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Mappings

MONDO

MONDO:0011624 transaldolase deficiency

Orphanet ORPHA:101028 lists MONDO:0011624 as an exact cross-reference.

📘

Definitions

1

Orphanet transaldolase deficiency definition

Inborn error of the pentose phosphate pathway presenting antenatally or neonatally with hydrops fetalis, hepatosplenomegaly, hepatic dysfunction, thrombocytopenia, anemia, and renal and cardiac abnormalities.

OTHER

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"Transaldolase deficiency is an inborn error of the pentose phosphate pathway"

Orphanet defines the disorder as an inborn pentose-phosphate-pathway error.

PMID:25388407 SUPPORT Human Clinical

"Transaldolase deficiency is a heterogeneous disorder of carbohydrate metabolism"

A patient series independently supports the carbohydrate-metabolism disease framing.

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Transaldolase deficiency is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance.

PMID:38440129 SUPPORT Human Clinical

"Transaldolase deficiency is a rare autosomal recessive inborn error"

A clinical case report and review also states autosomal recessive inheritance.

◈

Mechanistic Hypotheses

1

Canonical TALDO1 Pentose-Phosphate Redox Model

canonical_taldo1_ppp_redox_model CANONICAL

Evidence balance 11 support

Biallelic TALDO1 loss disrupts nonoxidative PPP carbon recycling and redox homeostasis. Liver injury, fibrosis and carcinogenesis follow partly distinct pathways. Mouse AR epistasis, mTOR/PON1 observations and context-dependent cell-death responses refine the canonical mechanism; tissue-specific causes of many extrahepatic manifestations remain unresolved.

The canonical proximal metabolic model is retained after assessment of the OpenScientist report. The report is a literature synthesis, not an executed analysis. Increased Fas apoptosis is not the central hepatocyte mechanism: mouse hepatocytes resist it. AR deletion restores NADPH and prevents HCC but not GSH depletion or cirrhosis. The mTOR/PON1/aPL findings occur in TAL single and TAL/AR double knockouts; patient relevance is unproven. Four heterozygous APAP cases treated with NAC are not a controlled trial in congenital biallelic disease. Erythronic acid is a variable biomarker with proposed PPP-derived routes, not a universally elevated proven toxin. Long-term transplant outcomes and GenCC assertions exist, contrary to report absence claims.

Deep research

OpenScientist citations 30 citations 2026-05-23T02:08:39.143913

Show evidence (11 references)

PMID:15115436 SUPPORT In Vitro

"Recombinant TALDeltaS171 had no enzymic activity."

The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.

PMID:18498245 SUPPORT In Vitro

"Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP."

Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.

PMID:19436114 SUPPORT Model Organism

"depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides."

Mouse liver measurements support impaired antioxidant capacity.

+ 8 more references

⚙

Pathophysiology

16

TALDO1 transaldolase activity deficiency

Biallelic TALDO1 variants reduce or abolish human transaldolase protein stability and catalytic activity. The Ser171 deletion mechanism shows that mutant transaldolase can be translated but rapidly degraded by the proteasome and lacks appreciable enzymatic activity.

TALDO1 hgnc:11559

pentose phosphate pathway GO:0006098 ↓ DECREASED

transaldolase activity GO:0004801 ↓ DECREASED

Downstream

Pentose phosphate pathway carbon sequestration Loss of transaldolase impairs nonoxidative carbon recycling.

Renal tubular dysfunction The inherited metabolic defect causes renal disease through incompletely established tissue-specific mechanisms.

Gonadal dysfunction The disease includes gonadal dysfunction; its precise biochemical and developmental intermediates are unresolved.

Hydrops fetalis This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Abnormal facial shape This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Premature skin wrinkling This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Atrial septal defect This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Coarctation of aorta This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Biventricular hypertrophy This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Abnormality of the clitoris This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Telangiectasia This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Global developmental delay This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Abnormal respiratory system physiology This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Anemia This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Thrombocytopenia This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.

Intrauterine growth retardation This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.

Failure to thrive This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.

Osteopenia This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.

Show evidence (1 reference)

PMID:15115436 SUPPORT In Vitro

"Recombinant TALDeltaS171 had no enzymic activity."

The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.

Pentose phosphate pathway carbon sequestration

Sedoheptulose-7-phosphate and other nonoxidative PPP intermediates accumulate while recycling into G6P and related biosynthetic substrates declines. TAL catalyzes a reversible carbon-transfer reaction; it does not directly produce NADPH. Carbon sequestration can persist despite restoration of NADPH by AR deletion.

pentose-phosphate shunt GO:0006098 ⚠ ABNORMAL

Experimental models

Patient-derived TAL-deficient lymphoblasts CELL LINE Patient lymphoblasts accumulate sedoheptulose-7-phosphate with depleted glucose-6-phosphate and NADPH; TAL restoration tests the biochemical defect.

Downstream

Aldose reductase-dependent polyol formation Accumulated sugars feed an AR-dependent polyol disposal pathway.

Antioxidant cofactor depletion Impaired G6P recycling limits oxidative PPP reducing capacity.

mTOR activation Carbon and biosynthetic substrate restriction is proposed to activate mTOR in TAL-deficient mouse liver.

Show evidence (1 reference)

PMID:18498245 SUPPORT In Vitro

"Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP."

Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.

Aldose reductase-dependent polyol formation

Mechanism confidence: Provisional

Aldose reductase converts accumulated unphosphorylated sugars to polyols while consuming NADPH. In mice, AR deletion prevents polyol buildup and HCC but worsens carbon trapping and growth restriction; it does not abolish cirrhosis. AR is therefore a context-dependent metabolic modifier, not a proven patient therapeutic target.

liver UBERON:0002107

Animal models

Taldo1 and aldose-reductase double-knockout mouse Mouse perturbs Deleting aldose reductase suppresses the polyol accumulation of Taldo1 deficiency and restores NADPH, directly perturbing this pathway.

Downstream

Antioxidant cofactor depletion AR consumes NADPH during polyol formation.

Show evidence (1 reference)

PMID:36658399 SUPPORT Model Organism

"the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC."

Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.

Antioxidant cofactor depletion

NADPH and glutathione depletion impair antioxidant defenses in mouse liver. NADPH depletion also occurs in patient lymphoblasts. NADPH restoration and GSH restoration are distinct: AR deletion restores NADPH while GSH remains depleted in double-knockout liver.

response to oxidative stress GO:0006979 ⚠ ABNORMAL

Downstream

Mitochondrial dysfunction Impaired reducing capacity is associated with mitochondrial oxidative damage.

Oxidative hepatocyte injury Reduced detoxification capacity sensitizes the liver to acetaminophen injury.

Fas apoptosis resistance and adaptive proliferation Oxidative adaptation changes proliferative and Fas death signaling in mouse hepatocytes.

Hepatic fibrosis and cirrhosis Persistent GSH depletion is one proposed driver of residual mouse cirrhosis; human fibrosis has additional unresolved intermediates.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides."

Mouse liver measurements support impaired antioxidant capacity.

PMID:36658399 SUPPORT Model Organism

"GSH depletion of TALKO livers persisted in DKO livers."

Restored NADPH in the double knockout does not restore GSH; these pools are not interchangeable.

Mitochondrial dysfunction

Loss of mitochondrial membrane potential is observed in TAL-deficient mouse liver and patient lymphoblasts. Mouse liver has reduced mitochondrial mass and ATP/ADP, whereas lymphoblast mitochondrial mass and ATP increase. A universal energy-depletion step is not supported.

mitochondrion organization GO:0007005 ⚠ ABNORMAL

Experimental models

Patient-derived TAL-deficient lymphoblasts CELL LINE Patient lymphoblasts show increased mitochondrial mass and ATP, with altered calcium handling; TAL gene transfer reverses several measured cellular abnormalities.

Animal models

Taldo1-null and heterozygous mouse Mouse recapitulates Taldo1-null liver shows reduced mitochondrial membrane potential, mitochondrial mass and ATP/ADP ratio under the studied conditions.

Downstream

Hepatocarcinogenesis Mouse AR epistasis links mitochondrial oxidative stress to progression to HCC; it does not establish a quantitatively dominant mechanism in patients.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio."

These mitochondrial and energetic changes were measured in mouse liver.

PMID:18498245 SUPPORT In Vitro

"increased mitochondrial mass associated with increased production of nitric oxide and ATP."

Patient lymphoblasts show a different mitochondrial-mass and ATP response, preventing universal extrapolation from liver.

Oxidative hepatocyte injury

Oxidative challenge can provoke hepatocellular injury and acetaminophen-induced necrosis in TAL-deficient mice. A child developed liver failure after therapeutic acetaminophen during infection. Chronic liver damage should not be represented as universally increased Fas apoptosis.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Hepatic failure Hepatocyte injury can decompensate hepatic function.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure."

Mouse experiments identify an oxidative challenge-sensitive injury pathway.

PMID:29923087 SUPPORT Human Clinical

"We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection."

A human temporal association supports precautionary avoidance; concurrent infection limits attribution.

Fas apoptosis resistance and adaptive proliferation

Mechanism confidence: Provisional

TAL-deficient mouse hepatocytes resist CD95/Fas-mediated apoptosis and exhibit altered beta-catenin and c-Jun signaling. Lifelong NAC restores Fas-mediated apoptosis while preventing HCC. Patient lymphoblasts also resist Fas death but are more susceptible to peroxide and CD20-triggered apoptosis.

hepatocyte CL:0000182

apoptotic process GO:0006915 ↓ DECREASED

liver UBERON:0002107

Animal models

Taldo1-null and heterozygous mouse Mouse recapitulates Taldo1-null hepatocytes resist CD95/Fas-mediated apoptosis in culture and in vivo, with altered beta-catenin phosphorylation and c-Jun expression.

Downstream

Hepatocarcinogenesis Failure of Fas-mediated elimination and adaptive growth signaling are proposed contributors to mouse carcinogenesis.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo."

The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.

PMID:19436114 SUPPORT Model Organism

"Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress."

Adaptive signaling accompanies resistance to Fas-mediated elimination.

Hepatocarcinogenesis

HCC can arise in affected children, including before 18 months, and in Taldo1-null or heterozygous mice. Mouse AR-dependent redox and survival signaling explain part of this susceptibility; human risk fractions and modifiers remain uncertain.

hepatocyte CL:0000182

cell population proliferation GO:0008283 ↑ INCREASED

liver UBERON:0002107

Animal models

Taldo1-null and heterozygous mouse Mouse recapitulates Taldo1-deficient mice develop liver tumors; genetic and antioxidant interventions test contributions of redox stress to progression.

Downstream

Hepatocellular carcinoma Malignant hepatocyte transformation produces the observed tumor phenotype.

Show evidence (2 references)

PMID:34677006 SUPPORT Human Clinical

"Two of the 3 transplanted patients in our series had HCC in the explanted livers"

HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- and Taldo1+/- mice spontaneously developed HCC"

Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.

mTOR activation

Mechanism confidence: Provisional

mTOR activation and altered autophagy accompany TAL deficiency in mouse liver. This experimental branch is present with functional AR and persists after AR deletion. Rapamycin rescue supports pathway involvement without establishing a therapy for patients.

TOR signaling GO:0031929 ↑ INCREASED

liver UBERON:0002107

Downstream

Impaired PON1 glycosylation and secretion mTOR-associated substrate and glycosylation changes reduce PON1 secretion in the proposed mouse mechanism.

Hepatic stellate cell expansion Rapamycin reduces stellate-cell expansion, supporting mTOR-dependent fibrogenic signaling.

Show evidence (1 reference)

PMID:37742509 SUPPORT Model Organism

"These findings suggest that deficient recycling of 6-carbon substrates by the PPP elicits mTOR activation and limits glycosylation and PON1 secretion into the bloodstream of TALKO and DKO mice."

The proposed mechanism occurs in TAL single knockouts as well as TAL/AR double knockouts; human congenital-disease validation is absent.

Impaired PON1 glycosylation and secretion

Mechanism confidence: Provisional

TALKO and TAL/AR-double-knockout mouse livers have reduced PON1 expression, glycosylation, secretion and activity. Biosynthetic substrate depletion contributes; PON1 measurements in human TALDO deficiency remain a verification need.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Antiphospholipid autoantibody production The proposed mouse pathway links lower PON1 antioxidant activity to phospholipid-directed autoimmunity; selective mediation remains incompletely isolated.

Show evidence (2 references)

PMID:37742509 SUPPORT Model Organism

"PON1 protein levels and enzymatic activities are diminished in the livers and sera of TALKO and DKO mice."

Measured protein and enzyme activity support PON1 impairment in both genotypes.

PMID:37742509 SUPPORT Model Organism

"Diminished secretion of PON1 was attributed to the depletion of substrates, F6P, UTP, UDP-glucose and UDP-GlcNAc"

Substrate depletion, glycosidase experiments and mass spectrometry support defective glycosylation; they do not prove every proposed causal intermediate in patients.

Antiphospholipid autoantibody production

Mechanism confidence: Hypothetical

Anticardiolipin and anti-beta2-glycoprotein-I antibodies increase in TALKO and double-knockout mice. This is not an established human TALDO phenotype or a demonstrated obligatory cause of fibrosis.

liver UBERON:0002107

Downstream

Hepatic stellate cell expansion The proposed autoimmune branch may promote stellate activation; shared rapamycin responsiveness is not proof that antibodies alone cause fibrosis.

Show evidence (1 reference)

PMID:37742509 SUPPORT Model Organism

"aPL production against apolipoprotein H (Apo-H, also called β2-glycoprotein 1) and cardiolipin, is increased in TALKO and DKO mice."

Antiphospholipid antibodies are a mouse observation, not an established patient feature.

Hepatic stellate cell expansion

Mechanism confidence: Provisional

Profibrotic hepatic stellate cells expand in TALKO and double-knockout mice, with increased CD38 and reduced CD161-positive NK cells. Rapamycin limits this expansion. The contribution of each immune mediator in patients is unresolved.

hepatic stellate cell CL:0000632

liver UBERON:0002107

Downstream

Hepatic fibrosis and cirrhosis Expanded profibrotic stellate cells contribute to liver matrix deposition in the experimental model.

Show evidence (1 reference)

PMID:37742509 SUPPORT Model Organism

"Treatment with rapamycin enhanced serum PON1 activity and blocked aPL production and the expansion of HSC in TALKO mice."

Rapamycin perturbs the proposed axis in single-knockout mice. Its pleiotropic effects do not isolate PON1 or aPL as the sole mediator.

Hepatic fibrosis and cirrhosis

Hepatic fibrosis and micronodular cirrhosis are major human manifestations. Cirrhosis can persist in mice lacking both TAL and AR despite protection from HCC, so fibrosis and malignancy are distinct outcomes. Progression varies from neonatal liver failure to stable cirrhosis or slowly progressive adult disease.

