RARE DISEASE
Triose phosphate-isomerase deficiency
Triose phosphate-isomerase deficiency
Triose phosphate-isomerase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
TPI deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, leading to impaired glycolysis. It presents with hemolytic anemia from infancy, progressive neurodegeneration (dystonia, tremors, hypotonia), cardiomyopathy, and recurrent infections. Severe cases often result in respiratory failure or fatal cardiomyopathy by early childhood, though rare survivors into adulthood exist [1][13][18]. Diagnosis involves reduced TPI enzyme activity and genetic testing [16][18].
Burden
High mortality: Most patients die by age 5–10 due to respiratory/cardiac failure [1][18].
Severe disability: Progressive neuromuscular decline necessitates lifelong multidisciplinary care [13][18].
Limited treatment efficacy: Chronic transfusions risk iron overload, while HSCT carries significant morbidity [3][13].
Therapies
Supportive care: Regular blood transfusions, splenectomy for hemolysis, and infection management [3][18].
Hematopoietic stem cell transplant (HSCT): Curative potential demonstrated in isolated cases, improving anemia and possibly delaying neurodegeneration [3][7].
Experimental approaches: Enzyme replacement therapy and small molecules targeting metabolic pathways remain under investigation [10][16].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
36 drug discovery papers about Triose phosphate-isomerase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
36 drug discovery papers about Triose phosphate-isomerase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2024-09-20 | Structural analysis of the TPI-Manchester, a thermolabile variant of human triosephosphate isomerase.
Human triosephosphate isomerase G122R, also known as TPI-Manchester, is a thermolabile variant detected in a screening of more than 3400 individuals from a population in Ann Arbor, Michigan. Here, the crystallographic structure of G122R was solved to determine the molecular basis of its thermal stability. Structural analysis revealed an increase in the flexibility of residues at the dimer interface, even though R122 is about 20 Å away, suggesting that long-range electrostatic interactions may play a key role in the mutation effect.
2013-11-26 | Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity.
Triosephosphate isomerase (TPI) is a glycolytic enzyme that converts dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP). Glycolytic enzyme dysfunction leads to metabolic diseases collectively known as glycolytic enzymopathies. Of these enzymopathies, TPI deficiency is unique in the severity of neurological symptoms. The Drosophila sugarkill mutant closely models TPI deficiency and encodes a protein prematurely degraded by the proteasome. This led us to question whether enzyme catalytic activity was crucial to the pathogenesis of TPI sugarkill neurological phenotypes. To study TPI deficiency in vivo we developed a genomic engineering system for the TPI locus that enables the efficient generation of novel TPI genetic variants. Using this system we demonstrate that TPI sugarkill can be genetically complemented by TPI encoding a catalytically inactive enzyme. Furthermore, our results demonstrate a non-metabolic function for TPI, the loss of which contributes significantly to the neurological dysfunction in this animal model.
2008-10-17 | Restoring a Metabolic Pathway
Gluconeogenesis is blocked in a strain of Escherichia coli that is deficient in triosephosphate isomerase, but it was restored by the insertion of a plasmid coding for an l-glyceraldehyde 3-phosphate reductase (YghZ). This reductase provides a "bypass" that produces dihydroxyacetone phosphate (DHAP) by the consecutive enzyme-catalyzed reduction of l-glyceraldehyde 3-phosphate (l-GAP) by NADPH to give l-glycerol 3-phosphate and reoxidation by NAD+ catalyzed by endogenous l-glycerol 3-phosphate dehydrogenase to give DHAP. The origin of cellular l-GAP remains to be determined.
2000-11-30 | Triosephosphate isomerase deficiency: historical perspectives and molecular aspects.
In this chapter, the original descriptions and pre-molecular studies of triosephosphate isomerase (TPI) deficiency are summarized, and the molecular aspects of the disease presented. The gene is well characterized, and several mutations have been described. Structure-function studies have led to an increased understanding of impaired catalysis. All kindreds that have been studied with the predominant Glu104Asp mutation are linked by a common haplotype, indicating descent from a common ancestor. Variant upstream substitutions occur in high frequency in persons of African and East Asian lineage and in lower frequency in other groups, but the possible role, if any, of these variants in clinical TPI deficiency requires further investigation. The possible contribution of deviant lipid metabolism to the pathogenesis of the disorder has been extensively investigated, and an intriguing new area of inquiry is the apparent cell-to-cell transfer of enzyme in cell culture systems, raising the question of the feasibility of enzyme or gene replacement therapy.
1999-02-03 | Regulation of triosephosphate isomerase (TPI) gene expression in TPI deficient lymphoblastoid cells.
