315486
      reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dystonia and tightness of her left side, as well as a tremor in her hands,
        were observed around the same time.
      explanation: Directly documents tremor in an affected person.
  - target: Skeletal muscle atrophy
    causal_link_type: DIRECT
    description: Progressive neuromuscular dysfunction can culminate in loss of muscle bulk and atrophy.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Decreased deep tendon reflexes, muscle atrophy, and hyperelasticity of the joints were detected in the extremities.
      explanation: Directly documents extremity muscle atrophy.
  - target: Respiratory Muscle and Diaphragm Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - weakness of respiratory musculature and diaphragm
    description: Neuromuscular weakness can involve the diaphragm and respiratory musculature.
    evidence:
    - reference: PMID:40981120
      reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An abdominal ultrasound showed bilateral diaphragmatic hypomotility.
      explanation: Directly demonstrates diaphragm dysfunction in an affected infant.
- name: Respiratory Muscle and Diaphragm Dysfunction
  description: >-
    Diaphragmatic hypomotility, paralysis, or broader respiratory muscle weakness
    can cause progressive ventilatory dependence and respiratory failure.
  role: effector
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An abdominal ultrasound showed bilateral diaphragmatic hypomotility.
    explanation: Provides a direct structural-functional respiratory-muscle finding.
  downstream:
  - target: Respiratory failure
    causal_link_type: DIRECT
    description: Severe diaphragm and respiratory muscle dysfunction produces respiratory failure.
    evidence:
    - reference: PMID:40981120
      reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Case Presentation: We describe the case of an infant diagnosed with TPI
        deficiency in the context of haemolytic anaemia with progressive
        neurological deterioration and respiratory failure.
      explanation: Directly documents respiratory failure in molecularly diagnosed disease.
- name: Recurrent Infection Susceptibility
  description: >-
    Recurrent bacterial and respiratory infections occur in the clinical
    spectrum. The responsible immune, hematologic, respiratory, or mixed
    mechanism is not known and is not inferred here.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:21215915
    reference_title: "Triosephosphate isomerase deficiency: a patient with Val231Met mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections
    explanation: Lists recurrent bacterial infections within the defining clinical spectrum.
  downstream:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: The susceptibility state manifests as recurrent bacterial infections.
    evidence:
    - reference: PMID:21215915
      reference_title: "Triosephosphate isomerase deficiency: a patient with Val231Met mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections
      explanation: Directly supports the phenotype link.
- name: Variable Cardiac Involvement
  description: >-
    Cardiomyopathy occurs in a subset of reported patients. A genotype-matched
    mouse develops hypertrophic and functional cardiac changes, but the human
    causal intermediates and penetrance are unresolved.
  role: consequence
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:39127839
    reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Other, less frequent symptoms include cardiomyopathy and seizures
    explanation: The clinical literature synthesis bounds cardiomyopathy as less frequent.
  downstream:
  - target: Cardiomyopathy
    causal_link_type: DIRECT
    description: Variable cardiac involvement can manifest clinically as cardiomyopathy.
    evidence:
    - reference: PMID:37323194
      reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Chronic haemolytic anaemia, increased susceptibility to infections,
        cardiomyopathy, neurodegeneration, and death in early childhood are the
        clinical findings of triosephosphate isomerase (TPI) deficiency, which is
        an ultra-rare disorder.
      explanation: Supports cardiomyopathy as part of the variable clinical spectrum.
phenotypes:
- name: Chronic hemolytic anemia
  description: >-
    Chronic nonspherocytic hemolytic anemia is a common early manifestation of
    the classical phenotype.
  phenotype_term:
    preferred_term: Chronic hemolytic anemia
    term:
      id: HP:0004870
      label: Chronic hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding.
    explanation: Supports the core anemia phenotype.
  - reference: PMID:41153421
    reference_title: "Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1(R5G)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TPIR5G/f.s.allelic combination results in TPI Df with locomotor and
      neurologic symptoms but lacking anemia.
    explanation: >-
      Documents that the phenotype is not universal across the allelic spectrum.
- name: Jaundice
  description: Jaundice can be neonatal or accompany ongoing hemolysis.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the second day after birth, the newborn was admitted to the neonatal unit with jaundice.
    explanation: Documents neonatal jaundice in a confirmed case.