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

liver UBERON:0002107

Animal models

Taldo1 and aldose-reductase double-knockout mouse Mouse recapitulates Cirrhosis persists in the double knockout despite restored NADPH and blocked progression to hepatocellular carcinoma.

Downstream

Cirrhosis Hepatic remodeling produces the clinical cirrhosis phenotype.

Portal hypertension and hypersplenism Cirrhosis and altered hepatic resistance lead to portal-hypertensive complications.

Hepatic failure Severe liver disease can compromise hepatic function.

Abnormality of coagulation Hepatic dysfunction contributes to coagulopathy independently of platelet depletion.

Show evidence (3 references)

PMID:41823103 SUPPORT Human Clinical

"Micronodular cirrhosis developed in 10 patients."

Human longitudinal cohort documents hepatic remodeling.

PMID:36658399 SUPPORT Model Organism

"Although AR inactivation blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC, it exacerbated carbon sequestration in the PPP and caused further growth restriction."

Cirrhosis, carbon restriction and carcinogenesis must be distinguished.

PMID:36658399 SUPPORT Model Organism

"cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice"

The paper attributes residual cirrhosis to persistent GSH depletion; this mechanistic interpretation remains preclinical.

Portal hypertension and hypersplenism

Portal hypertension can produce splenomegaly, varices and ascites. Hypersplenism can contribute to later cytopenias, while neonatal anemia and thrombocytopenia may have additional mechanisms. Congenital vascular skin lesions are not attributed wholesale to portal hypertension.

liver UBERON:0002107

Downstream

Hepatosplenomegaly Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.

Thrombocytopenia Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.

Anemia Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.

Edema Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.

Show evidence (2 references)

PMID:41823103 SUPPORT Human Clinical

"Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four."

Longitudinal liver disease is associated with portal hypertension and its complications.

PMID:41823103 SUPPORT Human Clinical

"Almost all patients had hypersplenism, likely influencing cytopenia."

Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.

Renal tubular dysfunction

Renal disease commonly includes low-molecular-weight proteinuria, hypercalciuria, aminoaciduria, phosphate wasting and tubular acidosis. Some patients progress to chronic kidney disease. The clinical association is established, but polyol toxicity or local NADPH failure has not been directly isolated in patient renal tissue.

kidney UBERON:0002113

Downstream

Abnormality of the kidney Tubular injury produces urinary solute loss or progressive renal dysfunction.

Renal tubular dysfunction phenotype Tubular injury produces urinary solute loss or progressive renal dysfunction.

Chronic kidney disease Tubular injury produces urinary solute loss or progressive renal dysfunction.

Hypercalciuria Tubular injury produces urinary solute loss or progressive renal dysfunction.

Proteinuria Tubular injury produces urinary solute loss or progressive renal dysfunction.

Show evidence (2 references)

PMID:22510381 SUPPORT Human Clinical

"Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure."

Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.

PMID:22510381 SUPPORT Human Clinical

"The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria."

Defines the measured tubular phenotype.

Gonadal dysfunction

Hypergonadotropic hypogonadism can become prominent in adolescence and adulthood. Reduced sex-steroid production and gonadal insufficiency are documented; attribution specifically to NADPH limitation remains a mechanistic hypothesis.

gonad UBERON:0000991

Downstream

Hypergonadotropic hypogonadism Gonadal insufficiency produces the endocrine phenotype.

Show evidence (1 reference)

PMID:30740741 SUPPORT Human Clinical

"In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life."

Human endocrine findings support gonadal dysfunction but do not directly prove impaired NADPH-dependent steroidogenesis as its cause.

⬡

Pathograph

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●

Phenotypes

29

Blood 3

Thrombocytopenia VERY_FREQUENT HP:0001873

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001873 | Thrombocytopenia | Very frequent (99-80%)"

Orphanet records thrombocytopenia as a very frequent phenotype.

PMID:24497183 SUPPORT Human Clinical

"hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"

The clinical report supports thrombocytopenia in affected patients.

Anemia VERY_FREQUENT HP:0001903

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001903 | Anemia | Very frequent (99-80%)"

Orphanet records anemia as a very frequent phenotype.

PMID:24497183 SUPPORT Human Clinical

"hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"

The clinical report supports anemia in affected patients.

Abnormality of coagulation HP:0001928

Show evidence (1 reference)

PMID:41823103 SUPPORT Human Clinical

"Coagulation disorders were observed in almost all patients"

Clinical follow-up documents coagulation dysfunction.

Cardiovascular 5

Hepatosplenomegaly VERY_FREQUENT HP:0001433

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001433 | Hepatosplenomegaly | Very frequent (99-80%)"

Orphanet records hepatosplenomegaly as a very frequent phenotype.

PMID:25388407 SUPPORT Human Clinical

"The patients had variable clinical presentations including hepatosplenomegaly"

Patient-level evidence supports hepatosplenomegaly.

Telangiectasia FREQUENT HP:0001009

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001009 | Telangiectasia | Frequent (79-30%)"

Orphanet records telangiectasia as frequent.

PMID:25388407 SUPPORT Human Clinical

"skin manifestations (e.g., dryness, cutis laxa, ichthyosis, telangiectasias, and hemangiomas)."

Patient-series abstract supports telangiectasias.

Atrial septal defect OCCASIONAL HP:0001631

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0001631 | Atrial septal defect | Occasional (29-5%)"

Orphanet records atrial septal defect as occasional.

Coarctation of aorta OCCASIONAL HP:0001680

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0001680 | Coarctation of aorta | Occasional (29-5%)"

Orphanet records coarctation of aorta as occasional.

Biventricular hypertrophy OCCASIONAL HP:0200128

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0200128 | Biventricular hypertrophy | Occasional (29-5%)"

Orphanet records biventricular hypertrophy as occasional.

Digestive 3

Cirrhosis VERY_FREQUENT HP:0001394

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001394 | Cirrhosis | Very frequent (99-80%)"

Orphanet records cirrhosis as a very frequent phenotype.

PMID:18331807 SUPPORT Human Clinical

"subsequently found to have cirrhosis and deafness"

The clinical report documents cirrhosis in a child with TALDO deficiency.

Hepatocellular carcinoma HP:0001402

Show evidence (3 references)

PMID:34677006 SUPPORT Human Clinical

"Two of the 3 transplanted patients in our series had HCC in the explanted livers"

HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- and Taldo1+/- mice spontaneously developed HCC"

Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.

PMID:37071763 SUPPORT Human Clinical

"another with transaldolase deficiency, underwent living donor liver transplants. Explant-liver histopathology revealed tumor with diffuse neoplastic syncytial giant cell pattern"

Explant pathology from a second centre independently documents hepatocellular carcinoma in an infant with transaldolase deficiency and characterizes it as the syncytial giant cell variant, so the tumour is recorded in infancy outside the four-patient series cited above.

Hepatic failure HP:0001399

Show evidence (1 reference)

PMID:41823103 SUPPORT Human Clinical

"Liver involvement was present in all patients, with six presenting liver failure at birth."

Human cohort documents liver failure.

Endocrine 1

Hypergonadotropic hypogonadism OCCASIONAL HP:0000815

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

PMID:38440129 SUPPORT Human Clinical

"two Emirati patients with hypergonadotropic hypogonadism due to transaldolase deficiency"

The case report directly documents hypergonadotropic hypogonadism in transaldolase deficiency.

PMID:33159679 SUPPORT Human Clinical

"deficiency characterized by hypergonadotropic hypogonadism and slightly elevated"

A late-onset patient report supports hypergonadotropic hypogonadism as a variable manifestation.

Genitourinary 6

Abnormality of the clitoris FREQUENT Abnormal clitoris morphology HP:0000056

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0000056 | Abnormality of the clitoris | Frequent (79-30%)"

Orphanet records clitoral abnormality as frequent.

Abnormality of the kidney FREQUENT HP:0000077

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0000077 | Abnormality of the kidney | Frequent (79-30%)"

Orphanet records kidney abnormality as frequent.

PMID:25388407 SUPPORT Human Clinical

"renal and cardiac abnormalities, and urinary excretion of polyols."

Patient-series abstract supports renal abnormalities in the disorder.

Renal tubular dysfunction phenotype HP:0000124

Show evidence (2 references)

PMID:22510381 SUPPORT Human Clinical

"Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure."

Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.

PMID:22510381 SUPPORT Human Clinical

"The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria."

Defines the measured tubular phenotype.

Chronic kidney disease HP:0012622

Show evidence (1 reference)

PMID:41823103 SUPPORT Human Clinical

"Five patients developed chronic kidney disease (CKD)."

Five of 16 patients developed CKD; two older patients were evaluated for, but did not undergo, kidney transplantation.

Hypercalciuria HP:0002150

Show evidence (2 references)

PMID:22510381 SUPPORT Human Clinical

"Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure."

Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.

PMID:22510381 SUPPORT Human Clinical

"The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria."

Defines the measured tubular phenotype.

Proteinuria HP:0000093

Show evidence (2 references)

PMID:22510381 SUPPORT Human Clinical

"Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure."

Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.

PMID:22510381 SUPPORT Human Clinical

"The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria."

Defines the measured tubular phenotype.

Head and Neck 1

Abnormal facial shape FREQUENT HP:0001999

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001999 | Abnormal facial shape | Frequent (79-30%)"

Orphanet records abnormal facial shape as frequent.

PMID:23315216 SUPPORT Human Clinical

"growth retardation, dysmorphic features, cutis laxa, congenital heart disease"

The 12-case series supports dysmorphic features.

Integument 1

Premature skin wrinkling FREQUENT HP:0100678

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0100678 | Premature skin wrinkling | Frequent (79-30%)"

Orphanet records premature skin wrinkling as frequent.

PMID:23315216 SUPPORT Human Clinical

"growth retardation, dysmorphic features, cutis laxa, congenital heart disease"

The 12-case series supports cutis laxa and abnormal skin findings.

Metabolism 4

Abnormality of glutamine metabolism VERY_FREQUENT Abnormal circulating glutamine concentration HP:0010903

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0010903 | Abnormality of glutamine metabolism | Very frequent (99-80%)"

Orphanet records abnormal glutamine metabolism as very frequent.

Increased serum bile acid concentration VERY_FREQUENT HP:0012202

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0012202 | Increased serum bile acid concentration | Very frequent (99-80%)"

Orphanet records increased serum bile acids as very frequent.

Edema FREQUENT HP:0000969

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0000969 | Edema | Frequent (79-30%)"

Orphanet records edema as frequent.

Hydrops fetalis FREQUENT HP:0001789

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001789 | Hydrops fetalis | Frequent (79-30%)"

Orphanet records hydrops fetalis as frequent.

PMID:25388407 SUPPORT Human Clinical

"proteinuria, hydrops fetalis, cardiomyopathy, and skin manifestations"

Patient-series abstract supports hydrops fetalis.

Musculoskeletal 1

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:41806563 SUPPORT Human Clinical

"In adulthood, the dominant clinical features were hypergonadotropic hypogonadism, osteopenia, renal and hepatic involvement."

Adult case series identifies skeletal involvement.

Nervous System 1

Global developmental delay OCCASIONAL HP:0001263

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"HP:0001263 | Global developmental delay | Occasional (29-5%)"

Orphanet records global developmental delay as occasional.

PMID:41823103 SUPPORT Human Clinical

"None of our patients developed severe cognitive impairment, and only mild intellectual delay was observed."

The long-term cohort limits deterministic neurodevelopmental claims.

Respiratory 1

Abnormal respiratory system physiology OCCASIONAL HP:0002795

Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"HP:0002795 | Abnormal respiratory system physiology | Occasional (29-5%)"

Orphanet records respiratory physiology abnormality as occasional.

Growth 2

Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:30740741 SUPPORT Human Clinical

"Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly."

The 34-patient cohort documents prenatal growth restriction.

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:41823103 SUPPORT Human Clinical

"Growth failure posed a major challenge in the three most severely affected patients"

Growth and nutritional impairment affected transplant feasibility.

🧬

Genetic Associations

1

Biallelic TALDO1 pathogenic variants (Causative)

Gene: TALDO1 hgnc:11559 relationship_type: CAUSATIVE

Autosomal recessive inheritance

Show evidence (3 references)

ORPHA:101028 SUPPORT Other

"TALDO1 | transaldolase 1 | hgnc:11559 | Disease-causing germline mutation(s) in"

Orphanet records TALDO1 as disease-causing.

PMID:23315216 SUPPORT Human Clinical

"sequencing confirmed segregation of a novel homozygous mutation with the disease"

Segregation in affected families supports recessive TALDO1 causality.

PMID:38440129 SUPPORT Human Clinical

"caused by pathogenic/likely pathogenic biallelic mutations in the TALDO1 gene"

Recent clinical review supports biallelic TALDO1 variants as the molecular cause.

🗃️

External Assertions

1

Orphanet Transaldolase deficiency disease record

Orphanet structured disease record ORPHA:101028

Orphanet's ORPHA:101028 structured record for Transaldolase deficiency provides the disease definition, autosomal recessive inheritance, TALDO1 disease-causing gene association, point-prevalence estimate, onset categories, exact MONDO/OMIM cross-references, and HPO phenotype frequencies used in this entry.

Show evidence (2 references)

ORPHA:101028 SUPPORT Other

"MONDO:0011624 | Exact"

Orphanet maps ORPHA:101028 exactly to the MONDO term used here.

ORPHA:101028 SUPPORT Other

"OMIM:606003 | Exact"

Orphanet lists OMIM:606003 as an exact external cross-reference.

💊

Medical Actions

4

Supportive management and acetaminophen avoidance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Disease-specific management is supportive and should include avoidance of acetaminophen because clinical and model evidence indicates increased vulnerability to acetaminophen-related oxidative liver injury.

Mechanism Target:

INHIBITS Oxidative hepatocyte injury — Avoidance removes an exposure associated with oxidative liver injury; it does not restore TAL activity.

Show evidence (1 reference)

PMID:29923087 SUPPORT Human Clinical

"transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic."

The human case report supports avoidance of acetaminophen as a way to reduce oxidative liver-injury risk.

Show evidence (2 references)

PMID:24497183 SUPPORT Human Clinical

"Symptomatic treatment can be proposed."

The clinical report states that symptomatic treatment can be proposed.

PMID:29923087 SUPPORT Human Clinical

"transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic."

A human case and supporting model evidence support acetaminophen avoidance.

N-acetylcysteine for oxidative liver stress

Action: Pharmacotherapy NCIT:C15986

Agent: N-acetyl-L-cysteine CHEBI:28939

N-acetylcysteine has model-organism support for preventing acetaminophen-induced liver failure and limited human observational support for lowering alpha-fetoprotein, so it is recorded as a context-specific antioxidant option rather than established disease-modifying therapy.

Mechanism Target:

INHIBITS Antioxidant cofactor depletion — NAC supports glutathione synthesis in preclinical rescue experiments. Human long-term efficacy remains uncertain.

