Febres-Aldana Christopher A, Pelaez Liset, Wright Meredith S, Maher Ossama M, Febres-Aldana Anthony J, Sasaki Jun, Jayakar Parul, Jayakar Anuj, Diaz-Barbosa Magaly, Janvier Michelin, Totapally Bala, Salyakina Daria, Galvez-Silva Jorge R
AM Rywlin, MD, Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.
Department of Pathology and Clinical Laboratories, Nicklaus Children's Hospital, Miami, Florida, USA.
Mol Syndromol. 2020 Dec;11(5-6):320-329. doi: 10.1159/000511343. Epub 2020 Oct 29.
The generalized form of UDP-galactose-4'-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP--acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring -glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in -linked protein glycosylation can explain the patient's phenotype.
UDP-半乳糖-4'-表异构酶（GALE）缺乏症的全身性形式会导致肌张力减退、生长发育迟缓、白内障和肝功能衰竭。非全身性形式的个体可能无症状，但长期预后不确定。我们报告了一名2岁儿童，其GALE基因存在p.R51W/p.G237D复合杂合变异，该患儿从未出现经典半乳糖血症的症状，但有先天性二尖瓣和三尖瓣联合畸形及幽门狭窄病史，并出现全血细胞减少。预测性计算工具和红细胞中测量的GALE活性降低支持了变异的致病性。GALE的功能通过UDP-N-乙酰半乳糖胺和N-乙酰葡糖胺的表异构化扩展到聚糖的生物合成。对基因本体联合会数据库的查询揭示了几种推定的蛋白质，它们参与正常造血和房室瓣形态发生，需要O-糖基化以实现充分的功能。我们推测，由于GALE缺乏导致底物供应受限，O-连接蛋白糖基化的改变可以解释该患者的表型。