- name: Progressive neurologic deterioration
  description: Progressive neurologic loss or regression is a hallmark of severe disease.
  phenotype_term:
    preferred_term: Progressive neurologic deterioration
    term:
      id: HP:0002344
      label: Progressive neurologic deterioration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic haemolytic anaemia, recurrent infections, cardiomyopathy,
      developmental delay, and progressive neurologic deterioration are variably
      combined in the different phenotypes in patients with TPI deficiency.
    explanation: Supports progressive neurologic deterioration while retaining variability.
- name: Progressive muscle weakness
  description: Muscle weakness progresses in many severe infantile presentations.
  phenotype_term:
    preferred_term: Progressive muscle weakness
    term:
      id: HP:0003323
      label: Progressive muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He became ventilator- and wheelchair-dependent with progressive muscle weakness.
    explanation: Directly documents progressive weakness.
- name: Hypotonia
  description: Axial and peripheral hypotonia can present in early infancy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological findings were significant for axial and peripheral hypotonia,
      with symmetrical distal brachial predominance paresis.
    explanation: Directly supports hypotonia.
- name: Dystonia
  description: Dystonia and dystonic posturing occur in some allelic presentations.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dystonia and tightness of her left side, as well as a tremor in her hands,
      were observed around the same time.
    explanation: Documents dystonia in a molecularly characterized person.
- name: Tremor
  description: Tremor is reported within the variable movement phenotype.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dystonia and tightness of her left side, as well as a tremor in her hands,
      were observed around the same time.
    explanation: Documents tremor in a molecularly characterized person.
- name: Skeletal muscle atrophy
  description: Progressive loss of muscle bulk can become severe.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decreased deep tendon reflexes, muscle atrophy, and hyperelasticity of the joints were detected in the extremities.
    explanation: Directly supports muscle atrophy.
- name: Respiratory failure
  description: Respiratory failure and ventilatory dependence are major complications of severe neuromuscular disease.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Case Presentation: We describe the case of an infant diagnosed with TPI
      deficiency in the context of haemolytic anaemia with progressive
      neurological deterioration and respiratory failure.
    explanation: Directly supports respiratory failure.
- name: Recurrent bacterial infections
  description: Recurrent infections are a classic association, although their mechanism is unresolved.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:21215915
    reference_title: "Triosephosphate isomerase deficiency: a patient with Val231Met mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections
    explanation: Directly supports recurrent bacterial infections.
- name: Cardiomyopathy
  description: Cardiomyopathy is variably reported and is not present in every genotype or patient.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic haemolytic anaemia, increased susceptibility to infections,
      cardiomyopathy, neurodegeneration, and death in early childhood are the
      clinical findings of triosephosphate isomerase (TPI) deficiency, which is
      an ultra-rare disorder.
    explanation: Supports cardiomyopathy as part of the variable spectrum.
biochemical:
- name: Erythrocyte triosephosphate isomerase activity
  presence: Decreased
  evidence:
  - reference: PMID:11196750
    reference_title: "Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A search for a red cell enzyme deficiency revealed that the red cell
      triosephosphate isomerase (TPI) activity was low.
    explanation: Directly supports the characteristic enzyme-assay abnormality.
- name: Erythrocyte dihydroxyacetone phosphate
  presence: Increased
  evidence:
  - reference: PMID:16086671
    reference_title: "Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results showed that the flux was 2.5-fold higher and the concentration
      of DHAP (dihydroxyacetone phosphate) and fructose 1,6-bisphosphate increased
      40- and 5-fold respectively in the erythrocytes of the patient compared with the control.
    explanation: Directly supports marked erythrocyte DHAP elevation.
genetic:
- name: Biallelic TPI1 pathogenic variants
  gene_term:
    preferred_term: TPI1
    term:
      id: hgnc:12009
      label: TPI1
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:40897044
      reference_title: "TPI deficiency: A case report and review of the literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due
        to biallelic pathogenic variants in TPI1.
      explanation: Establishes autosomal-recessive biallelic causation.
  features: >-
    Disease-causing genotypes are biallelic and include homozygous and
    compound-heterozygous combinations. The common p.Glu105Asp allele is called E104D in
    older structural literature because the historical numbering omitted the
    initiator methionine. Alleles differ in their effects on catalysis, dimer
    stability, protein turnover, and clinical severity; the entry is retained as
    one allelic spectrum rather than split by severity.
  evidence:
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Note: The classical convention for numbering TPI amino acids does not
      include the start methionine. Thus, E105D is also known as E104D in some
      previously published papers.
    explanation: Resolves current versus historical numbering of the common allele.