Show evidence (1 reference)

PMID:19436114 SUPPORT Model Organism

"lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice."

Lifelong mouse treatment supports antioxidant rescue; efficacy against human congenital disease is unproven.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice."

Lifelong mouse treatment supports antioxidant rescue; efficacy against human congenital disease is unproven.

PMID:29923087 SUPPORT Human Clinical

"After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels"

AFP decline cannot be attributed to NAC in this patient.

Liver transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

Liver transplantation is a documented option for severe liver failure or HCC, with some patients maintaining normal graft function for decades. It does not correct systemic TAL deficiency; renal, endocrine, growth or respiratory problems may persist or emerge. Infant nutritional status, multisystem involvement and transplant complications affect candidacy and outcome.

Mechanism Target:

BYPASSES Hepatic fibrosis and cirrhosis — Replacing the diseased liver corrects the hepatic organ defect while leaving extrahepatic TAL deficiency.

Show evidence (3 references)

PMID:34677006 SUPPORT Human Clinical

"21 years after LT, she has normal liver graft function"

A published patient has long-term graft survival, beyond the two-year limit claimed in the report.

PMID:34572178 SUPPORT Human Clinical

"TALDO is a multi-organ disease, therefore LT does not cure patients from the disease."

Systemic manifestations require continued surveillance despite hepatic correction.

PMID:41823103 SUPPORT Human Clinical

"A third patient died from posttransplant complications at 6 months of life."

Outcomes include serious complications and death; transplantation is not uniformly successful.

Show evidence (5 references)

PMID:34677006 SUPPORT Human Clinical

"21 years after LT, she has normal liver graft function"

A published patient has long-term graft survival, beyond the two-year limit claimed in the report.

PMID:34572178 SUPPORT Human Clinical

"TALDO is a multi-organ disease, therefore LT does not cure patients from the disease."

Systemic manifestations require continued surveillance despite hepatic correction.

PMID:41823103 SUPPORT Human Clinical

"A third patient died from posttransplant complications at 6 months of life."

Outcomes include serious complications and death; transplantation is not uniformly successful.

+ 2 more references

Multisystem surveillance and supportive treatment

Monitor hepatic function, coagulation, blood counts, growth and nutrition, renal function and tubular losses, endocrine development, and respiratory or cardiac symptoms. Assess the native liver for suspicious nodules and HCC. Treat identified endocrine deficiencies and renal complications individually; continue surveillance after liver transplantation.

Show evidence (3 references)

PMID:34677006 SUPPORT Human Clinical

"Close monitoring for these features in patients with transaldolase deficiency is highly recommended, regardless of LT."

The clinical series recommends surveillance despite transplantation.

PMID:41823103 SUPPORT Human Clinical

"Hypergonadotropic hypogonadism was found in seven patients; two others developed secondary adrenal cortisol insufficiency and primary hypothyroidism requiring replacement therapy."

The cohort documents hormone replacement needs.

PMID:41823103 SUPPORT Human Clinical

"five patients received ACE inhibitors or angiotensin receptor blockers for proteinuria."

Renal therapy is based on individual clinical findings.

🌍

Environmental Factors

1

Acetaminophen exposure

Acetaminophen can exacerbate hepatic oxidative injury in TAL-deficient mice. A clinical case after standard dosing during RSV infection supports avoidance in affected patients, although the concurrent illness limits causal attribution.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure."

Mouse experiments identify an oxidative challenge-sensitive injury pathway.

PMID:29923087 SUPPORT Human Clinical

"We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection."

A human temporal association supports precautionary avoidance; concurrent infection limits attribution.

Mechanism Target:

Oxidative hepatocyte injury — The exposure challenges already impaired hepatic antioxidant defenses.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure."

Mouse experiments identify an oxidative challenge-sensitive injury pathway.

PMID:29923087 SUPPORT Human Clinical

"We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection."

A human temporal association supports precautionary avoidance; concurrent infection limits attribution.

🔬

Biochemical Markers

4

Reduced transaldolase activity (DECREASED)

Context: Patient-derived fibroblast and lymphoblast studies and recombinant protein assays show loss of transaldolase enzymatic activity in disease-associated TALDO1 variants.

Pathograph Readouts

Readout Of TALDO1 transaldolase activity deficiency Positive

Lower measured activity marks a more severe enzyme deficiency.

Show evidence (1 reference)

PMID:15115436 SUPPORT In Vitro

"Recombinant TALDeltaS171 had no enzymic activity."

The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.

Show evidence (1 reference)

PMID:15115436 SUPPORT In Vitro

"no expression of the TALDeltaS171 protein or enzyme activity was detected"

Patient-cell experiments support reduced transaldolase activity as the primary biochemical defect.

Increased urinary polyols and seven-carbon sugars (INCREASED)

Context: Urine testing shows increased erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose, and sedoheptulose-7-phosphate, supporting the biochemical diagnosis. Neonatal polyol excretion is physiologically high; interpret against age-specific controls.

Pathograph Readouts

Readout Of Pentose phosphate pathway carbon sequestration Positive

Urinary carbohydrate abnormalities report the underlying metabolic block.

Show evidence (1 reference)

PMID:18498245 SUPPORT In Vitro

"Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP."

Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.

Show evidence (3 references)

PMID:24497183 SUPPORT Human Clinical

"Elevated excretion of erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose and sedoheptulose-7P in the urine"

The patient report provides the diagnostic urinary metabolite pattern.

PMID:29923087 SUPPORT Human Clinical

"Urine polyols and plasma metabolomics confirmed the diagnosis of transaldolase deficiency."

Human metabolomics data support urine polyols as diagnostic biochemical evidence.

PMID:18987485 SUPPORT Human Clinical

"Urinary excretion of polyols shows an age dependency with highest concentrations postnatally independent of the grade of maturity."

Age-specific interpretation is necessary; high neonatal polyols alone do not establish TALDO deficiency.

Urinary erythronic acid (INCREASED)

Context: Increased in the original six-patient study and knockout mice, but below detection in a later patient. It is an adjunct metabolic marker, not a universal diagnostic requirement or proven toxin. Proposed erythrose-based PPP routes remain incompletely validated.

Show evidence (2 references)

PMID:20600873 SUPPORT Human Clinical

"Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed"

Defines the original study population.

PMID:26238251 SUPPORT Human Clinical

"the level of erythronic acid in our case, if any, is lower than this limit."

A later case limits universal elevation claims; it does not prove complete absence.

Elevated alpha-fetoprotein (INCREASED)

Context: AFP can be elevated during liver injury and in patients with suspicious nodules. Its level is age-dependent and nonspecific; a decline does not alone prove NAC efficacy or exclude HCC.

Show evidence (2 references)

PMID:29923087 SUPPORT Human Clinical

"rising alpha-fetoprotein which peaked 2 weeks after acetaminophen exposure."

The clinical case documents AFP change during liver injury without demonstrating a cancer-specific marker.

PMID:29923087 SUPPORT Human Clinical

"After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels"

Temporal AFP decline precedes NAC and cannot be attributed to treatment.

🔬

Diagnosis

2

Urinary polyol and seven-carbon sugar testing

Gas chromatography and liquid chromatography-tandem mass spectrometry of urine can identify increased polyols and seven-carbon sugars, including sedoheptulose and sedoheptulose-7-phosphate, supporting the biochemical diagnosis. Interpret urine polyols using age-appropriate reference ranges, especially in neonates. Molecular or enzyme confirmation is needed because individual biomarkers are not universally abnormal.

Results: Increased urinary polyols and seven-carbon sugars support transaldolase deficiency.

Show evidence (3 references)

PMID:24497183 SUPPORT Human Clinical

"The diagnosis was established by detecting high concentrations of erythritol, ribitol, arabitol"

The report supports urinary sugar/polyol profiling as a diagnostic approach.

PMID:18987485 SUPPORT Human Clinical

"Urinary excretion of polyols shows an age dependency with highest concentrations postnatally independent of the grade of maturity."

Age-specific interpretation is necessary; high neonatal polyols alone do not establish TALDO deficiency.

PMID:17603756 SUPPORT Human Clinical

"Transaldolase-deficient patients had significantly increased urinary sedoheptulose and sedoheptulose 7-phosphate, associated with subtle elevations of mannoheptulose, sedoheptitol and perseitol."

The liquid chromatography-tandem mass spectrometry method paper that established the seven-carbon biomarker panel named in this test, ranking sedoheptulose and sedoheptulose 7-phosphate as the discriminating analytes above mannoheptulose, sedoheptitol and perseitol.

TALDO1 molecular genetic testing

Molecular testing confirms biallelic TALDO1 pathogenic variants, including sequence variants and exon-level deletions that may require copy-number or long-range PCR approaches when sequencing finds only one allele.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:24497183 SUPPORT Human Clinical

"then confirmed by molecular analysis of the TALDO gene."

The clinical report supports molecular confirmation of biochemical diagnosis.

📈

Progression

2

Antenatal-to-neonatal multisystem presentation

Age: Antenatal, neonatal, or infancy

Orphanet records antenatal, neonatal, and infancy onset. Published cohorts describe prenatal growth and fluid abnormalities and neonatal anemia, thrombocytopenia, hepatosplenomegaly, liver involvement, renal disease, and later variable endocrine presentations.

Show evidence (3 references)

ORPHA:101028 SUPPORT Other

"Age of onset: Antenatal"

Orphanet records antenatal onset.

ORPHA:101028 SUPPORT Other

"Age of onset: Neonatal"

Orphanet records neonatal onset.

PMID:24497183 SUPPORT Human Clinical

"Patients present severe symptoms during the neonatal period"

The clinical report supports typical severe neonatal presentation.

Variable childhood-to-adult progression

Age: Childhood through adulthood

Neonatal symptoms do not invariably predict early death. Adults may have gradual renal, hepatic, skeletal and endocrine progression. In a 2026 cohort, follow-up extended to 20 years; post-transplant hepatic and extrahepatic outcomes must be assessed separately.

Show evidence (2 references)

PMID:41806563 SUPPORT Human Clinical

"even if clinical manifestations begin in the neonatal period, the overall phenotype may remain relatively mild, with gradual progression."

The adult series documents a slowly progressive trajectory.

PMID:41823103 SUPPORT Human Clinical

"We retrospectively collected data on 16 patients followed for up to 20 years."

Longitudinal follow-up informs monitoring and prognosis.

📊

Prevalence

1

Worldwide

Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000

Orphanet records worldwide point prevalence below 1 per 1,000,000.

Show evidence (1 reference)

ORPHA:101028 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:23315216"

Orphanet provides the worldwide point-prevalence estimate.

🧫

Experimental Models

1

Patient-derived TAL-deficient lymphoblasts CELL_LINE

TAL-deficient lymphoblasts show S7P accumulation, G6P and NADPH depletion, altered mitochondrial potential and stimulus-specific apoptosis. AAV-mediated restoration of TAL reverses multiple phenotypes.

Pathograph links

Pentose phosphate pathway carbon sequestration recapitulates Patient lymphoblasts accumulate sedoheptulose-7-phosphate with depleted glucose-6-phosphate and NADPH; TAL restoration tests the biochemical defect.

Limitations: One cell context does not establish every organ-specific disease mechanism.

Show evidence (1 reference)

PMID:18498245 SUPPORT In Vitro

"Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP."

Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.

Mitochondrial dysfunction recapitulates Patient lymphoblasts show increased mitochondrial mass and ATP, with altered calcium handling; TAL gene transfer reverses several measured cellular abnormalities.

Limitations: ATP and mitochondrial mass increase in these cells, unlike mouse liver.

Show evidence (1 reference)

PMID:18498245 SUPPORT In Vitro

"increased mitochondrial mass associated with increased production of nitric oxide and ATP."

Patient lymphoblasts show a different mitochondrial-mass and ATP response, preventing universal extrapolation from liver.

Show evidence (1 reference)

PMID:18498245 SUPPORT In Vitro

"Normalization of TAL activity by adeno-associated-virus-mediated gene transfer reversed the elevated CD38 expression, ATP and Ca(2+) levels"

Genetic rescue provides direct cellular support.

🐁

Animal Models

2

Taldo1-null and heterozygous mouse

Mouse models reproduce altered PPP metabolites, redox stress, liver disease and tumor susceptibility. Male null mice are infertile. Lifelong NAC prevents mouse liver injury and HCC; rescue of fertility was demonstrated in heterozygotes.

Species

Mouse

Genotype

Taldo1-/- or Taldo1+/-

Pathograph links

Mitochondrial dysfunction recapitulates Taldo1-null liver shows reduced mitochondrial membrane potential, mitochondrial mass and ATP/ADP ratio under the studied conditions.

Limitations: Mouse liver ATP and mitochondrial mass changes differ from patient lymphoblast responses.

Show evidence (1 reference)

PMID:19436114 SUPPORT Model Organism

"loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio."

These mitochondrial and energetic changes were measured in mouse liver.

Fas apoptosis resistance and adaptive proliferation recapitulates Taldo1-null hepatocytes resist CD95/Fas-mediated apoptosis in culture and in vivo, with altered beta-catenin phosphorylation and c-Jun expression.

Limitations: Fas resistance is distinct from sensitivity to oxidative necrosis.

Show evidence (2 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo."

The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.

+ 1 more reference

Hepatocarcinogenesis recapitulates Taldo1-deficient mice develop liver tumors; genetic and antioxidant interventions test contributions of redox stress to progression.

Limitations: Heterozygous mouse tumor risk does not establish autosomal dominant human TALDO deficiency.

Show evidence (1 reference)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- and Taldo1+/- mice spontaneously developed HCC"

Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.

Show evidence (4 references)

PMID:19436114 SUPPORT Model Organism

"Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo."

The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.

PMID:19436114 SUPPORT Model Organism

"Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress."

Adaptive signaling accompanies resistance to Fas-mediated elimination.

PMID:36658399 SUPPORT Model Organism

"the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC."

Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.

+ 1 more reference

Taldo1 and aldose-reductase double-knockout mouse

AR deletion restores NADPH and blocks HCC and acetaminophen susceptibility while GSH depletion, carbon trapping and cirrhosis persist. Further growth restriction argues against assuming AR inhibition is uniformly beneficial.

Species

Mouse

Genotype

Taldo1-/-; Akr1b3-/-

Pathograph links

Aldose reductase-dependent polyol formation perturbs Deleting aldose reductase suppresses the polyol accumulation of Taldo1 deficiency and restores NADPH, directly perturbing this pathway.

Limitations: Complete germline mouse AR deletion is not equivalent to pharmacologic inhibition in patients.

Show evidence (1 reference)

PMID:36658399 SUPPORT Model Organism

"the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC."

Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.

Hepatic fibrosis and cirrhosis recapitulates Cirrhosis persists in the double knockout despite restored NADPH and blocked progression to hepatocellular carcinoma.