The metabolic defect of triosephosphate isomerase (TPI) deficiency is reversible in deficient lymphoblastoid cells when cultured in the presence of human K562 erythroleukemia cells or plasma as exogenous source of functional enzyme. However, plasma contains a variety of undefined biological response modifiers whose effects on TPI gene expression are unknown. In the present study, TPI deficient lymphoblastoid cells were cultured in serum-free medium for 24 h (controls) and stimulated with fresh frozen plasma (FFP) at final concentrations of 20, 40, and 60% for 9 h. Changes in TPI mRNA expression were monitored by slot and Northern blot hybridisations using a specific human TPI cDNA probe. For equivalent loading of total RNA, TPI mRNA expression in FFP-treated lymphoblastoid cells exceeded that for controls by on average 20-fold. Additional studies with the transcription inhibitor, actinomycin D, revealed a rapid degradation of TPI mRNA in controls compared to FFP-treated cells, indicating that the stability of the TPI transcript was affected by plasma. These data suggest that functional or regulatory elements within the TPI gene promoter can be modulated by biological response modifiers. An understanding of the transcriptional control of TPI may provide useful insights into the development of gene therapy strategies for TPI deficiency.
small molecules
2026-04-08 | Biophysical and biochemical studies support PHD inhibitor development as a TPI deficiency therapy.
Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare genetic enzymopathy. Previously, the TPIR5G allele was found to cause TPI Df when combined with a null allele. Here, we report a 1.15 Å TPIR5G crystal structure providing insight into disease pathogenesis. Previously, we conducted a high-throughput screen that identified TPI-inducing compounds, including predicted hypoxia inducible factor (HIF) inducers. We have investigated repurposing HIF activators/prolyl hydroxylase domain inhibitors (PHDIs) as TPI Df treatments. We tested the efficacy of these compounds in cells from individuals with TPI Df. Our results demonstrate that PHDIs increase TPI protein levels and TPI activity, suggesting they should be further developed for TPI Df. RNA-sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR) experiments were performed to analyze PHDI-induced gene expression changes. We discovered that chronic PHDI treatment results in HIF1-antisense 2 (HIF1-AS2) activation, which operates as a negative feedback loop in the HIF pathway. These results demonstrate that repurposing PHDIs for TPI Df is a promising avenue of research deserving further investigation. Our results also suggest that PHDIs may also benefit dozens of other heritable disease conditions if treatment avoids HIF1-AS2 activation.
2025-10-29 | Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1R5G.
Background/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPIR5G protein, studied mutant protein biochemistry, established and characterized TPIR5G/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPIR5G human protein and studied it biochemically in addition to studying TPIR5G/f.s.patient cells. We discovered that purified TPIR5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPIR5G/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPIR5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies.
2025-09-22 | Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report.
Background and Clinical Significance: Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive metabolic disorder caused by a pathogenic variant in the TPI1 gene. It is characterised by chronic haemolytic anaemia, progressive neuromuscular dysfunction, and reduced life expectancy. Patients typically present with symptoms in the first few months of life, including muscle weakness, ataxia, and recurrent respiratory infections. Diagnosis is confirmed by genetic testing, and management is generally symptomatic as no treatment is available. 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. Conclusions: This case illustrates the complexity of the disease and highlights the importance of early diagnosis and contributes to the limited literature by providing a detailed clinical description and highlighting the diagnostic challenges associated with this condition. Beyond its clinical relevance, this report emphasises the potential role of personalised medicine in the management of TPI deficiency. Early identification of specific genotypes may inform prognosis and guide individualised supportive strategies. As knowledge of the molecular underpinnings of TPI deficiency expands, opportunities may emerge for targeted therapeutic approaches tailored to patient-specific characteristics.
2025-09-19 | Discovery and validation of small molecule stabilizers of mutant triose phosphate isomerase (TPI) as potential lead candidates for TPI deficiency.