  - reference: PMID:10916682
    reference_title: "Triosephosphate isomerase deficiency: historical perspectives and molecular aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      All kindreds that have been studied with the predominant Glu104Asp mutation
      are linked by a common haplotype, indicating descent from a common ancestor.
    explanation: Documents the founder haplotype of the common historically numbered allele.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due
      to biallelic pathogenic variants in TPI1.
    explanation: Explicitly establishes autosomal-recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The exact incidence is unknown; a 2023 review reported fewer than 50
    clinically affected people in the literature and described the disorder as
    ultra-rare. Underdiagnosis is plausible because erythrocyte TPI activity is
    not routinely assayed and can be confounded by transfusion.
  evidence:
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fewer than 50 clinically affected patients have been described in the literature to date.
    explanation: Supports the literature-case scale underlying the ultra-rare classification.
diagnosis:
- name: Erythrocyte TPI enzyme activity assay
  description: >-
    Reduced erythrocyte TPI activity supports the biochemical diagnosis in a
    compatible congenital nonspherocytic hemolytic anemia. Interpretation must
    account for recent red-cell transfusion, which can raise measured activity
    toward normal; molecular confirmation is therefore important.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: Erythrocyte triosephosphate isomerase activity
  results: Reduced erythrocyte TPI activity supports TPI deficiency.
  evidence:
  - reference: PMID:11196750
    reference_title: "Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A search for a red cell enzyme deficiency revealed that the red cell
      triosephosphate isomerase (TPI) activity was low.
    explanation: Demonstrates biochemical detection of reduced red-cell TPI activity.
  - reference: PMID:37323194
    reference_title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It should also be noted that in patients who are frequently transfused with
      erythrocyte suspensions, the TPI activity might be within the normal range.
    explanation: Defines the important transfusion-related false-negative limitation.
- name: Molecular confirmation of biallelic TPI1 variants
  description: >-
    Identification of two pathogenic or likely pathogenic TPI1 variants in trans
    confirms the molecular diagnosis and can resolve cases in which enzyme
    testing is unavailable or confounded by transfusion.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  markers: Biallelic pathogenic or likely pathogenic TPI1 variants
  results: Pathogenic or likely pathogenic TPI1 variants on both alleles support the diagnosis.
  evidence:
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, trio whole-exome sequencing (WES) was performed, including
      analysis of the mitochondrial genome, revealing two heterozygous missense
      variants in the TPI1 gene, in trans, both classified as likely pathogenic
    explanation: Directly documents molecular confirmation with two variants in trans.
treatments:
- name: Supportive Multidisciplinary Management
  description: >-
    No proven disease-modifying therapy is available. Care is individualized and
    may include transfusion support for severe anemia, respiratory support,
    feeding assistance, and physical, occupational, or speech rehabilitation.
    Experimental enzyme replacement, gene therapy, bone-marrow transplantation,
    metabolic diets, and small-molecule stabilizers are not represented as
    established human treatments.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a severe paediatric condition without specific treatment, TPI
      deficiency requires primarily supportive care, such as feeding by
      nasogastric tube or gastrostomy and respiratory support.
    explanation: Directly supports supportive feeding and respiratory management.
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her medical history is significant for neonatal jaundice, needing
      phototherapy and a prior hospital admission at 2 months of age due to
      Respiratory Syncytial Virus (RSV) bronchiolitis and anaemia (haemoglobin
      6.5 g/dL), requiring blood transfusion support.
    explanation: Documents transfusion support for severe anemia in an affected infant.
  - reference: PMID:40981120
    reference_title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has maintained physical medicine and rehabilitation therapy (3 times
      per week), which has been integral in addressing her motor and
      developmental needs. She also has Speech Therapy once weekly and
      Occupational Therapy once weekly.
    explanation: Documents ongoing multidisciplinary rehabilitation in an affected child.