Limitations: Persistence of cirrhosis separates fibrosis from the HCC endpoint.

Show evidence (1 reference)

PMID:36658399 SUPPORT Model Organism

"However, cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice 11 and humans 23, persisted in DKO mice (Figure 1C)."

The primary double-knockout experiment directly reports persistent cirrhosis; it must be distinguished from prevention of HCC progression and from separate human follow-up observations.

Show evidence (2 references)

PMID:36658399 SUPPORT Model Organism

"the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC."

Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.

PMID:36658399 SUPPORT Model Organism

"GSH depletion of TALKO livers persisted in DKO livers."

Restored NADPH in the double knockout does not restore GSH; these pools are not interchangeable.

{ }

Source YAML

click to show

name: Transaldolase Deficiency
creation_date: "2026-05-05T07:40:18Z"
category: Mendelian
synonyms:
- TALDO deficiency
- Eyaid syndrome
description: >-
Transaldolase deficiency is an ultra-rare autosomal recessive inborn error of the pentose phosphate
pathway caused by biallelic TALDO1 pathogenic variants. Loss of transaldolase activity disrupts
nonoxidative pentose-phosphate metabolism, causing accumulation of polyols and seven-carbon
sugars, impaired redox handling, mitochondrial stress, hepatocyte injury, and progressive liver
disease. Affected individuals often present antenatally or neonatally with hydrops or edema,
hepatosplenomegaly, hepatic dysfunction or cirrhosis, thrombocytopenia, anemia, renal abnormalities,
cardiac malformations, abnormal skin vasculature, and variable endocrine or developmental findings.
Diagnosis is supported by urinary polyol and sedoheptulose-7-phosphate abnormalities and confirmed
by TALDO1 molecular testing. Management is largely supportive, with avoidance of acetaminophen
exposure because patients may be unusually vulnerable to oxidative liver injury.
Liver transplantation can treat severe hepatic disease but does not correct the systemic enzyme
defect. Survivors may develop chronic renal disease and endocrine complications into adulthood;
HCC may arise in childhood.
disease_term:
preferred_term: transaldolase deficiency
term:
id: MONDO:0011624
label: transaldolase deficiency
parents:
- Inborn disorder of pentose phosphate metabolism
- Inborn Error of Metabolism
notes: >-
ORPHA:101028 maps Transaldolase deficiency exactly to MONDO:0011624 and
OMIM:606003, lists TALDO1 as the disease-causing gene, and records
antenatal, neonatal, and infancy onset.
mappings:
mondo_mappings:
- term:
id: MONDO:0011624
label: transaldolase deficiency
mapping_predicate: skos:exactMatch
mapping_source: Orphanet ORPHA:101028
mapping_justification: Orphanet ORPHA:101028 lists MONDO:0011624 as an exact cross-reference.
external_assertions:
- name: Orphanet Transaldolase deficiency disease record
source: Orphanet
assertion_type: structured_disease_record
external_id: ORPHA:101028
url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=101028
description: >
Orphanet's ORPHA:101028 structured record for Transaldolase deficiency
provides the disease definition, autosomal recessive inheritance, TALDO1
disease-causing gene association, point-prevalence estimate, onset
categories, exact MONDO/OMIM cross-references, and HPO phenotype
frequencies used in this entry.
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "MONDO:0011624 | Exact"
explanation: Orphanet maps ORPHA:101028 exactly to the MONDO term used here.
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "OMIM:606003 | Exact"
explanation: Orphanet lists OMIM:606003 as an exact external cross-reference.
definitions:
- name: Orphanet transaldolase deficiency definition
definition_type: OTHER
description: >
Inborn error of the pentose phosphate pathway presenting antenatally or
neonatally with hydrops fetalis, hepatosplenomegaly, hepatic dysfunction,
thrombocytopenia, anemia, and renal and cardiac abnormalities.
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "Transaldolase deficiency is an inborn error of the pentose phosphate pathway"
explanation: Orphanet defines the disorder as an inborn pentose-phosphate-pathway error.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Transaldolase deficiency is a heterogeneous disorder of carbohydrate metabolism"
explanation: A patient series independently supports the carbohydrate-metabolism disease framing.
inheritance:
- name: Autosomal recessive inheritance
description: Transaldolase deficiency is inherited in an autosomal recessive pattern.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "Autosomal recessive"
explanation: Orphanet records autosomal recessive inheritance.
- reference: PMID:38440129
reference_title: "Hypergonadotropic Hypogonadism Due to Transaldolase Deficiency: Two Cases and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Transaldolase deficiency is a rare autosomal recessive inborn error"
explanation: A clinical case report and review also states autosomal recessive inheritance.
prevalence:
- population: Worldwide
measure_type: POINT_PREVALENCE
prevalence_class: BELOW_1_IN_1000000
rate_high: 0.1
percentage: <1 per 1,000,000
notes: Orphanet records worldwide point prevalence below 1 per 1,000,000.
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:23315216"
explanation: Orphanet provides the worldwide point-prevalence estimate.
progression:
- phase: Antenatal-to-neonatal multisystem presentation
age_range: Antenatal, neonatal, or infancy
notes: >
Orphanet records antenatal, neonatal, and infancy onset. Published cohorts
describe prenatal growth and fluid abnormalities and neonatal anemia,
thrombocytopenia, hepatosplenomegaly, liver involvement, renal disease,
and later variable endocrine presentations.
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "Age of onset: Antenatal"
explanation: Orphanet records antenatal onset.
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "Age of onset: Neonatal"
explanation: Orphanet records neonatal onset.
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients present severe symptoms during the neonatal period"
explanation: The clinical report supports typical severe neonatal presentation.
- phase: Variable childhood-to-adult progression
age_range: Childhood through adulthood
notes: Neonatal symptoms do not invariably predict early death. Adults may have gradual renal, hepatic, skeletal and endocrine progression. In a 2026 cohort, follow-up extended to 20 years; post-transplant hepatic and extrahepatic outcomes must be assessed separately.
evidence:
- reference: PMID:41806563
reference_title: Transaldolase deficiency - natural disease course towards adulthood.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: even if clinical manifestations begin in the neonatal period, the overall phenotype may remain relatively mild, with gradual progression.
explanation: The adult series documents a slowly progressive trajectory.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We retrospectively collected data on 16 patients followed for up to 20 years.
explanation: Longitudinal follow-up informs monitoring and prognosis.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_taldo1_ppp_redox_model
hypothesis_label: Canonical TALDO1 Pentose-Phosphate Redox Model
status: CANONICAL
description: >-
Biallelic TALDO1 loss disrupts nonoxidative PPP carbon recycling and redox homeostasis. Liver
injury, fibrosis and carcinogenesis follow partly distinct pathways. Mouse AR epistasis, mTOR/PON1
observations and context-dependent cell-death responses refine the canonical mechanism; tissue-specific
causes of many extrahepatic manifestations remain unresolved.
notes: >-
The canonical proximal metabolic model is retained after assessment of the OpenScientist report.
The report is a literature synthesis, not an executed analysis. Increased Fas apoptosis is
not the central hepatocyte mechanism: mouse hepatocytes resist it. AR deletion restores NADPH
and prevents HCC but not GSH depletion or cirrhosis. The mTOR/PON1/aPL findings occur in TAL
single and TAL/AR double knockouts; patient relevance is unproven. Four heterozygous APAP
cases treated with NAC are not a controlled trial in congenital biallelic disease. Erythronic
acid is a variable biomarker with proposed PPP-derived routes, not a universally elevated
proven toxin. Long-term transplant outcomes and GenCC assertions exist, contrary to report
absence claims.
evidence:
- reference: PMID:15115436
reference_title: Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Recombinant TALDeltaS171 had no enzymic activity.
explanation: The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides.
explanation: Mouse liver measurements support impaired antioxidant capacity.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: GSH depletion of TALKO livers persisted in DKO livers.
explanation: Restored NADPH in the double knockout does not restore GSH; these pools are not interchangeable.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These findings suggest that deficient recycling of 6-carbon substrates by the PPP elicits mTOR activation and limits glycosylation and PON1 secretion into the bloodstream of TALKO and DKO mice.
explanation: The proposed mechanism occurs in TAL single knockouts as well as TAL/AR double knockouts; human congenital-disease validation is absent.
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two of the 3 transplanted patients in our series had HCC in the explanted livers
explanation: HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- and Taldo1+/- mice spontaneously developed HCC
explanation: Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.
- reference: PMID:30323337
reference_title: Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: "TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis."
explanation: >-
Corroborates the model's proximal molecular step from outside the
inborn-error literature: an unbiased CRISPR/Cas9 screen in HER2-amplified
breast cancer cells shows that removing transaldolase lowers NADPH and
raises reactive oxygen species. The inference step is that the effect was
measured only in combination with HER2 blockade and in a cell type
unrelated to transaldolase deficiency, so it speaks to the consequence of
losing the enzyme and not to the patient phenotype.
pathophysiology:
- name: TALDO1 transaldolase activity deficiency
description: >
Biallelic TALDO1 variants reduce or abolish human transaldolase protein
stability and catalytic activity. The Ser171 deletion mechanism shows that
mutant transaldolase can be translated but rapidly degraded by the
proteasome and lacks appreciable enzymatic activity.
genes:
- preferred_term: TALDO1
term:
id: hgnc:11559
label: TALDO1
molecular_functions:
- preferred_term: transaldolase activity
modifier: DECREASED
term:
id: GO:0004801
label: transaldolase activity
biological_processes:
- preferred_term: pentose phosphate pathway
term:
id: GO:0006098
label: pentose-phosphate shunt
modifier: DECREASED
evidence:
- reference: PMID:15115436
reference_title: Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Recombinant TALDeltaS171 had no enzymic activity.
explanation: The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.
downstream:
- target: Pentose phosphate pathway carbon sequestration
description: Loss of transaldolase impairs nonoxidative carbon recycling.
causal_link_type: DIRECT
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
- target: Renal tubular dysfunction
description: The inherited metabolic defect causes renal disease through incompletely established tissue-specific mechanisms.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- target: Gonadal dysfunction
description: The disease includes gonadal dysfunction; its precise biochemical and developmental intermediates are unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:30740741
reference_title: 'Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life.
explanation: Human endocrine findings support gonadal dysfunction but do not directly prove impaired NADPH-dependent steroidogenesis as its cause.
- target: Hydrops fetalis
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001789 | Hydrops fetalis | Frequent (79-30%)"
explanation: Orphanet records hydrops fetalis as frequent.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "proteinuria, hydrops fetalis, cardiomyopathy, and skin manifestations"
explanation: Patient-series abstract supports hydrops fetalis.
- target: Abnormal facial shape
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001999 | Abnormal facial shape | Frequent (79-30%)"
explanation: Orphanet records abnormal facial shape as frequent.
- reference: PMID:23315216
reference_title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "growth retardation, dysmorphic features, cutis laxa, congenital heart disease"
explanation: The 12-case series supports dysmorphic features.
- target: Premature skin wrinkling
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0100678 | Premature skin wrinkling | Frequent (79-30%)"
explanation: Orphanet records premature skin wrinkling as frequent.
- reference: PMID:23315216
reference_title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "growth retardation, dysmorphic features, cutis laxa, congenital heart disease"
explanation: The 12-case series supports cutis laxa and abnormal skin findings.
- target: Atrial septal defect
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001631 | Atrial septal defect | Occasional (29-5%)"
explanation: Orphanet records atrial septal defect as occasional.
- target: Coarctation of aorta
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001680 | Coarctation of aorta | Occasional (29-5%)"
explanation: Orphanet records coarctation of aorta as occasional.
- target: Biventricular hypertrophy
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0200128 | Biventricular hypertrophy | Occasional (29-5%)"
explanation: Orphanet records biventricular hypertrophy as occasional.
- target: Abnormality of the clitoris
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000056 | Abnormality of the clitoris | Frequent (79-30%)"
explanation: Orphanet records clitoral abnormality as frequent.
- target: Telangiectasia
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001009 | Telangiectasia | Frequent (79-30%)"
explanation: Orphanet records telangiectasia as frequent.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "skin manifestations (e.g., dryness, cutis laxa, ichthyosis, telangiectasias, and hemangiomas)."
explanation: Patient-series abstract supports telangiectasias.
- target: Global developmental delay
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001263 | Global developmental delay | Occasional (29-5%)"
explanation: Orphanet records global developmental delay as occasional.
- target: Abnormal respiratory system physiology
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002795 | Abnormal respiratory system physiology | Occasional (29-5%)"
explanation: Orphanet records respiratory physiology abnormality as occasional.
- target: Anemia
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001903 | Anemia | Very frequent (99-80%)"
explanation: Orphanet records anemia as a very frequent phenotype.
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"
explanation: The clinical report supports anemia in affected patients.
- target: Thrombocytopenia
description: This associated phenotype has no established organ-specific mechanistic chain; metabolite toxicity is not assumed.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001873 | Thrombocytopenia | Very frequent (99-80%)"
explanation: Orphanet records thrombocytopenia as a very frequent phenotype.
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"
explanation: The clinical report supports thrombocytopenia in affected patients.
- target: Intrauterine growth retardation
description: This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:30740741
reference_title: 'Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly.
explanation: The 34-patient cohort documents prenatal growth restriction.
- target: Failure to thrive
description: This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Growth failure posed a major challenge in the three most severely affected patients
explanation: Growth and nutritional impairment affected transplant feasibility.
- target: Osteopenia
description: This clinical consequence is documented, but the specific developmental, nutritional or endocrine intermediates remain incompletely established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41806563
reference_title: Transaldolase deficiency - natural disease course towards adulthood.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In adulthood, the dominant clinical features were hypergonadotropic hypogonadism, osteopenia, renal and hepatic involvement.
explanation: Adult case series identifies skeletal involvement.
- name: Pentose phosphate pathway carbon sequestration
description: Sedoheptulose-7-phosphate and other nonoxidative PPP intermediates accumulate while recycling into G6P and related biosynthetic substrates declines. TAL catalyzes a reversible carbon-transfer reaction; it does not directly produce NADPH. Carbon sequestration can persist despite restoration of NADPH by AR deletion.
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
downstream:
- target: Aldose reductase-dependent polyol formation
description: Accumulated sugars feed an AR-dependent polyol disposal pathway.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
- target: Antioxidant cofactor depletion
description: Impaired G6P recycling limits oxidative PPP reducing capacity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
- target: mTOR activation
description: Carbon and biosynthetic substrate restriction is proposed to activate mTOR in TAL-deficient mouse liver.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These findings suggest that deficient recycling of 6-carbon substrates by the PPP elicits mTOR activation and limits glycosylation and PON1 secretion into the bloodstream of TALKO and DKO mice.
explanation: The proposed mechanism occurs in TAL single knockouts as well as TAL/AR double knockouts; human congenital-disease validation is absent.
biological_processes:
- preferred_term: pentose-phosphate shunt
term:
id: GO:0006098
label: pentose-phosphate shunt
modifier: ABNORMAL
- name: Aldose reductase-dependent polyol formation
description: Aldose reductase converts accumulated unphosphorylated sugars to polyols while consuming NADPH. In mice, AR deletion prevents polyol buildup and HCC but worsens carbon trapping and growth restriction; it does not abolish cirrhosis. AR is therefore a context-dependent metabolic modifier, not a proven patient therapeutic target.
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
downstream:
- target: Antioxidant cofactor depletion
description: AR consumes NADPH during polyol formation.
causal_link_type: DIRECT
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
- name: Antioxidant cofactor depletion
description: 'NADPH and glutathione depletion impair antioxidant defenses in mouse liver. NADPH depletion also occurs in patient lymphoblasts. NADPH restoration and GSH restoration are distinct: AR deletion restores NADPH while GSH remains depleted in double-knockout liver.'
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides.
explanation: Mouse liver measurements support impaired antioxidant capacity.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: GSH depletion of TALKO livers persisted in DKO livers.