Triosephosphate Isomerase deficiency (TPI-Df) is a devastating untreatable childhood metabolic disease resulting in anemia, severe locomotor impairment, and premature death. Numerous single amino acid substitutions in TPI are pathogenic and result in rapidly progressing multisystem disease. Importantly, all known pathogenic TPI-Df mutations result in a protein that retains function, and pathogenesis is known to result from decreased steady state levels of the functioning protein. There are no small molecule therapies for TPI-Df; current treatments are limited to symptomatic support and dietary interventions. We reasoned that a phenotypic screen was most appropriate to capture agents that stabilize mutant TPI and developed a human cellular TPI-Df assay based on a cellular model of the "common" TPIE105D mutant protein fused with a GFP and a fluorescent ROS biosensor. The assay was implemented for high-content, high-throughput imaging, optimized to full HTS standards, and used to screen a 2,560 compound pilot library and the 220,700 compound NIH MLSMR compound collection to identify candidate compounds for development into small molecule TPI-Df therapies. Hits were validated in dose-response, TPI-Df patient cells, and various orthogonal assays. Limited SAR revealed three promising compound series, which were evaluated for potential mechanisms of action. The lead series had previously been identified as inducers of HIF1 alpha, spawning a novel hypothesis that HIF1 alpha activation might be a potential avenue to treat TPI-Df patients. A lead molecule was moved into preliminary mouse studies to evaluate pharmacokinetics and tissue distribution and was shown to be moderately brain-penetrant. The lead compound is now positioned for target identification studies and efficacy testing in vivo TPI Df models, including a newly validated mouse model.
2025-09-02 | TPI deficiency: A case report and review of the literature.
Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a TPI1 p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant in trans to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant Drosophila, known as TPIsugarkill, although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.
cell therapies
2026-02-16 | Familial Dystonia Due to Homozygous TPI1 c.718G>A (p.Glu240Lys): A Three-Sibling Case Series Including Two Treated with Deep Brain Stimulation of the Globus Pallidus Internus.
Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, typically presenting with anemia, infections, and neurological decline. We report three siblings with a homozygous c.718G>A (p.Glu240Lys) variant presenting predominantly with dystonia. Clinical and genetic evaluations were performed in three affected siblings from a consanguineous Turkish family. Neurological examinations, imaging, and surgical outcomes were reviewed. All three siblings exhibited truncal and axial dystonia with orthopedic deformities but without anemia or cardiac involvement. Cognitive functions were preserved. Two underwent bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS), resulting in partial yet clinically meaningful improvement in posture and gait. The third sibling received orthopedic interventions. Notably, one homozygous sibling remained asymptomatic, highlighting incomplete penetrance. This is the first genetically confirmed report of TPI1 -associated dystonia treated with GPi-DBS. Our findings expand the clinical spectrum of TPI deficiency, showing a neurologically predominant phenotype without hematologic manifestations. The observed variability suggests the role of modifier factors, and GPi-DBS may provide symptomatic benefit in severe cases.
2018-11-09 | Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency.
In this study, we performed a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued.
1997-02-01 | Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency
Conference Abstract| February 01 1997 Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency Art Ationu; Art Ationu 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Ann Humphries; Ann Humphries 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Alistair Bellingham; Alistair Bellingham 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Mark Layton Mark Layton 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1997) 92 (s36): 12P. https://doi.org/10.1042/cs092012P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation Art Ationu, Ann Humphries, Alistair Bellingham, Mark Layton; Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency. Clin Sci (Lond) 1 February 1997; 92 (s36): 12P. doi: https://doi.org/10.1042/cs092012P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1997 The Biochemical Society and the Medical Research Society1997 Article PDF first page preview Close Modal You do not currently have access to this content.
gene therapies
2024-09-20 | Structural analysis of the TPI-Manchester, a thermolabile variant of human triosephosphate isomerase.
Human triosephosphate isomerase G122R, also known as TPI-Manchester, is a thermolabile variant detected in a screening of more than 3400 individuals from a population in Ann Arbor, Michigan. Here, the crystallographic structure of G122R was solved to determine the molecular basis of its thermal stability. Structural analysis revealed an increase in the flexibility of residues at the dimer interface, even though R122 is about 20 Å away, suggesting that long-range electrostatic interactions may play a key role in the mutation effect.
2013-11-26 | Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity.
Triosephosphate isomerase (TPI) is a glycolytic enzyme that converts dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP). Glycolytic enzyme dysfunction leads to metabolic diseases collectively known as glycolytic enzymopathies. Of these enzymopathies, TPI deficiency is unique in the severity of neurological symptoms. The Drosophila sugarkill mutant closely models TPI deficiency and encodes a protein prematurely degraded by the proteasome. This led us to question whether enzyme catalytic activity was crucial to the pathogenesis of TPI sugarkill neurological phenotypes. To study TPI deficiency in vivo we developed a genomic engineering system for the TPI locus that enables the efficient generation of novel TPI genetic variants. Using this system we demonstrate that TPI sugarkill can be genetically complemented by TPI encoding a catalytically inactive enzyme. Furthermore, our results demonstrate a non-metabolic function for TPI, the loss of which contributes significantly to the neurological dysfunction in this animal model.
