Submission Details

GALE was first reported in relation to autosomal recessive galactose epimerase deficiency in 1997 (Quimby et al., PMID:9326324). Galactose epimerase deficiency is described in the literature as a spectrum with general, peripheral, and intermediate forms. The general form of the disease is associated with markedly decreased enzyme activity in all tissues in addition to hypotonia, jaundice, hepatomegaly, and developmental delays. Immediate dietary intervention by putting patients on a galactose/lactose-free diet can help prevent further development of these symptoms. The peripheral form is accompanied by enzyme activity deficient in blood cells and normal in other tissues. The intermediate form is similarly demonstrated by deficiency in blood cells, yet can have up to 50% enzyme activity in other tissues (GeneReviews, PMID: 20301295). Recently, thrombocytopenia has been reported as an additional feature of this disease in multiple affected families, and has been recognized as part of the expanded phenotype of galactose epimerase deficiency (PMIDs:7562286, 36395340).

19 variants (17 missense, 2 frameshift) that have been reported in 15 probands in 6 publications (PMIDs: 36395340, 34159722, 30247636, 36056436, 16301867, 9326324) are included in this curation. Recurrent variant V94M is associated with an especially severe phenotype (PMIDs:36056436, 28247339, 9973283). One consanguineous family with a history of thrombocytopenia was reported in association with the GALE variant c.151C>T (p.Arg51Trp). The variant segregated with the disease in 5 affected and 10 unaffected individuals (Estimated LOD score: 4.26, PMID:30247636). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (if applicable. The mechanism of pathogenicity is known to be loss of function.

This gene-disease relationship is also supported by biochemical assays, functional alteration experiments, model systems, and rescue evidence (PMIDs: 28877911, 20519568, 3948246, 29409891, 7305435). First, GALE is known to encode the galactose epimerase enzyme. A deficiency in this enzyme would lead to excess of galactose products according to the Leloir pathway, which is consistent with hypergalactosemia observed in patients with GALE deficiency (PMID:7305435). Next, GALT is a gene that encodes a separate protein within the Leloir pathway, and is classified as definitely associated with hereditary galactosemia by the General Inborn Errors of Metabolism GCEP (PMID:29409891). Yeast cells with the homolog GAL10 gene removed were functionally altered compared to control cells, as they failed to grow on galactose-based media, which reiterates the importance of this protein in the conversion of galactose to glucose (PMID:3948246). An shRNA knockdown of gale in mice was included as part of this curation, but not scored due to low phenotypic overlap with the disease and absence of gale enzymatic testing (PMID:28877911). An entire cohort (100%) of drosophila with Gale deficiency (and 2 LOF alleles) died within the embryonic stage. Drosophila with partial Gale deficiency (1 LOF allele) survived into adulthood, but could only survive if fed a galactose-free diet. Humans with gale epimerase deficiency can have developmental delays, and can see improvement in symptoms by removing galactose from the diet. When a human copy of GALE was inserted into the null Gale drosophila, enzyme activity was restored to wildtype, and survival frequency was also rescued to wild-type levels (PMID:20519568).

In summary, GALE is definitively associated with autosomal recessive galactose epimerase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen General Inborn Errors of Metabolism on the meeting date 8/25/2023 (SOP Version 9).