explanation: Restored NADPH in the double knockout does not restore GSH; these pools are not interchangeable.
downstream:
- target: Mitochondrial dysfunction
description: Impaired reducing capacity is associated with mitochondrial oxidative damage.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio.
explanation: These mitochondrial and energetic changes were measured in mouse liver.
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: increased mitochondrial mass associated with increased production of nitric oxide and ATP.
explanation: Patient lymphoblasts show a different mitochondrial-mass and ATP response, preventing universal extrapolation from liver.
- target: Oxidative hepatocyte injury
description: Reduced detoxification capacity sensitizes the liver to acetaminophen injury.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure.
explanation: Mouse experiments identify an oxidative challenge-sensitive injury pathway.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection.
explanation: A human temporal association supports precautionary avoidance; concurrent infection limits attribution.
- target: Fas apoptosis resistance and adaptive proliferation
description: Oxidative adaptation changes proliferative and Fas death signaling in mouse hepatocytes.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
- target: Hepatic fibrosis and cirrhosis
description: Persistent GSH depletion is one proposed driver of residual mouse cirrhosis; human fibrosis has additional unresolved intermediates.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Micronodular cirrhosis developed in 10 patients.
explanation: Human longitudinal cohort documents hepatic remodeling.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Although AR inactivation blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC, it exacerbated carbon sequestration in the PPP and caused further growth restriction.
explanation: Cirrhosis, carbon restriction and carcinogenesis must be distinguished.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice
explanation: The paper attributes residual cirrhosis to persistent GSH depletion; this mechanistic interpretation remains preclinical.
biological_processes:
- preferred_term: response to oxidative stress
term:
id: GO:0006979
label: response to oxidative stress
modifier: ABNORMAL
- name: Mitochondrial dysfunction
description: Loss of mitochondrial membrane potential is observed in TAL-deficient mouse liver and patient lymphoblasts. Mouse liver has reduced mitochondrial mass and ATP/ADP, whereas lymphoblast mitochondrial mass and ATP increase. A universal energy-depletion step is not supported.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio.
explanation: These mitochondrial and energetic changes were measured in mouse liver.
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: increased mitochondrial mass associated with increased production of nitric oxide and ATP.
explanation: Patient lymphoblasts show a different mitochondrial-mass and ATP response, preventing universal extrapolation from liver.
downstream:
- target: Hepatocarcinogenesis
description: Mouse AR epistasis links mitochondrial oxidative stress to progression to HCC; it does not establish a quantitatively dominant mechanism in patients.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
biological_processes:
- preferred_term: mitochondrion organization
term:
id: GO:0007005
label: mitochondrion organization
modifier: ABNORMAL
- name: Oxidative hepatocyte injury
description: Oxidative challenge can provoke hepatocellular injury and acetaminophen-induced necrosis in TAL-deficient mice. A child developed liver failure after therapeutic acetaminophen during infection. Chronic liver damage should not be represented as universally increased Fas apoptosis.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure.
explanation: Mouse experiments identify an oxidative challenge-sensitive injury pathway.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection.
explanation: A human temporal association supports precautionary avoidance; concurrent infection limits attribution.
downstream:
- target: Hepatic failure
description: Hepatocyte injury can decompensate hepatic function.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure.
explanation: Mouse experiments identify an oxidative challenge-sensitive injury pathway.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection.
explanation: A human temporal association supports precautionary avoidance; concurrent infection limits attribution.
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
- name: Fas apoptosis resistance and adaptive proliferation
description: TAL-deficient mouse hepatocytes resist CD95/Fas-mediated apoptosis and exhibit altered beta-catenin and c-Jun signaling. Lifelong NAC restores Fas-mediated apoptosis while preventing HCC. Patient lymphoblasts also resist Fas death but are more susceptible to peroxide and CD20-triggered apoptosis.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
downstream:
- target: Hepatocarcinogenesis
description: Failure of Fas-mediated elimination and adaptive growth signaling are proposed contributors to mouse carcinogenesis.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
biological_processes:
- preferred_term: apoptotic process
term:
id: GO:0006915
label: apoptotic process
modifier: DECREASED
- name: Hepatocarcinogenesis
description: HCC can arise in affected children, including before 18 months, and in Taldo1-null or heterozygous mice. Mouse AR-dependent redox and survival signaling explain part of this susceptibility; human risk fractions and modifiers remain uncertain.
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two of the 3 transplanted patients in our series had HCC in the explanted livers
explanation: HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- and Taldo1+/- mice spontaneously developed HCC
explanation: Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.
downstream:
- target: Hepatocellular carcinoma
description: Malignant hepatocyte transformation produces the observed tumor phenotype.
causal_link_type: DIRECT
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two of the 3 transplanted patients in our series had HCC in the explanted livers
explanation: HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- and Taldo1+/- mice spontaneously developed HCC
explanation: Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
biological_processes:
- preferred_term: cell population proliferation
term:
id: GO:0008283
label: cell population proliferation
modifier: INCREASED
- name: mTOR activation
description: mTOR activation and altered autophagy accompany TAL deficiency in mouse liver. This experimental branch is present with functional AR and persists after AR deletion. Rapamycin rescue supports pathway involvement without establishing a therapy for patients.
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These findings suggest that deficient recycling of 6-carbon substrates by the PPP elicits mTOR activation and limits glycosylation and PON1 secretion into the bloodstream of TALKO and DKO mice.
explanation: The proposed mechanism occurs in TAL single knockouts as well as TAL/AR double knockouts; human congenital-disease validation is absent.
downstream:
- target: Impaired PON1 glycosylation and secretion
description: mTOR-associated substrate and glycosylation changes reduce PON1 secretion in the proposed mouse mechanism.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These findings suggest that deficient recycling of 6-carbon substrates by the PPP elicits mTOR activation and limits glycosylation and PON1 secretion into the bloodstream of TALKO and DKO mice.
explanation: The proposed mechanism occurs in TAL single knockouts as well as TAL/AR double knockouts; human congenital-disease validation is absent.
- target: Hepatic stellate cell expansion
description: Rapamycin reduces stellate-cell expansion, supporting mTOR-dependent fibrogenic signaling.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Treatment with rapamycin enhanced serum PON1 activity and blocked aPL production and the expansion of HSC in TALKO mice.
explanation: Rapamycin perturbs the proposed axis in single-knockout mice. Its pleiotropic effects do not isolate PON1 or aPL as the sole mediator.
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
biological_processes:
- preferred_term: TOR signaling
term:
id: GO:0031929
label: TOR signaling
modifier: INCREASED
- name: Impaired PON1 glycosylation and secretion
description: TALKO and TAL/AR-double-knockout mouse livers have reduced PON1 expression, glycosylation, secretion and activity. Biosynthetic substrate depletion contributes; PON1 measurements in human TALDO deficiency remain a verification need.
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: PON1 protein levels and enzymatic activities are diminished in the livers and sera of TALKO and DKO mice.
explanation: Measured protein and enzyme activity support PON1 impairment in both genotypes.
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Diminished secretion of PON1 was attributed to the depletion of substrates, F6P, UTP, UDP-glucose and UDP-GlcNAc
explanation: Substrate depletion, glycosidase experiments and mass spectrometry support defective glycosylation; they do not prove every proposed causal intermediate in patients.
downstream:
- target: Antiphospholipid autoantibody production
description: The proposed mouse pathway links lower PON1 antioxidant activity to phospholipid-directed autoimmunity; selective mediation remains incompletely isolated.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: aPL production against apolipoprotein H (Apo-H, also called β2-glycoprotein 1) and cardiolipin, is increased in TALKO and DKO mice.
explanation: Antiphospholipid antibodies are a mouse observation, not an established patient feature.
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
- name: Antiphospholipid autoantibody production
description: Anticardiolipin and anti-beta2-glycoprotein-I antibodies increase in TALKO and double-knockout mice. This is not an established human TALDO phenotype or a demonstrated obligatory cause of fibrosis.
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: aPL production against apolipoprotein H (Apo-H, also called β2-glycoprotein 1) and cardiolipin, is increased in TALKO and DKO mice.
explanation: Antiphospholipid antibodies are a mouse observation, not an established patient feature.
downstream:
- target: Hepatic stellate cell expansion
description: The proposed autoimmune branch may promote stellate activation; shared rapamycin responsiveness is not proof that antibodies alone cause fibrosis.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Treatment with rapamycin enhanced serum PON1 activity and blocked aPL production and the expansion of HSC in TALKO mice.
explanation: Rapamycin perturbs the proposed axis in single-knockout mice. Its pleiotropic effects do not isolate PON1 or aPL as the sole mediator.
mechanism_confidence: HYPOTHETICAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
- name: Hepatic stellate cell expansion
description: Profibrotic hepatic stellate cells expand in TALKO and double-knockout mice, with increased CD38 and reduced CD161-positive NK cells. Rapamycin limits this expansion. The contribution of each immune mediator in patients is unresolved.
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Treatment with rapamycin enhanced serum PON1 activity and blocked aPL production and the expansion of HSC in TALKO mice.
explanation: Rapamycin perturbs the proposed axis in single-knockout mice. Its pleiotropic effects do not isolate PON1 or aPL as the sole mediator.
downstream:
- target: Hepatic fibrosis and cirrhosis
description: Expanded profibrotic stellate cells contribute to liver matrix deposition in the experimental model.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37742509
reference_title: mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Treatment with rapamycin enhanced serum PON1 activity and blocked aPL production and the expansion of HSC in TALKO mice.
explanation: Rapamycin perturbs the proposed axis in single-knockout mice. Its pleiotropic effects do not isolate PON1 or aPL as the sole mediator.
mechanism_confidence: PROVISIONAL
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatic stellate cell
term:
id: CL:0000632
label: hepatic stellate cell
- name: Hepatic fibrosis and cirrhosis
description: Hepatic fibrosis and micronodular cirrhosis are major human manifestations. Cirrhosis can persist in mice lacking both TAL and AR despite protection from HCC, so fibrosis and malignancy are distinct outcomes. Progression varies from neonatal liver failure to stable cirrhosis or slowly progressive adult disease.
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Micronodular cirrhosis developed in 10 patients.
explanation: Human longitudinal cohort documents hepatic remodeling.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Although AR inactivation blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC, it exacerbated carbon sequestration in the PPP and caused further growth restriction.
explanation: Cirrhosis, carbon restriction and carcinogenesis must be distinguished.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice
explanation: The paper attributes residual cirrhosis to persistent GSH depletion; this mechanistic interpretation remains preclinical.
downstream:
- target: Cirrhosis
description: Hepatic remodeling produces the clinical cirrhosis phenotype.
causal_link_type: DIRECT
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Micronodular cirrhosis developed in 10 patients.
explanation: Human longitudinal cohort documents hepatic remodeling.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Although AR inactivation blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC, it exacerbated carbon sequestration in the PPP and caused further growth restriction.
explanation: Cirrhosis, carbon restriction and carcinogenesis must be distinguished.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice
explanation: The paper attributes residual cirrhosis to persistent GSH depletion; this mechanistic interpretation remains preclinical.
- target: Portal hypertension and hypersplenism
description: Cirrhosis and altered hepatic resistance lead to portal-hypertensive complications.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
- target: Hepatic failure
description: Severe liver disease can compromise hepatic function.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Liver involvement was present in all patients, with six presenting liver failure at birth.
explanation: Documents severe hepatic dysfunction in the cohort.
- target: Abnormality of coagulation
description: Hepatic dysfunction contributes to coagulopathy independently of platelet depletion.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Coagulopathy, a sensitive indicator of liver disease progression, was linked to severe hemorrhagic episodes
explanation: Separates coagulation dysfunction from hypersplenic thrombocytopenia.
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: ABNORMAL
- name: Portal hypertension and hypersplenism
description: Portal hypertension can produce splenomegaly, varices and ascites. Hypersplenism can contribute to later cytopenias, while neonatal anemia and thrombocytopenia may have additional mechanisms. Congenital vascular skin lesions are not attributed wholesale to portal hypertension.
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
downstream:
- target: Hepatosplenomegaly
description: Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
- target: Thrombocytopenia
description: Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
- target: Anemia
description: Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
- target: Edema
description: Portal hypertension and hypersplenism contribute to this manifestation without explaining every case.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Nearly all (n = 15) developed clinical portal hypertension (PH), initially splenomegaly, followed by esophageal varices in five patients and ascites in four.
explanation: Longitudinal liver disease is associated with portal hypertension and its complications.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Almost all patients had hypersplenism, likely influencing cytopenia.
explanation: Hypersplenism is a plausible later contributor, not a complete explanation for neonatal cytopenias.
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
- name: Renal tubular dysfunction
description: Renal disease commonly includes low-molecular-weight proteinuria, hypercalciuria, aminoaciduria, phosphate wasting and tubular acidosis. Some patients progress to chronic kidney disease. The clinical association is established, but polyol toxicity or local NADPH failure has not been directly isolated in patient renal tissue.
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
downstream:
- target: Abnormality of the kidney
description: Tubular injury produces urinary solute loss or progressive renal dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- target: Renal tubular dysfunction phenotype
description: Tubular injury produces urinary solute loss or progressive renal dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- target: Chronic kidney disease
description: Tubular injury produces urinary solute loss or progressive renal dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- target: Hypercalciuria
description: Tubular injury produces urinary solute loss or progressive renal dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- target: Proteinuria
description: Tubular injury produces urinary solute loss or progressive renal dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
- name: Gonadal dysfunction
description: Hypergonadotropic hypogonadism can become prominent in adolescence and adulthood. Reduced sex-steroid production and gonadal insufficiency are documented; attribution specifically to NADPH limitation remains a mechanistic hypothesis.
evidence:
- reference: PMID:30740741
reference_title: 'Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life.
explanation: Human endocrine findings support gonadal dysfunction but do not directly prove impaired NADPH-dependent steroidogenesis as its cause.
downstream:
- target: Hypergonadotropic hypogonadism
description: Gonadal insufficiency produces the endocrine phenotype.
causal_link_type: DIRECT
evidence:
- reference: PMID:30740741
reference_title: 'Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life.
explanation: Human endocrine findings support gonadal dysfunction but do not directly prove impaired NADPH-dependent steroidogenesis as its cause.
locations:
- preferred_term: gonad
term:
id: UBERON:0000991
label: gonad
biochemical:
- name: Reduced transaldolase activity
presence: DECREASED
context: >
Patient-derived fibroblast and lymphoblast studies and recombinant protein
assays show loss of transaldolase enzymatic activity in disease-associated
TALDO1 variants.
readouts:
- target: TALDO1 transaldolase activity deficiency
description: Lower measured activity marks a more severe enzyme deficiency.
direction: POSITIVE
evidence:
- reference: PMID:15115436
reference_title: Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Recombinant TALDeltaS171 had no enzymic activity.
explanation: The deletion causes loss of activity and protein instability; it is not equivalent to removal of the bacterial catalytic lysine.
relationship: READOUT_OF
evidence:
- reference: PMID:15115436
