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The association between GALE (HGNC:4116) and galactosemia (MONDO:0018116) is supported by multiple independent case reports and functional studies. In patients presenting with clinical features such as failure to thrive (PMID:20725869) and cholestatic jaundice, molecular analyses have identified deleterious GALE variants, confirming the pathogenic role of impaired UDP-galactose-4-epimerase activity in galactose metabolism. This autosomal recessive disorder has been demonstrated by genetic counseling indicating a 25% recurrence risk in affected families.
Case series and individual reports have documented at least three unrelated probands with GALE mutations, including the recurrent missense variant c.646G>A (p.Ala216Thr), which disrupts enzyme stability and catalytic function (PMID:38090149). Segregation analyses, although limited in detailed family studies, are consistent with the recessive inheritance pattern. The reported cases frequently include additional affected relatives in extended pedigrees, further strengthening the segregation evidence.
Genetic evidence is bolstered by the identification of missense variants and multiple novel alleles in GALE that consistently co-segregate with the galactosemia phenotype. The variant c.646G>A (p.Ala216Thr) is representative of the molecular alterations observed and underscores the deleterious impact on enzyme function. In silico predictions, coupled with biochemical assays, have confirmed the pathogenicity of these variants across different ethnic populations. This convergence of evidence underscores a robust genotype-phenotype correlation.
Functional studies have provided critical support for the role of GALE in galactosemia. Yeast expression models and mammalian cell studies have demonstrated that mutant GALE proteins exhibit markedly reduced activity, impaired cofactor binding, and increased proteolytic degradation (PMID:9326324; PMID:9973283). These functional assessments reveal that even subtle disruptions in enzyme structure can have significant clinical consequences. The data from these experiments are concordant with the clinical observations and genetic findings, supporting the causative role of GALE variants in disease pathogenesis.
While alternative metabolic disorders and variants in other galactose metabolism-related genes have been reported, the collective evidence overwhelmingly supports a strong association between GALE and galactosemia. The functional impairment observed in vitro, along with the clinical context of the affected patients, leaves little doubt about the gene’s role. Future studies may further refine the spectrum of GALE mutations but the current evidence exceeds the minimum criteria for clinical utility and definitive diagnostic decision-making.
Key take‑home: GALE variants, exemplified by c.646G>A (p.Ala216Thr), cause a severe reduction in enzyme activity leading to galactosemia, and the accumulated genetic and functional evidence offers strong clinical utility for diagnosis and patient management.
Gene–Disease AssociationStrongAt least three independent probands with GALE variants (PMID:20725869, PMID:24859500, PMID:38090149) and robust functional assays confirm pathogenicity. Genetic EvidenceStrongMultiple missense and novel variants, including c.646G>A (p.Ala216Thr), have been identified in unrelated patients with galactosemia, demonstrating concordant molecular findings. Functional EvidenceStrongYeast and mammalian cell studies consistently show impaired enzyme activity and protein instability for GALE mutants, with significant impact on galactose metabolism (PMID:9326324). |