Immunological Manifestations in GALE Deficiency: Extending the Spectrum Beyond Thrombocytopenia and Galactosemia

Mutations in the UDP-galactose 4’-epimerase (GALE) gene disrupt the Leloir pathway of galactose metabolism and play a key role in protein and lipid glycosylation by providing essential nucleotide sugar donors. While GALE deficiency is known to cause galactosemia and thrombocytopenia, its impact on the human immune system remains largely unexplored. We aimed to characterize a novel immunodeficiency phenotype associated with the homozygous p.R51W GALE variant. We performed a comprehensive immunological evaluation of seven pediatric patients (aged 2.5–10 years) homozygous for the p.R51W GALE variant. Assessments included immunoglobulin levels, vaccine-specific antibody responses, lymphocyte subsets, and kappa-deleting recombination excision circles (KRECs). All patients exhibited profound B-cell lymphopenia (0.06–0.12 × 10^3/µl). While KREC levels were detectable, absolute counts (6–50 copies/µL) were significantly below the age-specific 5th percentile, suggesting a quantitative defect in central B-cell output. Detailed B-cell phenotyping demonstrated preservation of the full spectrum of maturation stages, indicating no absolute block in differentiation. Serum IgA and IgM were consistently low, whereas IgG levels were preserved or elevated, driven by a paradoxical increase in the IgG3 subclass. Specific antibody responses were impaired. Clinically, patients suffered from recurrent viral respiratory infections but lacked invasive bacterial disease. The p.R51W GALE variant results in a distinct hematopoietic stress phenotype characterized by significant quantitative B-cell deficiency. The absence of a clear differentiation block suggests that lymphopenia results from reduced central B-cell output combined with impaired peripheral homeostasis. We propose that the underlying GALE-mediated glycosylation defect compromises B-cell homeostasis. These findings identify GALE deficiency as a novel cause of primary immunodeficiency and suggest that immunological screening is warranted in affected patients.