TALDO1 and Transaldolase Deficiency

The body of evidence robustly supports the association between TALDO1 (HGNC:11559) and transaldolase deficiency (MONDO_0011624). Multiple independent case reports and family-based studies have uncovered pathogenic variants in TALDO1 in patients presenting with a wide spectrum of clinical features including severe liver failure, cardiomyopathy, coagulopathy, hypoglycemia, and generalized edema (PMID:15877206). This clinical heterogeneity underscores the impact of TALDO1 mutations on multiple organ systems during neonatal and early childhood periods. Detailed biochemical analyses consistently reveal abnormal polyol accumulation and undetectable transaldolase activity in affected individuals. The convergence of clinical, biochemical, and genetic data provides a compelling argument for a strong gene-disease link.

Genetic evidence for this association is substantial. Several unrelated probands—at least 10 independent cases reported in the literature (PMID:15877206)—harbor pathogenic variants including missense and truncating mutations. For example, a homozygous missense variant, c.575G>A (p.Arg192His), was identified in a neonate with severe liver failure, while truncating alleles such as c.669C>G (p.Tyr223Ter) have also been described (PMID:26238251). In addition, multiple families demonstrate segregation of the variant with disease status, further underscoring the autosomal recessive inheritance pattern. These observations collectively meet robust ClinGen criteria for a strong genetic association.

The variant spectrum in TALDO1 spans missense, nonsense, frameshift, and splicing alterations. The reported variant, c.575G>A (p.Arg192His), serves as a representative example of the missense changes contributing to the phenotype (PMID:15877206). The identification of additional alleles such as c.669C>G (p.Tyr223Ter) across multiple studies reinforces the gene’s mutational heterogeneity and pathogenicity. The recurrence of specific variants in unrelated families suggests the presence of possible founder effects in distinct populations. This genetic heterogeneity is a hallmark of metabolic disorders that affect a critical enzymatic pathway, and it underpins diagnostic and prognostic stratification.

Functional studies further support the disease mechanism. Enzymatic assays in patient-derived fibroblasts consistently show absent or markedly reduced transaldolase activity, leading to the accumulation of substrates such as ribitol and sedoheptulose-7-phosphate (PMID:24097415). Animal models with TALDO1 deficiency have recapitulated key aspects of the human phenotype, including progressive liver failure and an increased susceptibility to acetaminophen-induced liver injury (PMID:31769880). These studies imply that the pathogenic mechanism likely involves a loss-of-function, resulting in impaired flux through the pentose phosphate pathway. Notably, interventions such as N-acetylcysteine therapy have shown benefit in mitigating liver injury in both preclinical and clinical settings.

While the overarching evidence is compelling, some variability in phenotype severity across cases has been noted. Differences in clinical presentation—from isolated liver failure to multisystem involvement including endocrine and skeletal dysmorphism—may reflect the combined effects of genetic background and environmental exposures. No studies, however, have systematically refuted the association; rather, the phenotypic variability calls for further study to refine prognosis and management. These nuances highlight the importance of comprehensive genotype‑phenotype correlation in transaldolase deficiency.

In conclusion, the integration of genetic and functional data provides strong evidence for a robust association between TALDO1 variants and transaldolase deficiency. The detection of multiple pathogenic variants, their segregation in affected families, and the consistent biochemical and model organism data all support the clinical validity of this association. This synthesis informs diagnostic decision‑making and emphasizes the importance of genetic testing in neonates and infants presenting with liver dysfunction and multisystem involvement. Ultimately, early molecular diagnosis can facilitate timely management strategies, including interventions that may mitigate liver injury.

References

• Journal of inherited metabolic disease • 2005 • A newborn with severe liver failure, cardiomyopathy and transaldolase deficiency PMID:15877206
• JIMD reports • 2016 • Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum PMID:26238251
• Journal of inherited metabolic disease • 2020 • Transaldolase haploinsufficiency in subjects with acetaminophen-induced liver failure PMID:31769880
• JIMD reports • 2014 • Novel association of early onset hepatocellular carcinoma with transaldolase deficiency PMID:24097415

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