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While there are no proven therapies available at this time, we hope this
      review will lead the discussion to consider future therapeutic options.
    explanation: Bounds all disease-modifying approaches as unproven.
animal_models:
- name: Tpi1 p.Glu105Asp/null mouse
  species: Mus musculus
  genotype: Compound heterozygous Tpi1 E105D and frameshift-null alleles
  genes:
  - preferred_term: TPI1
    term:
      id: hgnc:12009
      label: TPI1
  publication: PMID:36405628
  description: >-
    This mammalian model carries the common human disease allele in trans with a
    null allele. It has markedly reduced TPI protein, shortened survival,
    hemolytic anemia, splenic pathology, and progressive neuromuscular
    dysfunction; later work identified brain, neuromuscular-junction, muscle,
    cardiac, and vascular abnormalities.
  modeled_mechanisms:
  - target: Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The model reproduces severe loss of steady-state TPI protein.
    limitations: >-
      The compound E105D/null genotype is not identical to common human E105D
      homozygosity, and mouse tissue thresholds may differ from humans.
    evidence:
    - reference: PMID:36405628
      reference_title: Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        There is a ∼95% reduction in TPI protein levels in Tpi1 E105D/null animals
        compared to wild-type littermates, consistent with decreased TPI protein stability
      explanation: Directly supports severe protein loss in the model.
  - target: Chronic Hemolytic Anemia
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The mouse reproduces anemia and splenic pathology.
    limitations: The exact erythrocyte-destruction route was not resolved by the cited summary.
    evidence:
    - reference: PMID:36405628
      reference_title: Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        hemolytic anemia, pathological changes in spleen, and decreased body weight
      explanation: Directly supports the hematologic phenotype.
  - target: Progressive Central and Neuromuscular Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The mouse reproduces progressive motor dysfunction and candidate pathology in brain, NMJ, and muscle.
    limitations: >-
      The roughly 40-day mouse course is compressed relative to human disease;
      spinal cord and demyelination were not assessed, and several findings were
      sex-dependent or late-stage.
    readouts:
    - name: Brain, neuromuscular-junction, and muscle pathology
      target: Progressive Central and Neuromuscular Dysfunction
      interpretation: >-
        Neurodegeneration, altered NMJ transmission, and reduced muscle-fiber
        size jointly report the modeled neuromuscular state.
      evidence:
      - reference: PMID:39127839
        reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We identified several contributors to neuromuscular symptoms, including
          neurodegeneration in the brain, alterations in neurotransmission at the
          neuromuscular junction, and reduced muscle fiber size.
        explanation: Defines the model's major neuromuscular readouts.
    evidence:
    - reference: PMID:39127839
      reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We identified several contributors to neuromuscular symptoms, including
        neurodegeneration in the brain, alterations in neurotransmission at the
        neuromuscular junction, and reduced muscle fiber size.
      explanation: Directly supports modeled neuromuscular pathology.
  evidence:
  - reference: PMID:36405628
    reference_title: Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Tpi1 E105D/null mice experience a markedly shortened lifespan, postural
      abnormalities consistent with extensive neuromuscular dysfunction,
      hemolytic anemia, pathological changes in spleen, and decreased body weight.
    explanation: Summarizes the model's disease-relevant phenotype.
- name: Stable low-activity Tpi1 p.Ile170Val mouse
  species: Mus musculus
  genotype: Homozygous Tpi1 I170V catalytic-site variant on a C57BL/6J background
  genes:
  - preferred_term: TPI1
    term:
      id: hgnc:12009
      label: TPI1
  publication: PMID:31111503
  description: >-
    This critical negative model retains approximately 13-15% TPI activity across
    tissues but preserves dimer stability and protein abundance. Despite altered
    metabolites, it does not develop anemia, neurologic, neuromuscular, immune,
    respiratory, or cardiac disease, demonstrating that low catalysis alone is
    insufficient.
  modeled_mechanisms:
  - target: Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: The catalytic variant deliberately preserves protein stability and lacks tissue-selective loss.
    limitations: >-
      It is a falsification model for low catalytic activity, not a genetic model
      of the common destabilizing human allele.
    evidence:
    - reference: PMID:31111503
      reference_title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        While monitoring protein expression levels revealed no evidence for
        protein instability, metabolite quantification indicated that glycolysis
        is affected by the active site mutation.
      explanation: Directly establishes the intended stability/activity separation.