reference_title: "Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "no expression of the TALDeltaS171 protein or enzyme activity was detected"
explanation: Patient-cell experiments support reduced transaldolase activity as the primary biochemical defect.
- name: Increased urinary polyols and seven-carbon sugars
presence: INCREASED
context: >-
Urine testing shows increased erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose, and sedoheptulose-7-phosphate, supporting the biochemical diagnosis.
Neonatal polyol excretion is physiologically high; interpret against age-specific controls.
readouts:
- target: Pentose phosphate pathway carbon sequestration
description: Urinary carbohydrate abnormalities report the underlying metabolic block.
direction: POSITIVE
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
relationship: READOUT_OF
evidence:
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Elevated excretion of erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose and sedoheptulose-7P in the urine"
explanation: The patient report provides the diagnostic urinary metabolite pattern.
- reference: PMID:29923087
reference_title: "Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Urine polyols and plasma metabolomics confirmed the diagnosis of transaldolase deficiency."
explanation: Human metabolomics data support urine polyols as diagnostic biochemical evidence.
- reference: PMID:18987485
reference_title: Urinary excretion of pentose phosphate pathway-associated polyols in early postnatal life.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Urinary excretion of polyols shows an age dependency with highest concentrations postnatally independent of the grade of maturity.
explanation: Age-specific interpretation is necessary; high neonatal polyols alone do not establish TALDO deficiency.
- name: Urinary erythronic acid
presence: INCREASED
context: Increased in the original six-patient study and knockout mice, but below detection in a later patient. It is an adjunct metabolic marker, not a universal diagnostic requirement or proven toxin. Proposed erythrose-based PPP routes remain incompletely validated.
evidence:
- reference: PMID:20600873
reference_title: Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed
explanation: Defines the original study population.
- reference: PMID:26238251
reference_title: 'Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the level of erythronic acid in our case, if any, is lower than this limit.
explanation: A later case limits universal elevation claims; it does not prove complete absence.
- name: Elevated alpha-fetoprotein
presence: INCREASED
context: AFP can be elevated during liver injury and in patients with suspicious nodules. Its level is age-dependent and nonspecific; a decline does not alone prove NAC efficacy or exclude HCC.
evidence:
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: rising alpha-fetoprotein which peaked 2 weeks after acetaminophen exposure.
explanation: The clinical case documents AFP change during liver injury without demonstrating a cancer-specific marker.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels
explanation: Temporal AFP decline precedes NAC and cannot be attributed to treatment.
genetic:
- name: Biallelic TALDO1 pathogenic variants
gene_term:
preferred_term: TALDO1
term:
id: hgnc:11559
label: TALDO1
association: Causative
relationship_type: CAUSATIVE
features: >
Transaldolase deficiency is caused by biallelic pathogenic variants in
TALDO1. Reported mechanisms include missense variants and deletions that
abolish enzyme activity or destabilize transaldolase protein.
inheritance:
- name: Autosomal recessive inheritance
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "TALDO1 | transaldolase 1 | hgnc:11559 | Disease-causing germline mutation(s) in"
explanation: Orphanet records TALDO1 as disease-causing.
- reference: PMID:23315216
reference_title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "sequencing confirmed segregation of a novel homozygous mutation with the disease"
explanation: Segregation in affected families supports recessive TALDO1 causality.
- reference: PMID:38440129
reference_title: "Hypergonadotropic Hypogonadism Due to Transaldolase Deficiency: Two Cases and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "caused by pathogenic/likely pathogenic biallelic mutations in the TALDO1 gene"
explanation: Recent clinical review supports biallelic TALDO1 variants as the molecular cause.
phenotypes:
- name: Cirrhosis
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Cirrhosis
term:
id: HP:0001394
label: Cirrhosis
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001394 | Cirrhosis | Very frequent (99-80%)"
explanation: Orphanet records cirrhosis as a very frequent phenotype.
- reference: PMID:18331807
reference_title: "Transaldolase deficiency in a two-year-old boy with cirrhosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "subsequently found to have cirrhosis and deafness"
explanation: The clinical report documents cirrhosis in a child with TALDO deficiency.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Hepatosplenomegaly
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hepatosplenomegaly
term:
id: HP:0001433
label: Hepatosplenomegaly
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001433 | Hepatosplenomegaly | Very frequent (99-80%)"
explanation: Orphanet records hepatosplenomegaly as a very frequent phenotype.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients had variable clinical presentations including hepatosplenomegaly"
explanation: Patient-level evidence supports hepatosplenomegaly.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Thrombocytopenia
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001873 | Thrombocytopenia | Very frequent (99-80%)"
explanation: Orphanet records thrombocytopenia as a very frequent phenotype.
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"
explanation: The clinical report supports thrombocytopenia in affected patients.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Anemia
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001903 | Anemia | Very frequent (99-80%)"
explanation: Orphanet records anemia as a very frequent phenotype.
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure"
explanation: The clinical report supports anemia in affected patients.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Abnormality of glutamine metabolism
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Abnormal circulating glutamine concentration
term:
id: HP:0010903
label: Abnormal circulating glutamine concentration
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0010903 | Abnormality of glutamine metabolism | Very frequent (99-80%)"
explanation: Orphanet records abnormal glutamine metabolism as very frequent.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Increased serum bile acid concentration
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Increased serum bile acid concentration
term:
id: HP:0012202
label: Increased serum bile acid concentration
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0012202 | Increased serum bile acid concentration | Very frequent (99-80%)"
explanation: Orphanet records increased serum bile acids as very frequent.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Abnormality of the clitoris
frequency: FREQUENT
phenotype_term:
preferred_term: Abnormality of the clitoris
term:
id: HP:0000056
label: Abnormal clitoris morphology
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000056 | Abnormality of the clitoris | Frequent (79-30%)"
explanation: Orphanet records clitoral abnormality as frequent.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Abnormality of the kidney
frequency: FREQUENT
phenotype_term:
preferred_term: Abnormality of the kidney
term:
id: HP:0000077
label: Abnormality of the kidney
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000077 | Abnormality of the kidney | Frequent (79-30%)"
explanation: Orphanet records kidney abnormality as frequent.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "renal and cardiac abnormalities, and urinary excretion of polyols."
explanation: Patient-series abstract supports renal abnormalities in the disorder.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Edema
frequency: FREQUENT
phenotype_term:
preferred_term: Edema
term:
id: HP:0000969
label: Edema
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000969 | Edema | Frequent (79-30%)"
explanation: Orphanet records edema as frequent.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Telangiectasia
frequency: FREQUENT
phenotype_term:
preferred_term: Telangiectasia
term:
id: HP:0001009
label: Telangiectasia
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001009 | Telangiectasia | Frequent (79-30%)"
explanation: Orphanet records telangiectasia as frequent.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "skin manifestations (e.g., dryness, cutis laxa, ichthyosis, telangiectasias, and hemangiomas)."
explanation: Patient-series abstract supports telangiectasias.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Hydrops fetalis
frequency: FREQUENT
phenotype_term:
preferred_term: Hydrops fetalis
term:
id: HP:0001789
label: Hydrops fetalis
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001789 | Hydrops fetalis | Frequent (79-30%)"
explanation: Orphanet records hydrops fetalis as frequent.
- reference: PMID:25388407
reference_title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "proteinuria, hydrops fetalis, cardiomyopathy, and skin manifestations"
explanation: Patient-series abstract supports hydrops fetalis.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Abnormal facial shape
frequency: FREQUENT
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001999 | Abnormal facial shape | Frequent (79-30%)"
explanation: Orphanet records abnormal facial shape as frequent.
- reference: PMID:23315216
reference_title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "growth retardation, dysmorphic features, cutis laxa, congenital heart disease"
explanation: The 12-case series supports dysmorphic features.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Premature skin wrinkling
frequency: FREQUENT
phenotype_term:
preferred_term: Premature skin wrinkling
term:
id: HP:0100678
label: Premature skin wrinkling
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0100678 | Premature skin wrinkling | Frequent (79-30%)"
explanation: Orphanet records premature skin wrinkling as frequent.
- reference: PMID:23315216
reference_title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "growth retardation, dysmorphic features, cutis laxa, congenital heart disease"
explanation: The 12-case series supports cutis laxa and abnormal skin findings.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Global developmental delay
frequency: OCCASIONAL
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001263 | Global developmental delay | Occasional (29-5%)"
explanation: Orphanet records global developmental delay as occasional.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: None of our patients developed severe cognitive impairment, and only mild intellectual delay was observed.
explanation: The long-term cohort limits deterministic neurodevelopmental claims.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
description: ' Severe cognitive impairment is not typical among reported long-term survivors; developmental outcome varies.'
- name: Atrial septal defect
frequency: OCCASIONAL
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001631 | Atrial septal defect | Occasional (29-5%)"
explanation: Orphanet records atrial septal defect as occasional.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Coarctation of aorta
frequency: OCCASIONAL
phenotype_term:
preferred_term: Coarctation of aorta
term:
id: HP:0001680
label: Coarctation of aorta
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001680 | Coarctation of aorta | Occasional (29-5%)"
explanation: Orphanet records coarctation of aorta as occasional.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Abnormal respiratory system physiology
frequency: OCCASIONAL
phenotype_term:
preferred_term: Abnormal respiratory system physiology
term:
id: HP:0002795
label: Abnormal respiratory system physiology
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002795 | Abnormal respiratory system physiology | Occasional (29-5%)"
explanation: Orphanet records respiratory physiology abnormality as occasional.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Biventricular hypertrophy
frequency: OCCASIONAL
phenotype_term:
preferred_term: Biventricular hypertrophy
term:
id: HP:0200128
label: Biventricular hypertrophy
evidence:
- reference: ORPHA:101028
reference_title: "Transaldolase deficiency"
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0200128 | Biventricular hypertrophy | Occasional (29-5%)"
explanation: Orphanet records biventricular hypertrophy as occasional.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Hypergonadotropic hypogonadism
frequency: OCCASIONAL
phenotype_term:
preferred_term: Hypergonadotropic hypogonadism
term:
id: HP:0000815
label: Hypergonadotropic hypogonadism
evidence:
- reference: PMID:38440129
reference_title: "Hypergonadotropic Hypogonadism Due to Transaldolase Deficiency: Two Cases and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two Emirati patients with hypergonadotropic hypogonadism due to transaldolase deficiency"
explanation: The case report directly documents hypergonadotropic hypogonadism in transaldolase deficiency.
- reference: PMID:33159679
reference_title: "Hypergonadotrophic hypogonadism in a patient with transaldolase deficiency: novel mutation in the pentose phosphate pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "deficiency characterized by hypergonadotropic hypogonadism and slightly elevated"
explanation: A late-onset patient report supports hypergonadotropic hypogonadism as a variable manifestation.
notes: Frequency is the Orphanet annotation used by this entry, not a pooled estimate from the selected clinical cohorts.
- name: Hepatocellular carcinoma
description: Early-childhood HCC is documented in selected liver cohorts; a population incidence is not known.
phenotype_term:
preferred_term: Hepatocellular carcinoma
term:
id: HP:0001402
label: Hepatocellular carcinoma
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two of the 3 transplanted patients in our series had HCC in the explanted livers
explanation: HCC was identified in a selected four-patient liver series; this is not a population incidence estimate.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- and Taldo1+/- mice spontaneously developed HCC
explanation: Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.
- reference: PMID:37071763
reference_title: Pathologic and Immunophenotypic Characterization of Syncytial Giant Cell Variant of Pediatric Hepatocellular Carcinoma. A Distinct Subtype.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "another with transaldolase deficiency, underwent living donor liver transplants. Explant-liver histopathology revealed tumor with diffuse neoplastic syncytial giant cell pattern"
explanation: >-
Explant pathology from a second centre independently documents
hepatocellular carcinoma in an infant with transaldolase deficiency and
characterizes it as the syncytial giant cell variant, so the tumour is
recorded in infancy outside the four-patient series cited above.
- name: Hepatic failure
description: Severe neonatal or progressive hepatic failure may require transplantation.
phenotype_term:
preferred_term: Hepatic failure
term:
id: HP:0001399
label: Hepatic failure
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Liver involvement was present in all patients, with six presenting liver failure at birth.
explanation: Human cohort documents liver failure.
- name: Renal tubular dysfunction phenotype
description: Tubulopathy includes multiple urinary solute losses.
phenotype_term:
preferred_term: Renal tubular dysfunction
term:
id: HP:0000124
label: Renal tubular dysfunction
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- name: Chronic kidney disease
description: Progressive kidney dysfunction can become a major adult complication.
phenotype_term:
preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Five patients developed chronic kidney disease (CKD).
explanation: Five of 16 patients developed CKD; two older patients were evaluated for, but did not undergo, kidney transplantation.
- name: Hypercalciuria
description: Urinary calcium loss is common in the renal series.
phenotype_term:
preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- name: Proteinuria
description: Low-molecular-weight proteinuria indicates tubular dysfunction.
phenotype_term:
preferred_term: Proteinuria
term:
id: HP:0000093
label: Proteinuria
evidence:
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure.
explanation: Human renal disease is well documented; polyol toxicity as its specific mechanism remains inferred.
- reference: PMID:22510381
reference_title: Nephrological abnormalities in patients with transaldolase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria.
explanation: Defines the measured tubular phenotype.
- name: Osteopenia
description: Reduced bone density is reported in adults; endocrine and renal contributions are plausible but not isolated.
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
evidence:
- reference: PMID:41806563
reference_title: Transaldolase deficiency - natural disease course towards adulthood.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In adulthood, the dominant clinical features were hypergonadotropic hypogonadism, osteopenia, renal and hepatic involvement.
explanation: Adult case series identifies skeletal involvement.
- name: Intrauterine growth retardation
description: Prenatal growth restriction can accompany the multisystem disease.
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:30740741
reference_title: 'Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly.
explanation: The 34-patient cohort documents prenatal growth restriction.
- name: Abnormality of coagulation
description: Coagulopathy can cause major bleeding independently of thrombocytopenia.
phenotype_term:
preferred_term: Abnormality of coagulation
term:
id: HP:0001928
label: Abnormality of coagulation
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Coagulation disorders were observed in almost all patients
explanation: Clinical follow-up documents coagulation dysfunction.
- name: Failure to thrive
description: Severe growth failure may limit suitability for infant transplantation.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Growth failure posed a major challenge in the three most severely affected patients
explanation: Growth and nutritional impairment affected transplant feasibility.
diagnosis:
- name: Urinary polyol and seven-carbon sugar testing
description: >-
Gas chromatography and liquid chromatography-tandem mass spectrometry of urine can identify increased polyols and seven-carbon sugars, including sedoheptulose and sedoheptulose-7-phosphate, supporting the biochemical diagnosis.
Interpret urine polyols using age-appropriate reference ranges, especially in neonates. Molecular or enzyme confirmation is needed because individual biomarkers are not universally abnormal.
results: Increased urinary polyols and seven-carbon sugars support transaldolase deficiency.
evidence:
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis was established by detecting high concentrations of erythritol, ribitol, arabitol"
explanation: The report supports urinary sugar/polyol profiling as a diagnostic approach.
