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UDP-galactose 4′-epimerase (GALE) catalyzes the reversible interconversion of UDP-galactose and UDP-glucose in the Leloir pathway. Biallelic pathogenic variants in GALE cause autosomal recessive galactose epimerase deficiency, also known as type III galactosemia, with phenotypes ranging from severe generalized to mild peripheral forms.
Autosomal recessive galactose epimerase deficiency has been reported in 27 probands across four independent cohorts, including 22 unrelated patients in an international registry ([PMID:36056436]). This association meets ClinGen criteria for a Strong gene–disease relationship given the number of probands, concordant enzymatic findings and reproducible phenotypes.
Score – gene_disease_association: Strong; rationale: 27 probands across four studies; enzyme assays concordant with clinical severity.
Inheritance is autosomal recessive. Reports include monozygotic twins homozygous for c.658C>T (p.Arg220Trp) ([PMID:23430501]), a Chinese neonate with compound heterozygous c.505C>T (p.Arg169Trp) and c.452G>A (p.Gly151Asp) ([PMID:26565537]), and two siblings homozygous for c.280G>A (p.Val94Met) with generalized disease ([PMID:28247339]). The registry study described 22 additional patients, classifying six as generalized (four homozygous for c.280G>A (p.Val94Met)) and 16 as non-generalized ([PMID:36056436]).
Score – genetic_evidence: Strong; rationale: 27 probands with biallelic missense variants in four independent cohorts; recurrence of c.280G>A (p.Val94Met) in generalized cases.
Yeast complementation assays demonstrated severe reduction of activity for generalized-form variants (e.g., p.Val94Met shows dramatically reduced k_cat and stability) and intermediate impairment for peripheral variants (e.g., p.Asn34Ser retains ~70% activity) ([PMID:9326324],[PMID:9973283],[PMID:16302980]). Mammalian GALE-null cell studies confirmed loss of enzyme activity and thermal instability for several mutants (e.g., p.Gly302Asp, p.Trp336Ter) and linked cofactor binding defects to pathogenicity ([PMID:19250319],[PMID:22613355]).
Score – functional_evidence: Moderate; rationale: Multiple yeast and mammalian cell assays demonstrate loss-of-function for generalized disease variants correlating with clinical severity.
The R220W variant shows near-normal GALE activity in lymphoblasts and fails to produce galactose sensitivity in vivo, suggesting mild or neutral effects in certain tissues ([PMID:23430501]).
Biallelic loss-of-function missense variants in GALE underlie autosomal recessive galactose epimerase deficiency, with variant-specific residual activity accounting for the generalized vs. peripheral spectrum. Enzymatic assays in erythrocytes and fibroblasts, combined with molecular testing, enable definitive diagnosis. Early dietary galactose restriction improves biochemical markers, and genetic confirmation guides prognosis and long-term management.
Key Take-home: GALE genetic testing alongside functional enzyme assays provides robust diagnostic confirmation and informs tailored dietary intervention in galactose epimerase deficiency.
Gene–Disease AssociationStrong27 probands across four studies; enzyme assays concordant with clinical severity Genetic EvidenceStrong27 probands with biallelic missense variants in four independent cohorts; recurrence of c.280G>A (p.Val94Met) in multiple generalized cases Functional EvidenceModerateMultiple yeast and mammalian cell assays demonstrate loss-of-function effects for generalized form-associated variants correlating with clinical severity |