  - target: Progressive Central and Neuromuscular Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: The mice lack the neurologic and neuromuscular phenotype despite severe catalytic reduction.
    limitations: >-
      This stable catalytic-site allele is not a genetic match for destabilizing
      human alleles, so its negative phenotype isolates catalytic insufficiency
      but does not test the full human disease genotype.
    evidence:
    - reference: PMID:31111503
      reference_title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TPIIle170Val/Ile170Val mice develop normally and show none of the disease
        symptoms associated with TPI deficiency.
      explanation: Directly supports failure to reproduce disease pathology.
  evidence:
  - reference: PMID:31111503
    reference_title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI
      activity consistently across all examined tissues
    explanation: Establishes the strong, tissue-consistent catalytic reduction.
- name: sugarkill TPI-mutant fly
  species: Drosophila melanogaster
  genotype: Recessive missense mutation in the TPI-encoding sugarkill (sgk) gene
  publication: PMID:16980388
  description: >-
    The invertebrate model has reduced longevity, progressive locomotor decline,
    and neural degeneration without a detectable bioenergetic deficit. It is
    informative for neural phenotypes but does not reproduce the human
    hematologic or mammalian respiratory context.
  modeled_mechanisms:
  - target: Progressive Central and Neuromuscular Dysfunction
    relationship: RECAPITULATES
    fidelity: LOW
    description: The fly reproduces progressive locomotor and neural degeneration phenotypes.
    limitations: >-
      Invertebrate anatomy, lifespan, and oxygen transport limit extrapolation
      to human motor systems, erythrocytes, and respiratory failure.
    evidence:
    - reference: PMID:16980388
      reference_title: Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our analysis of sgk mutants revealed TPI impairment associated with
        reduced longevity, progressive locomotor deficiency, and neural degeneration.
      explanation: Directly supports the modeled neurologic phenotype.
  evidence:
  - reference: PMID:16980388
    reference_title: Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Biochemical studies demonstrate that mutation of this glycolytic enzyme
      gene does not result in a bioenergetic deficit, suggesting an alternate
      cause of enzymopathy associated with TPI impairment.
    explanation: Supports use of the model to test mechanisms beyond simple energy failure.
experimental_models:
- name: TPI p.Gln181Pro/p.Glu105Asp patient-fibroblast stability model
  description: >-
    Primary fibroblasts from compound-heterozygous affected siblings and carrier
    parents were used to measure steady-state TPI protein and pharmacologic
    stabilization. The model directly addresses human protein abundance but not
    disease-relevant neural, muscle, or erythrocyte physiology.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary skin fibroblasts from affected siblings and carrier parents
  culture_system: Fibroblast monolayer with immunoblot measurement of TPI abundance
  publication: PMID:35315486
  modeled_mechanisms:
  - target: Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Patient fibroblasts reproduce reduced steady-state TPI protein abundance.
    limitations: Fibroblast abundance does not establish TPI turnover or thresholds in human motor neurons, muscle, or erythrocytes.
    evidence:
    - reference: PMID:35315486
      reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both patients exhibited ∼40% of normal TPI levels.
      explanation: Quantifies reduced steady-state TPI in patient fibroblasts.
  evidence:
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts were obtained from both the patients and parents, and
      the TPI locus was PCR amplified and coding regions were sequenced.
    explanation: Defines the genotype-confirmed primary-cell model.
datasets: []
discussions:
- discussion_id: gap_tpi_human_neuromuscular_causal_bridge
  prompt: >-
    Which variant- and tissue-dependent event is causally necessary for human
    neurologic and neuromuscular disease: loss of stable TPI protein,
    DHAP-methylglyoxal/glycation-redox stress, proteostasis/aggregation, synaptic or
    neuromuscular-junction dysfunction, or a combination?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
  - pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
  - pathophysiology#Progressive Central and Neuromuscular Dysfunction
  rationale: >-
    Genotype-matched brothers can differ neurologically; a stable low-activity
    mouse remains well; methylglyoxal evidence is associative and blood-based;
    and the positive mouse reveals several candidate tissue lesions. Resolving
    causal necessity is essential for choosing between protein stabilization,
    metabolic detoxification, and neural or muscle-directed therapies.
  evidence:
  - reference: PMID:17424909
    reference_title: "Triosephosphate isomerase deficiency: facts and doubts."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Two germ-line identical Hungarian compound heterozygote brothers with
      distinct phenotypes question the exclusive role of the inherited mutations
      in the etiology of neurodegeneration.
    explanation: Human phenotypic discordance shows that genotype alone does not resolve the neural mechanism.