2008-10-17 | Restoring a Metabolic Pathway
Gluconeogenesis is blocked in a strain of Escherichia coli that is deficient in triosephosphate isomerase, but it was restored by the insertion of a plasmid coding for an l-glyceraldehyde 3-phosphate reductase (YghZ). This reductase provides a "bypass" that produces dihydroxyacetone phosphate (DHAP) by the consecutive enzyme-catalyzed reduction of l-glyceraldehyde 3-phosphate (l-GAP) by NADPH to give l-glycerol 3-phosphate and reoxidation by NAD+ catalyzed by endogenous l-glycerol 3-phosphate dehydrogenase to give DHAP. The origin of cellular l-GAP remains to be determined.
2000-11-30 | Triosephosphate isomerase deficiency: historical perspectives and molecular aspects.
In this chapter, the original descriptions and pre-molecular studies of triosephosphate isomerase (TPI) deficiency are summarized, and the molecular aspects of the disease presented. The gene is well characterized, and several mutations have been described. Structure-function studies have led to an increased understanding of impaired catalysis. All kindreds that have been studied with the predominant Glu104Asp mutation are linked by a common haplotype, indicating descent from a common ancestor. Variant upstream substitutions occur in high frequency in persons of African and East Asian lineage and in lower frequency in other groups, but the possible role, if any, of these variants in clinical TPI deficiency requires further investigation. The possible contribution of deviant lipid metabolism to the pathogenesis of the disorder has been extensively investigated, and an intriguing new area of inquiry is the apparent cell-to-cell transfer of enzyme in cell culture systems, raising the question of the feasibility of enzyme or gene replacement therapy.
1999-02-03 | Regulation of triosephosphate isomerase (TPI) gene expression in TPI deficient lymphoblastoid cells.
The metabolic defect of triosephosphate isomerase (TPI) deficiency is reversible in deficient lymphoblastoid cells when cultured in the presence of human K562 erythroleukemia cells or plasma as exogenous source of functional enzyme. However, plasma contains a variety of undefined biological response modifiers whose effects on TPI gene expression are unknown. In the present study, TPI deficient lymphoblastoid cells were cultured in serum-free medium for 24 h (controls) and stimulated with fresh frozen plasma (FFP) at final concentrations of 20, 40, and 60% for 9 h. Changes in TPI mRNA expression were monitored by slot and Northern blot hybridisations using a specific human TPI cDNA probe. For equivalent loading of total RNA, TPI mRNA expression in FFP-treated lymphoblastoid cells exceeded that for controls by on average 20-fold. Additional studies with the transcription inhibitor, actinomycin D, revealed a rapid degradation of TPI mRNA in controls compared to FFP-treated cells, indicating that the stability of the TPI transcript was affected by plasma. These data suggest that functional or regulatory elements within the TPI gene promoter can be modulated by biological response modifiers. An understanding of the transcriptional control of TPI may provide useful insights into the development of gene therapy strategies for TPI deficiency.
small molecules
2026-04-08 | Biophysical and biochemical studies support PHD inhibitor development as a TPI deficiency therapy.
Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare genetic enzymopathy. Previously, the TPIR5G allele was found to cause TPI Df when combined with a null allele. Here, we report a 1.15 Å TPIR5G crystal structure providing insight into disease pathogenesis. Previously, we conducted a high-throughput screen that identified TPI-inducing compounds, including predicted hypoxia inducible factor (HIF) inducers. We have investigated repurposing HIF activators/prolyl hydroxylase domain inhibitors (PHDIs) as TPI Df treatments. We tested the efficacy of these compounds in cells from individuals with TPI Df. Our results demonstrate that PHDIs increase TPI protein levels and TPI activity, suggesting they should be further developed for TPI Df. RNA-sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR) experiments were performed to analyze PHDI-induced gene expression changes. We discovered that chronic PHDI treatment results in HIF1-antisense 2 (HIF1-AS2) activation, which operates as a negative feedback loop in the HIF pathway. These results demonstrate that repurposing PHDIs for TPI Df is a promising avenue of research deserving further investigation. Our results also suggest that PHDIs may also benefit dozens of other heritable disease conditions if treatment avoids HIF1-AS2 activation.
2025-10-29 | Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1R5G.
Background/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPIR5G protein, studied mutant protein biochemistry, established and characterized TPIR5G/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPIR5G human protein and studied it biochemically in addition to studying TPIR5G/f.s.patient cells. We discovered that purified TPIR5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPIR5G/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPIR5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies.
2025-09-22 | Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report.