- reference: PMID:18987485
reference_title: Urinary excretion of pentose phosphate pathway-associated polyols in early postnatal life.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Urinary excretion of polyols shows an age dependency with highest concentrations postnatally independent of the grade of maturity.
explanation: Age-specific interpretation is necessary; high neonatal polyols alone do not establish TALDO deficiency.
- reference: PMID:17603756
reference_title: Detection of transaldolase deficiency by quantification of novel seven-carbon chain carbohydrate biomarkers in urine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Transaldolase-deficient patients had significantly increased urinary sedoheptulose and sedoheptulose 7-phosphate, associated with subtle elevations of mannoheptulose, sedoheptitol and perseitol."
explanation: >-
The liquid chromatography-tandem mass spectrometry method paper that
established the seven-carbon biomarker panel named in this test, ranking
sedoheptulose and sedoheptulose 7-phosphate as the discriminating
analytes above mannoheptulose, sedoheptitol and perseitol.
- name: TALDO1 molecular genetic testing
description: >
Molecular testing confirms biallelic TALDO1 pathogenic variants, including
sequence variants and exon-level deletions that may require copy-number or
long-range PCR approaches when sequencing finds only one allele.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "then confirmed by molecular analysis of the TALDO gene."
explanation: The clinical report supports molecular confirmation of biochemical diagnosis.
treatments:
- name: Supportive management and acetaminophen avoidance
description: >
Disease-specific management is supportive and should include avoidance of
acetaminophen because clinical and model evidence indicates increased
vulnerability to acetaminophen-related oxidative liver injury.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Oxidative hepatocyte injury
treatment_effect: INHIBITS
description: Avoidance removes an exposure associated with oxidative liver injury; it does not restore TAL activity.
evidence:
- reference: PMID:29923087
reference_title: "Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic."
explanation: The human case report supports avoidance of acetaminophen as a way to reduce oxidative liver-injury risk.
evidence:
- reference: PMID:24497183
reference_title: "Clinical and molecular characteristics of two transaldolase-deficient patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Symptomatic treatment can be proposed."
explanation: The clinical report states that symptomatic treatment can be proposed.
- reference: PMID:29923087
reference_title: "Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic."
explanation: A human case and supporting model evidence support acetaminophen avoidance.
- name: N-acetylcysteine for oxidative liver stress
description: >
N-acetylcysteine has model-organism support for preventing acetaminophen-induced
liver failure and limited human observational support for lowering
alpha-fetoprotein, so it is recorded as a context-specific antioxidant
option rather than established disease-modifying therapy.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: N-acetyl-L-cysteine
term:
id: CHEBI:28939
label: N-acetyl-L-cysteine
target_mechanisms:
- target: Antioxidant cofactor depletion
treatment_effect: INHIBITS
description: NAC supports glutathione synthesis in preclinical rescue experiments. Human long-term efficacy remains uncertain.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice.
explanation: Lifelong mouse treatment supports antioxidant rescue; efficacy against human congenital disease is unproven.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice.
explanation: Lifelong mouse treatment supports antioxidant rescue; efficacy against human congenital disease is unproven.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels
explanation: AFP decline cannot be attributed to NAC in this patient.
- name: Liver transplantation
description: >-
Liver transplantation is a documented option for severe liver failure or HCC, with some patients
maintaining normal graft function for decades. It does not correct systemic TAL deficiency;
renal, endocrine, growth or respiratory problems may persist or emerge. Infant nutritional
status, multisystem involvement and transplant complications affect candidacy and outcome.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: organ transplantation
term:
id: NCIT:C15289
label: Organ Transplantation
target_mechanisms:
- target: Hepatic fibrosis and cirrhosis
treatment_effect: BYPASSES
description: Replacing the diseased liver corrects the hepatic organ defect while leaving extrahepatic TAL deficiency.
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 21 years after LT, she has normal liver graft function
explanation: A published patient has long-term graft survival, beyond the two-year limit claimed in the report.
- reference: PMID:34572178
reference_title: Successful Liver Transplantation in Two Polish Brothers with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: TALDO is a multi-organ disease, therefore LT does not cure patients from the disease.
explanation: Systemic manifestations require continued surveillance despite hepatic correction.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A third patient died from posttransplant complications at 6 months of life.
explanation: Outcomes include serious complications and death; transplantation is not uniformly successful.
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 21 years after LT, she has normal liver graft function
explanation: A published patient has long-term graft survival, beyond the two-year limit claimed in the report.
- reference: PMID:34572178
reference_title: Successful Liver Transplantation in Two Polish Brothers with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: TALDO is a multi-organ disease, therefore LT does not cure patients from the disease.
explanation: Systemic manifestations require continued surveillance despite hepatic correction.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A third patient died from posttransplant complications at 6 months of life.
explanation: Outcomes include serious complications and death; transplantation is not uniformly successful.
- reference: PMID:39992042
reference_title: Successful Liver Transplantation in a Pediatric Patient With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Liver transplantation has emerged as a potential treatment for end-stage liver disease in TALDO patients, though clinical evidence is limited to seven reported cases."
explanation: >-
Sizes the reported transplant experience at seven published cases before
this one, so the option rests on an accumulating case series rather than
on any comparative study.
- reference: PMID:39992042
reference_title: Successful Liver Transplantation in a Pediatric Patient With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Postoperatively, coagulopathy and bleeding episodes resolved, with stable liver function at 1 year."
explanation: >-
A three-year-old transplanted for end-stage liver disease with suspected
hepatocellular carcinoma had coagulopathy and bleeding resolve after
living donor grafting, with one year of follow-up.
- name: Multisystem surveillance and supportive treatment
description: Monitor hepatic function, coagulation, blood counts, growth and nutrition, renal function and tubular losses, endocrine development, and respiratory or cardiac symptoms. Assess the native liver for suspicious nodules and HCC. Treat identified endocrine deficiencies and renal complications individually; continue surveillance after liver transplantation.
evidence:
- reference: PMID:34677006
reference_title: Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Close monitoring for these features in patients with transaldolase deficiency is highly recommended, regardless of LT.
explanation: The clinical series recommends surveillance despite transplantation.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hypergonadotropic hypogonadism was found in seven patients; two others developed secondary adrenal cortisol insufficiency and primary hypothyroidism requiring replacement therapy.
explanation: The cohort documents hormone replacement needs.
- reference: PMID:41823103
reference_title: Long-Term Follow-Up of Patients With Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: five patients received ACE inhibitors or angiotensin receptor blockers for proteinuria.
explanation: Renal therapy is based on individual clinical findings.
references:
- reference: ORPHA:101028
title: Transaldolase deficiency
findings:
- statement: Orphanet provides definition, inheritance, prevalence, onset, TALDO1 association, exact MONDO/OMIM mappings, and HPO phenotype frequencies.
supporting_text: ORPHA:101028 structured record.
- reference: PMID:23315216
title: "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."
findings:
- statement: Twelve new cases expand the clinical phenotype and support TALDO segregation.
supporting_text: Cohort abstract reporting growth retardation, dysmorphism, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, bleeding tendency, and TALDO segregation.
- reference: PMID:25388407
title: "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."
findings:
- statement: Four-patient series supports broad phenotypic variability, urinary polyols, and biallelic TALDO1 causality.
supporting_text: Abstract lists dysmorphic, skin, liver, renal, cardiac, hematologic, hydrops, and urinary polyol findings.
- reference: PMID:24497183
title: Clinical and molecular characteristics of two transaldolase-deficient patients.
findings:
- statement: Full-text clinical report supports neonatal presentation, urinary sugar/polyol diagnostics, liver fibrosis, tubulopathy, and symptomatic management.
supporting_text: Full-text cache includes biochemical diagnosis and clinical course of two patients.
- reference: PMID:15115436
title: "Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase."
findings:
- statement: Patient-cell and recombinant protein experiments support loss of transaldolase activity through proteasome-mediated degradation.
supporting_text: Abstract reports no mutant protein/enzyme activity and proteasome-dependent accumulation.
- reference: PMID:17613166
title: The pathogenesis of transaldolase deficiency.
findings:
- statement: Historical review of PPP redox balance and hepatocyte injury, interpreted alongside later primary evidence for stimulus-specific cell death.
supporting_text: Abstract describes NADPH, reactive oxygen intermediates, mitochondrial membrane potential, and hepatocyte cell death.
- reference: PMID:29923087
title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
findings:
- statement: Case report and mouse-model evidence support acetaminophen sensitivity, acetaminophen avoidance, and limited NAC evidence.
supporting_text: Abstract reports acetaminophen-associated liver failure, model rescue by N-acetylcysteine, and avoidance recommendation.
- reference: PMID:33159679
title: "Hypergonadotrophic hypogonadism in a patient with transaldolase deficiency: novel mutation in the pentose phosphate pathway."
findings:
- statement: Later-onset case supports expanded endocrine phenotype and variable presentation.
supporting_text: Abstract reports hypergonadotropic hypogonadism and elevated AFP with novel TALDO1 mutation.
- reference: PMID:38440129
title: "Hypergonadotropic Hypogonadism Due to Transaldolase Deficiency: Two Cases and Literature Review."
findings:
- statement: Recent case report and review support autosomal recessive TALDO1 causality and multisystem phenotype.
supporting_text: Abstract describes biallelic TALDO1 mutations and variable multisystem involvement.
- reference: PMID:18331807
title: Transaldolase deficiency in a two-year-old boy with cirrhosis.
findings:
- statement: Case report supports neonatal anemia/thrombocytopenia, renal tubulopathy, cirrhosis, and deafness.
supporting_text: Abstract describes clinical presentation and laboratory findings in a two-year-old boy.
differential_diagnoses: []
animal_models:
- name: Taldo1-null and heterozygous mouse
species: Mouse
genotype: Taldo1-/- or Taldo1+/-
description: Mouse models reproduce altered PPP metabolites, redox stress, liver disease and tumor susceptibility. Male null mice are infertile. Lifelong NAC prevents mouse liver injury and HCC; rescue of fertility was demonstrated in heterozygotes.
modeled_mechanisms:
- target: Mitochondrial dysfunction
relationship: RECAPITULATES
description: Taldo1-null liver shows reduced mitochondrial membrane potential, mitochondrial mass and ATP/ADP ratio under the studied conditions.
limitations: Mouse liver ATP and mitochondrial mass changes differ from patient lymphoblast responses.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio.
explanation: These mitochondrial and energetic changes were measured in mouse liver.
- target: Fas apoptosis resistance and adaptive proliferation
relationship: RECAPITULATES
description: Taldo1-null hepatocytes resist CD95/Fas-mediated apoptosis in culture and in vivo, with altered beta-catenin phosphorylation and c-Jun expression.
limitations: Fas resistance is distinct from sensitivity to oxidative necrosis.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
- target: Hepatocarcinogenesis
relationship: RECAPITULATES
description: Taldo1-deficient mice develop liver tumors; genetic and antioxidant interventions test contributions of redox stress to progression.
limitations: Heterozygous mouse tumor risk does not establish autosomal dominant human TALDO deficiency.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- and Taldo1+/- mice spontaneously developed HCC
explanation: Mouse tumors establish a model endpoint; heterozygous mouse tumors do not establish dominant human disease.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo.
explanation: The direction is apoptosis resistance, not generally increased hepatocyte apoptosis.
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress.
explanation: Adaptive signaling accompanies resistance to Fas-mediated elimination.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
- reference: PMID:17003133
reference_title: Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Stimulation of de novo GSH synthesis by oral N-acetyl-cysteine normalized the low fertility rate of TAL(+/-) males
explanation: The demonstrated fertility rescue was in heterozygous males, while null males have a more severe infertility phenotype.
- name: Taldo1 and aldose-reductase double-knockout mouse
species: Mouse
genotype: Taldo1-/-; Akr1b3-/-
description: AR deletion restores NADPH and blocks HCC and acetaminophen susceptibility while GSH depletion, carbon trapping and cirrhosis persist. Further growth restriction argues against assuming AR inhibition is uniformly beneficial.
modeled_mechanisms:
- target: Aldose reductase-dependent polyol formation
relationship: PERTURBS
description: Deleting aldose reductase suppresses the polyol accumulation of Taldo1 deficiency and restores NADPH, directly perturbing this pathway.
limitations: Complete germline mouse AR deletion is not equivalent to pharmacologic inhibition in patients.
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
- target: Hepatic fibrosis and cirrhosis
relationship: RECAPITULATES
description: Cirrhosis persists in the double knockout despite restored NADPH and blocked progression to hepatocellular carcinoma.
limitations: Persistence of cirrhosis separates fibrosis from the HCC endpoint.
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: However, cirrhosis, which is caused by GSH depletion and responds to treatment with N-acetylcysteine (NAC) in TALKO mice 11 and humans 23, persisted in DKO mice (Figure 1C).
explanation: The primary double-knockout experiment directly reports persistent cirrhosis; it must be distinguished from prevention of HCC progression and from separate human follow-up observations.
evidence:
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the inactivation of AR reversed NADPH depletion and polyol buildup in the absence of TAL and blocked mitochondrial oxidative stress and liver disease progression from cirrhosis to HCC.
explanation: Genetic epistasis separates AR-dependent oxidative carcinogenesis from persistent carbon trapping and cirrhosis in mice.
- reference: PMID:36658399
reference_title: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: GSH depletion of TALKO livers persisted in DKO livers.
explanation: Restored NADPH in the double knockout does not restore GSH; these pools are not interchangeable.
experimental_models:
- name: Patient-derived TAL-deficient lymphoblasts
experimental_model_type: CELL_LINE
description: TAL-deficient lymphoblasts show S7P accumulation, G6P and NADPH depletion, altered mitochondrial potential and stimulus-specific apoptosis. AAV-mediated restoration of TAL reverses multiple phenotypes.
modeled_mechanisms:
- target: Pentose phosphate pathway carbon sequestration
relationship: RECAPITULATES
description: Patient lymphoblasts accumulate sedoheptulose-7-phosphate with depleted glucose-6-phosphate and NADPH; TAL restoration tests the biochemical defect.
limitations: One cell context does not establish every organ-specific disease mechanism.
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP.
explanation: Patient lymphoblasts directly demonstrate the nonoxidative carbon-recycling defect.
- target: Mitochondrial dysfunction
relationship: RECAPITULATES
description: Patient lymphoblasts show increased mitochondrial mass and ATP, with altered calcium handling; TAL gene transfer reverses several measured cellular abnormalities.
limitations: ATP and mitochondrial mass increase in these cells, unlike mouse liver.
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: increased mitochondrial mass associated with increased production of nitric oxide and ATP.
explanation: Patient lymphoblasts show a different mitochondrial-mass and ATP response, preventing universal extrapolation from liver.
evidence:
- reference: PMID:18498245
reference_title: Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Normalization of TAL activity by adeno-associated-virus-mediated gene transfer reversed the elevated CD38 expression, ATP and Ca(2+) levels
explanation: Genetic rescue provides direct cellular support.
environmental:
- name: Acetaminophen exposure
description: Acetaminophen can exacerbate hepatic oxidative injury in TAL-deficient mice. A clinical case after standard dosing during RSV infection supports avoidance in affected patients, although the concurrent illness limits causal attribution.
effect: EXACERBATES
influences_mechanisms:
- target: Oxidative hepatocyte injury
description: The exposure challenges already impaired hepatic antioxidant defenses.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure.
explanation: Mouse experiments identify an oxidative challenge-sensitive injury pathway.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection.
explanation: A human temporal association supports precautionary avoidance; concurrent infection limits attribution.
evidence:
- reference: PMID:19436114
reference_title: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure.
explanation: Mouse experiments identify an oxidative challenge-sensitive injury pathway.
- reference: PMID:29923087
reference_title: Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection.
explanation: A human temporal association supports precautionary avoidance; concurrent infection limits attribution.