  - reference: PMID:12023819
    reference_title: "Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the mutations of TPI explain in themselves neither the severe decrease in
      the enzyme activity characteristic of TPI deficiency nor the enhanced
      ability of the mutant enzyme from haemolysate of the propositus to associate
      with subcellular particles.
    explanation: The misfolding literature itself identifies unexplained steps beyond the variants.
  - reference: PMID:40897044
    reference_title: "TPI deficiency: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the
      life-limiting neuromuscular phenotype seen in humans, but the exact
      pathomechanism remains unclear.
    explanation: A current review explicitly identifies the exact pathomechanism as unresolved.
  proposed_experiments:
  - experiment_id: tpi_isogenic_human_motor_unit_mechanism_dissection
    name: Isogenic human motor-unit mechanism dissection
    description: >-
      Generate genotype-corrected and p.Glu105Asp/null isogenic human iPSC motor
      neurons co-cultured with skeletal muscle. Independently restore TPI protein
      stability or modulate methylglyoxal detoxification, then measure TPI
      abundance and turnover, DHAP/MG/AGE-redox markers, neuronal survival,
      synaptic release, NMJ transmission, and muscle contraction over time.
    readouts:
    - name: TPI abundance, turnover, and tissue threshold
      target: pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    - name: Methylglyoxal/glycation-redox burden
      target: pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
    - name: Motor-neuron, NMJ, and muscle functional rescue
      target: pathophysiology#Progressive Central and Neuromuscular Dysfunction
    decision_criterion: >-
      A perturbation that rescues neural/NMJ/muscle function while selectively
      normalizing one candidate arm would support causal necessity; dissociation
      of biomarkers from functional rescue would argue against that arm as the
      primary driver.
    would_support:
    - pathophysiology#Reduced TPI Dimer Stability and Tissue-Dependent Protein Abundance
    - pathophysiology#Candidate Methylglyoxal, Glycation, and Redox Neurotoxic Stress
    - pathophysiology#Progressive Central and Neuromuscular Dysfunction
- discussion_id: mismatch_tpi_models_to_human_motor_system
  prompt: >-
    How faithfully do the E105D/null mouse, sugarkill fly, stable low-activity
    mouse, and patient fibroblast reproduce the cell-type-specific mechanisms of
    human embryonic and childhood motor-system disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Tpi1 p.Glu105Asp/null mouse
  - animal_models#Stable low-activity Tpi1 p.Ile170Val mouse
  - animal_models#sugarkill TPI-mutant fly
  - experimental_models#TPI p.Gln181Pro/p.Glu105Asp patient-fibroblast stability model
  - pathophysiology#Progressive Central and Neuromuscular Dysfunction
  rationale: >-
    The positive mouse has a compressed lethal course and a compound genotype,
    the negative mouse deliberately lacks the stability defect, the fly lacks
    mammalian erythrocyte and respiratory physiology, and fibroblasts do not
    model motor neurons or muscle. Cross-model agreement generates candidates
    but cannot by itself establish the corresponding human cellular mechanism.
  evidence:
  - reference: PMID:39127839
    reference_title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      An additional limitation is the lack of spinal cord analysis. It is
      possible that there are structural defects and denervation occurring
      between upper and lower motor neurons within the spinal cord, that these
      studies would have missed.
    explanation: The positive mouse study explicitly identifies an unexamined motor-system compartment.
  - reference: PMID:35315486
    reference_title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, the patient fibroblast studies presented here are important,
      but studies with nervous tissues are needed to better elucidate the basis
      of the apparent genetic complementation.
    explanation: The human-cell study explicitly limits fibroblast-to-neural extrapolation.
  proposed_experiments:
  - experiment_id: tpi_cross_model_human_neural_concordance
    name: Cross-model human neural concordance study
    description: >-
      Compare matched longitudinal proteomic, metabolomic, and functional
      signatures across human isogenic motor neurons/muscle, E105D/null mouse
      brain-spinal cord-NMJ-muscle, stable I170V mouse, and sugarkill fly, using
      prespecified orthologous endpoints and genotype rescue controls.
    readouts:
    - name: Cross-species concordance of neural, NMJ, and muscle signatures
      target: pathophysiology#Progressive Central and Neuromuscular Dysfunction
    decision_criterion: >-
      Reproducible directionally concordant signatures that normalize after
      genotype correction in human cells would increase model fidelity;
      model-specific signatures absent from human cells would constrain extrapolation.
    would_support:
    - pathophysiology#Progressive Central and Neuromuscular Dysfunction
references:
- reference: PMID:19786097
  title: "Triosephosphate isomerase deficiency: new insights into an enigmatic disease."