Background and Clinical Significance: Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive metabolic disorder caused by a pathogenic variant in the TPI1 gene. It is characterised by chronic haemolytic anaemia, progressive neuromuscular dysfunction, and reduced life expectancy. Patients typically present with symptoms in the first few months of life, including muscle weakness, ataxia, and recurrent respiratory infections. Diagnosis is confirmed by genetic testing, and management is generally symptomatic as no treatment is available. 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. Conclusions: This case illustrates the complexity of the disease and highlights the importance of early diagnosis and contributes to the limited literature by providing a detailed clinical description and highlighting the diagnostic challenges associated with this condition. Beyond its clinical relevance, this report emphasises the potential role of personalised medicine in the management of TPI deficiency. Early identification of specific genotypes may inform prognosis and guide individualised supportive strategies. As knowledge of the molecular underpinnings of TPI deficiency expands, opportunities may emerge for targeted therapeutic approaches tailored to patient-specific characteristics.
2025-09-19 | Discovery and validation of small molecule stabilizers of mutant triose phosphate isomerase (TPI) as potential lead candidates for TPI deficiency.
Triosephosphate Isomerase deficiency (TPI-Df) is a devastating untreatable childhood metabolic disease resulting in anemia, severe locomotor impairment, and premature death. Numerous single amino acid substitutions in TPI are pathogenic and result in rapidly progressing multisystem disease. Importantly, all known pathogenic TPI-Df mutations result in a protein that retains function, and pathogenesis is known to result from decreased steady state levels of the functioning protein. There are no small molecule therapies for TPI-Df; current treatments are limited to symptomatic support and dietary interventions. We reasoned that a phenotypic screen was most appropriate to capture agents that stabilize mutant TPI and developed a human cellular TPI-Df assay based on a cellular model of the "common" TPIE105D mutant protein fused with a GFP and a fluorescent ROS biosensor. The assay was implemented for high-content, high-throughput imaging, optimized to full HTS standards, and used to screen a 2,560 compound pilot library and the 220,700 compound NIH MLSMR compound collection to identify candidate compounds for development into small molecule TPI-Df therapies. Hits were validated in dose-response, TPI-Df patient cells, and various orthogonal assays. Limited SAR revealed three promising compound series, which were evaluated for potential mechanisms of action. The lead series had previously been identified as inducers of HIF1 alpha, spawning a novel hypothesis that HIF1 alpha activation might be a potential avenue to treat TPI-Df patients. A lead molecule was moved into preliminary mouse studies to evaluate pharmacokinetics and tissue distribution and was shown to be moderately brain-penetrant. The lead compound is now positioned for target identification studies and efficacy testing in vivo TPI Df models, including a newly validated mouse model.
2025-09-02 | TPI deficiency: A case report and review of the literature.
Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a TPI1 p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant in trans to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant Drosophila, known as TPIsugarkill, although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.
cell therapies
2026-02-16 | Familial Dystonia Due to Homozygous TPI1 c.718G>A (p.Glu240Lys): A Three-Sibling Case Series Including Two Treated with Deep Brain Stimulation of the Globus Pallidus Internus.
Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, typically presenting with anemia, infections, and neurological decline. We report three siblings with a homozygous c.718G>A (p.Glu240Lys) variant presenting predominantly with dystonia. Clinical and genetic evaluations were performed in three affected siblings from a consanguineous Turkish family. Neurological examinations, imaging, and surgical outcomes were reviewed. All three siblings exhibited truncal and axial dystonia with orthopedic deformities but without anemia or cardiac involvement. Cognitive functions were preserved. Two underwent bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS), resulting in partial yet clinically meaningful improvement in posture and gait. The third sibling received orthopedic interventions. Notably, one homozygous sibling remained asymptomatic, highlighting incomplete penetrance. This is the first genetically confirmed report of TPI1 -associated dystonia treated with GPi-DBS. Our findings expand the clinical spectrum of TPI deficiency, showing a neurologically predominant phenotype without hematologic manifestations. The observed variability suggests the role of modifier factors, and GPi-DBS may provide symptomatic benefit in severe cases.
2018-11-09 | Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency.
In this study, we performed a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued.
1997-02-01 | Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency
Conference Abstract| February 01 1997 Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency Art Ationu; Art Ationu 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Ann Humphries; Ann Humphries 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Alistair Bellingham; Alistair Bellingham 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Mark Layton Mark Layton 1Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1997) 92 (s36): 12P. https://doi.org/10.1042/cs092012P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation Art Ationu, Ann Humphries, Alistair Bellingham, Mark Layton; Feasibility of Fresh Frozen Plasma as a Replacement Therapy for Human Triose Phosphate Isomerase Deficiency. Clin Sci (Lond) 1 February 1997; 92 (s36): 12P. doi: https://doi.org/10.1042/cs092012P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1997 The Biochemical Society and the Medical Research Society1997 Article PDF first page preview Close Modal You do not currently have access to this content.
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