📚

References & Deep Research

References

10

ORPHA:101028

Transaldolase deficiency

1 finding

Orphanet provides definition, inheritance, prevalence, onset, TALDO1 association, exact MONDO/OMIM mappings, and HPO phenotype frequencies.

"ORPHA:101028 structured record."

PMID:23315216

Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype.

1 finding

Twelve new cases expand the clinical phenotype and support TALDO segregation.

"Cohort abstract reporting growth retardation, dysmorphism, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, bleeding tendency, and TALDO segregation."

PMID:25388407

Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability.

1 finding

Four-patient series supports broad phenotypic variability, urinary polyols, and biallelic TALDO1 causality.

"Abstract lists dysmorphic, skin, liver, renal, cardiac, hematologic, hydrops, and urinary polyol findings."

PMID:24497183

Clinical and molecular characteristics of two transaldolase-deficient patients.

1 finding

Full-text clinical report supports neonatal presentation, urinary sugar/polyol diagnostics, liver fibrosis, tubulopathy, and symptomatic management.

"Full-text cache includes biochemical diagnosis and clinical course of two patients."

PMID:15115436

Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.

1 finding

Patient-cell and recombinant protein experiments support loss of transaldolase activity through proteasome-mediated degradation.

"Abstract reports no mutant protein/enzyme activity and proteasome-dependent accumulation."

PMID:17613166

The pathogenesis of transaldolase deficiency.

1 finding

Historical review of PPP redox balance and hepatocyte injury, interpreted alongside later primary evidence for stimulus-specific cell death.

"Abstract describes NADPH, reactive oxygen intermediates, mitochondrial membrane potential, and hepatocyte cell death."

PMID:29923087

Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.

1 finding

Case report and mouse-model evidence support acetaminophen sensitivity, acetaminophen avoidance, and limited NAC evidence.

"Abstract reports acetaminophen-associated liver failure, model rescue by N-acetylcysteine, and avoidance recommendation."

PMID:33159679

Hypergonadotrophic hypogonadism in a patient with transaldolase deficiency: novel mutation in the pentose phosphate pathway.

1 finding

Later-onset case supports expanded endocrine phenotype and variable presentation.

"Abstract reports hypergonadotropic hypogonadism and elevated AFP with novel TALDO1 mutation."

PMID:38440129

Hypergonadotropic Hypogonadism Due to Transaldolase Deficiency: Two Cases and Literature Review.

1 finding

Recent case report and review support autosomal recessive TALDO1 causality and multisystem phenotype.

"Abstract describes biallelic TALDO1 mutations and variable multisystem involvement."

PMID:18331807

Transaldolase deficiency in a two-year-old boy with cirrhosis.

1 finding

Case report supports neonatal anemia/thrombocytopenia, renal tubulopathy, cirrhosis, and deafness.

"Abstract describes clinical presentation and laboratory findings in a two-year-old boy."

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review TALDO1 pathograph, clinical course and OpenScientist evidence · 2026-09-04T23:01:57Z · View source

Phenotypes: retained scoped Orphanet annotations and added HCC, hepatic failure, tubulopathy, CKD, proteinuria, hypercalciuria, osteopenia, growth and coagulation outcomes from primary cohorts. Subtypes/progression: reviewed early/late presentation and variable adult progression; no unsupported discrete mechanistic subtype invented. Pathophysiology: expanded five nodes to sixteen, corrected Fas apoptosis direction, separated AR-dependent HCC from persistent GSH depletion/cirrhosis and modeled provisional mTOR/PON1/aPL findings in both single and double knockouts. Extrahepatic mechanistic gaps remain explicit unknown-intermediate associations. Treatments/trials: replaced proposed-only transplantation with decades-long graft outcomes and systemic limits; calibrated NAC and APAP evidence, added ongoing renal/endocrine/liver surveillance. ClinicalTrials.gov condition and TALDO1 API queries returned zero records on 2026-09-04. Genetics: checked TALDO1 biallelic causality, Ser171 deletion instability and intragenotypic variability; did not infer human dominant disease from heterozygous mouse tumors or APAP susceptibility. Biomarkers/diagnostics: corrected enzyme-activity readout direction, removed biomarker causal duplication, added age-dependent urine interpretation, variable erythronic acid and nonspecific AFP. References: reviewed complete disorder YAML, complete OpenScientist report/citation sidecar and research/QC narrative. The deep-research draft was shallow and had identifier/content errors already flagged by its curator note; primary human cohorts and experiments drive this review. GeneReviews was searched and NCBI Gene reports no standalone chapter. References were fetched through sanctioned tools; ontology terms independently validated. Consumption/assessment: integrated verified OS AR, PON1 and biomarker leads with explicit limits, rejected incorrect apoptosis/genotype/absence claims, and created 23 claim assessments with six unexecuted proposals. Complete clinical baseline includes 2019 34-patient and 2026 long-term/adult cohorts. No provider analyses or missing figure artifacts were represented as completed.

Transaldolase Deficiency Deep Research Fallback ▸

Transaldolase Deficiency Deep Research Fallback

Date: 2026-05-05T07:40:18Z

Provider Attempts

Falcon deep-research client was invoked directly with the disease pathophysiology template for Transaldolase deficiency (MONDO:0011624) and timed out after the bounded timeout interval with no usable report.
Earlier just research-disorder falcon Transaldolase_Deficiency could not run before the YAML file existed.

Evidence Scope Used for Curation

Because the provider attempt did not return a usable artifact, curation proceeded from structured Orphanet ORPHA:101028 and cached literature references. The main evidence set used was:

ORPHA:101028 for disease definition, inheritance, prevalence, TALDO1 gene association, MONDO/OMIM cross-references, and HPO phenotype frequency rows.
PMID:23315216 for a 12-patient clinical series defining the multisystem phenotype and TALDO segregation.
PMID:25388407 and PMID:24497183 for patient-level clinical variability, urinary polyol diagnostics, renal/cardiac/liver/skin features, and TALDO1 molecular confirmation.
PMID:15115436 for the Ser171 deletion mechanism causing transaldolase inactivation and proteasome-mediated degradation in patient-derived cells.
PMID:17613166 for pentose phosphate pathway redox biology and the hepatocyte cell-death/cirrhosis pathogenesis model.
PMID:29923087 for acetaminophen sensitivity, diagnostic metabolomics, and N-acetylcysteine/acetaminophen-avoidance management implications.
PMID:33159679 and PMID:38440129 for later endocrine presentations and the expanded multisystem clinical spectrum.

No uncached claims from the failed provider attempt were used.

OpenAI ▸

1. Disease Information

gpt-4o 2026-05-05T01:31:23.753458

1. Disease Information

Overview

Transaldolase deficiency is a rare autosomal recessive metabolic disorder characterized by impaired function of the transaldolase enzyme. This enzyme plays a critical role in the pentose phosphate pathway, influencing cellular redox balance and nucleotide synthesis.

Key Identifiers

OMIM: 606003
Orphanet: 1930
ICD-10: E88.8 (Other specified metabolic disorders)
MeSH: D055443
Mondo ID: MONDO:0010173

Synonyms

TALDO Deficiency
Taldo Deficiency

Data Source

The information derives from aggregated disease-level resources, primarily based on case reports and small patient cohorts due to its rarity.

2. Etiology

Disease Causal Factors

Genetic: Caused by mutations in the TALDO1 gene, which disrupt the function of the transaldolase enzyme (PMID: 15489859).

Risk Factors

Genetic: Mutations like c.708G>A, c.272_273del (PMID: 15489859).

Protective Factors

There are no well-documented genetic or environmental protective factors due to the rarity of the condition.

Gene-Environment Interactions

No significant gene-environment interactions have been documented.

3. Phenotypes

Phenotype Type

Symptoms: Hepatomegaly, liver failure, metabolic acidosis, and congenital heart defects (PMID: 15489859).

Phenotype Characteristics

Age of Onset: Early infancy
Symptom Severity: Severe; can be life-threatening
Progression: Progressive liver and multiorgan failure
Frequency: Present in all documented cases but based on a small sample size

Quality of Life Impact

Significant impact due to severe hepatomegaly and progressive liver failure. Affected individuals require comprehensive medical care.

Suggested HPO Terms

Hepatomegaly (HP:0002240)
Liver failure (HP:0001395)

4. Genetic/Molecular Information

Causal Genes

Gene: TALDO1
OMIM ID: 602061

Pathogenic Variants

Variant Type: Missense, nonsense
Allele Frequency: Rare in general population databases
Somatic vs. Germline Origin: Germline mutations

Functional Consequences

Loss of function leading to disruption of metabolic flux in the pentose phosphate pathway.

5. Environmental Information

Environmental Factors

No specific environmental factors have been implicated due to the genetic nature of the disorder.

Lifestyle Factors

No documented influence of lifestyle on the disorder's presentation or severity.

6. Mechanism / Pathophysiology

Molecular Pathways

Involves the pentose phosphate pathway; impairment leads to reduced antioxidant capacity and accumulation of toxic sugar metabolites (PMID: 15489859).

Protein Dysfunction

Enzyme deficiency results in abnormal cellular redox states and impaired nucleotide synthesis, leading to cell damage.

Metabolic Changes

Increased glutaric acid levels, reduced ribose-5-phosphate, and erythrose-4-phosphate.

7. Anatomical Structures Affected

Organ Level

Primary: Liver
Secondary: Heart

Tissue and Cell Level

Tissue Type: Hepatic tissue
Cell Populations: Hepatocytes

Subcellular Level

Cellular Compartments: Cytoplasm, where the enzyme primarily functions.

Localization

Anatomical Sites: Liver, potential involvement of cardiac tissue (UBERON:0002107).

8. Temporal Development

Onset

Age of Onset: Congenital to early infancy
Onset Pattern: Chronic, insidious

Progression

Rate: Rapid if untreated, with progressive liver failure

Patterns

Consistent progressive degeneration without remission

9. Inheritance and Population

Epidemiology

Prevalence: Extremely rare; exact prevalence not well-documented.
Inheritance Pattern: Autosomal recessive

Population Demographics

No specific ethnic or demographic predilection identified.

10. Diagnostics

Clinical Tests

Laboratory Tests: Measurement of pentose phosphate pathway metabolites
Genetic Testing: Mutation analysis of TALDO1 via sequencing or specific gene panels

Genetic Testing

Whole Exome Sequencing (WES): Preferred for diagnosing unknown metabolic disorders

Clinical Criteria

Diagnosis based on clinical presentation, biochemical testing, and genetic confirmation.

11. Outcome/Prognosis

Survival and Mortality

Mortality Rate: High without treatment due to liver failure

Morbidity and Function

Significant disability due to liver dysfunction.

12. Treatment

Pharmacotherapy

Supportive Care: Managing liver symptoms, addressing metabolic crises
Liver Transplant: Considered in severe cases for liver failure (MAXO:0001198).

13. Prevention

Genetic Counseling

Essential for families with known mutations, especially for planning future pregnancies.

14. Other Species / Natural Disease

No comparative animal models identified; condition largely unique to humans.

15. Model Organisms

No specific model organisms are used due to the rare nature of the disease and availability of clinical data.

This report integrates current knowledge on Transaldolase Deficiency relevant to clinical, genetic, and biochemical domains. Further research is critical to expand therapeutic and diagnostic developments. For comprehensive primary sources, please access linked PubMed articles using provided PMIDs.

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OpenScientist Report

Mappings

Definitions

Inheritance

Mechanistic Hypotheses

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Progression

Prevalence

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Transaldolase Deficiency Deep Research Fallback

Provider Attempts

Evidence Scope Used for Curation

1. Disease Information

Overview

Key Identifiers

Synonyms

Data Source

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Phenotype Type

Phenotype Characteristics

Quality of Life Impact

Suggested HPO Terms

4. Genetic/Molecular Information

Causal Genes

Pathogenic Variants

Functional Consequences

5. Environmental Information

Environmental Factors

Lifestyle Factors

6. Mechanism / Pathophysiology

Molecular Pathways

Protein Dysfunction

Metabolic Changes

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Population Demographics

10. Diagnostics

Clinical Tests

Genetic Testing

Clinical Criteria

11. Outcome/Prognosis

Survival and Mortality

Morbidity and Function

12. Treatment

Pharmacotherapy

13. Prevention

Genetic Counseling

14. Other Species / Natural Disease

15. Model Organisms