- reference: PMID:17424909
  title: "Triosephosphate isomerase deficiency: facts and doubts."
- reference: PMID:12023819
  title: "Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease."
- reference: PMID:21215915
  title: "Triosephosphate isomerase deficiency: a patient with Val231Met mutation."
- reference: PMID:36405628
  title: Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
- reference: PMID:10916682
  title: "Triosephosphate isomerase deficiency: historical perspectives and molecular aspects."
- reference: PMID:37323194
  title: "Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature."
- reference: PMID:40981120
  title: "Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report."
- reference: PMID:11196750
  title: "Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case."
- reference: PMID:16086671
  title: "Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels."
- reference: PMID:14559119
  title: Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
- reference: PMID:16980388
  title: Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy.
- reference: PMID:40897044
  title: "TPI deficiency: A case report and review of the literature."
- reference: PMID:31111503
  title: Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
- reference: PMID:18562316
  title: "Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface."
- reference: PMID:35315486
  title: Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
- reference: PMID:41153421
  title: "Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1(R5G)."
- reference: PMID:39127839
  title: Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
- reference: PMID:15202694
  title: Hemolytic anemia.
review_notes: >-
  Identity was reviewed as one TPI1 allelic-spectrum disorder: MONDO:0014221,
  OMIM:615512, ORPHA:868, and autosomal-recessive TPI1 disease are concordant.
  Severe and attenuated genotypes were not split because they do not represent
  separate exact MONDO disease identities. Current p.Glu105Asp numbering is used;
  E104D is retained only as the documented historical name. The prior graph's
  low-flux/ATP-failure and established methylglyoxal-neurotoxicity claims were
  corrected: patient erythrocyte modeling shows increased flux with compensated
  energy state, while human methylglyoxal/glycation evidence remains associative.
  Reviews are typed OTHER rather than HUMAN_CLINICAL unless a claim comes from a
  directly reported case. All clinical phenotypes are linked to the pathograph,
  and TPI1 is wired at the molecular trigger. The positive E105D/null mouse,
  stable low-activity negative mouse, fly, and human fibroblast model are retained
  with explicit fidelity limits. No dedicated GeneReviews chapter was found.
  Dataset discovery returned only GENE_ONLY candidates GSE268772 (mouse lung
  endothelial regeneration), GSE120262 (mouse microbiome/m6A study), and GSE8983
  (Geobacter omcB study); none is disease-specific, so `datasets` is explicitly
  empty. No curative treatment is established, and preclinical stabilization,
  diet, transplant, enzyme, and gene-therapy approaches are not promoted to
  standard care.
📚

References & Deep Research

References

19
PMID:19786097
Triosephosphate isomerase deficiency: new insights into an enigmatic disease.
No top-level findings curated for this source.
PMID:17424909
Triosephosphate isomerase deficiency: facts and doubts.
No top-level findings curated for this source.
PMID:12023819
Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease.
No top-level findings curated for this source.
PMID:21215915
Triosephosphate isomerase deficiency: a patient with Val231Met mutation.
No top-level findings curated for this source.
PMID:36405628
Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
No top-level findings curated for this source.
PMID:10916682
Triosephosphate isomerase deficiency: historical perspectives and molecular aspects.
No top-level findings curated for this source.
PMID:37323194
Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature.
No top-level findings curated for this source.
PMID:40981120
Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report.
No top-level findings curated for this source.
PMID:11196750
Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case.
No top-level findings curated for this source.
PMID:16086671
Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels.
No top-level findings curated for this source.
PMID:14559119
Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.
No top-level findings curated for this source.
PMID:16980388
Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy.
No top-level findings curated for this source.
PMID:40897044
TPI deficiency: A case report and review of the literature.
No top-level findings curated for this source.
PMID:31111503
Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
No top-level findings curated for this source.
PMID:18562316
Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface.
No top-level findings curated for this source.
PMID:35315486
Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.
No top-level findings curated for this source.
PMID:41153421
Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1(R5G).
No top-level findings curated for this source.
PMID:39127839
Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.
No top-level findings curated for this source.
PMID:15202694
Hemolytic anemia.
No top-level findings curated for this source.