Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | Thrombocytopenia 13, syndromic | 620776 | Autosomal recessive | 3 | GALE | 606953 |
A number sign (#) is used with this entry because of evidence that syndromic thrombocytopenia-13 (THC13) is caused by homozygous or compound heterozygous mutation in the GALE gene (606953) on chromosome 1p36.
Biallelic mutation in the GALE gene can also cause galactosemia III (GALAC3; 230350).
Syndromic thrombocytopenia-13 (THC13) is an autosomal recessive disorder characterized mainly by congenital thrombocytopenia resulting in increased bleeding. Platelets tend to be enlarged (macrothrombocytopenia) and/or gray and show functional defects. Some patients have infection-induced leukopenia or anemia and pancytopenia. Additional more variable features have also been reported, including mitral valve malformations, pyloric stenosis, and impaired intellectual development (Seo et al., 2019; Febres-Aldana et al., 2020; Marin-Quilez et al., 2023).
For a discussion of genetic heterogeneity of thrombocytopenia, see THC1 (313900).
Seo et al. (2019) reported a multigenerational consanguineous Bedouin family in which 6 individuals presented with thrombocytopenia in childhood manifest mainly as skin bleeding; 3 had intracranial hemorrhage. The family had previously been reported by Tamary et al. (2003). Some patients also had mild anemia and neutropenia during infections. Three patients were successfully treated with hematopoietic bone marrow transplant.
Febres-Aldana et al. (2020) reported a 2-year-old Hispanic boy with congenital combined mitral and tricuspid valve malformation, pyloric stenosis, and infection-induced episodes of pancytopenia. Bone marrow biopsy showed increased myelomonocytes with immature features, hypogranular and hypersegmented neutrophils, erythroid precursors with nuclear irregularities and megaloblastic changes, and megakaryocytic hyperplasia with few small hypolobulated forms. He did not have classic signs of galactosemia.
Markovitz et al. (2021) reported a 19-year-old Hispanic woman, born of distantly related parents, who presented at 13 days of age with elevated galactose associated with low GALE enzymatic activity detected on newborn screening. At 29 months of age, she presented with pancytopenia and mild macrocytic anemia. Large platelets were observed on peripheral blood smear. Bone marrow examination at age 7 years showed mild dysmegakaryopoiesis and mild megaloblastic changes. She had mild epistaxis and gingival bleeding, but no severe or recurrent infections. At age 17, she had macrocytic anemia and thrombocytopenia, increased circulating immature platelets, absolute lymphopenia, and mild short stature. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc.
Marin-Quilez et al. (2023) reported 3 adult patients from 2 unrelated families with lifelong thrombocytopenia, bleeding diatheses (epistaxis, mucocutaneous, menorrhagia), anemia, mitral valve prolapse, increased bilirubin levels, jaundice, and developmental delay. Two sibs in family A also had retinal disease and cataracts. Peripheral blood showed increased reticulated platelets and enlarged, giant, and/or grey platelets. Bone marrow aspirate showed erythroid hyperplasia and increased megakaryocytes. Patient platelets showed reduced platelet aggregation in response to stimulation and reduced expression of GP1BA (606672) and GPIX (173515)/GPV (173511).
The transmission pattern of THC13 in the family reported by Seo et al. (2019) was consistent with autosomal recessive inheritance.
In 6 patients from a consanguineous Bedouin family (AH) with THC13, Seo et al. (2019) identified a homozygous missense mutation in the GALE gene (R51W; 606953.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both GALE enzymatic interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). The findings suggested that loss of GALE results in defective megakaryocyte differentiation. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE may have a detrimental effect on hematopoiesis.
In a 2-year-old Hispanic boy with THC13, Febres-Aldana et al. (2020) identified compound heterozygous missense mutations in the GALE gene: R51W and G237D (606953.0010). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD.
In a 19-year-old Hispanic woman with THC13, Markovitz et al. (2021) identified a homozygous T150M mutation in the GALE gene (606953.0011). The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc.
In 3 patients from 2 unrelated families with THC13, Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene (606953.0011-606953.0014). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. Patient peripheral blood progenitor cells showed normal megakaryocyte differentiation, although there was a 60 to 80% reduction in GALE expression in mature megakaryocytes and impaired formation of proplatelets with abnormal morphology and altered distribution of actin (see 102630) and filamin A (300017). Analysis of patient platelets showed decreased GALE levels and enzymatic activity, decreased glycosylation patterns, and increased apoptosis compared to controls. Patient platelets had reduced aggregation in response to stimulation associated with a sharp reduction in glycosylation and membrane expression of GP1BA (606672) and ITGB1 (135630), which were retained abnormally in the endoplasmic reticulum. VWF (613160) expression was also decreased on patient megakaryocytes compared to controls. ITGA2B (607759)/ITGB3 (173470) expression and function were preserved, as was the thrombopoietin (600044) receptor (MPL; 159530).
Febres-Aldana, C. A., Pelaez, L., Wright, M. S., Maher, O. M., Febres-Aldana, A. J., Sasaki, J., Jayakar, P., Jayakar, A., Diaz-Barbosa, M., Janvier, M., Totapally, B., Salyakina, D., Galvez-Silva, J. R. A case of UDP-galactose 4-prime-epimerase deficiency associated with dyshematopoiesis and atrioventricular valve malformations: an exceptional clinical phenotype explained by altered N-glycosylation with relative preservation of the Leloir pathway. Molec. Syndromol. 11: 320-329, 2020. [PubMed: 33510604] [Full Text: https://doi.org/10.1159/000511343]
Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis. Blood 141: 406-421, 2023. [PubMed: 36395340] [Full Text: https://doi.org/10.1182/blood.2022016995]
Markovitz, R., Owen, N., Satter, L. F., Kirk, S., Mahoney, D. H., Bertuch, A. A., Scaglia, F. Expansion of the clinical phenotype of GALE deficiency. Am. J. Med. Genet. 185A: 3118-3121, 2021. [PubMed: 34159722] [Full Text: https://doi.org/10.1002/ajmg.a.62384]
Seo, A., Gulsuner, S., Pierce, S., Ben-Harosh, M., Shalev, H., Walsh, T., Krasnov, T., Dgany, O., Doulatov, S., Tamary, H., Shimamura, A., King, M. C. Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE). Hum. Molec. Genet. 28: 133-142, 2019. [PubMed: 30247636] [Full Text: https://doi.org/10.1093/hmg/ddy334]
Tamary, H., Yaniv, I., Stein, J., Dgany, O., Shalev, Z., Shechter, T., Resnitzky, P., Shaft, D., Zoldan, M., Kornreich, L., Levy, R., Cohen, A., Moser, R. A., Kapelushnik, J., Shalev, H. A clinical and molecular study of a Bedouin family with dysmegakaryopoiesis, mild anemia, and neutropenia cured by bone marrow transplantation. Europ. J. Haemat. 71: 196-203, 2003. [PubMed: 12930321] [Full Text: https://doi.org/10.1034/j.1600-0609.2003.00126.x]