Tulane University Medical Center, Department of Pediatrics, Hayward Genetics Center, New Orleans, LA, USA; Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Mol Genet Metab. 2014 Aug;112(4):275-9. doi: 10.1016/j.ymgme.2014.06.002. Epub 2014 Jun 21.
We recently redefined phosphoglucomutase-1 deficiency not only as an enzyme defect, involved in normal glycogen metabolism, but also an inborn error of protein glycosylation. Phosphoglucomutase-1 is a key enzyme in glycolysis and glycogenesis by catalyzing in the bidirectional transfer of phosphate from position 1 to 6 on glucose. Glucose-1-P and UDP-glucose are closely linked to galactose metabolism. Normal PGM1 activity is important for effective glycolysis during fasting. Activated glucose and galactose are essential for normal protein glycosylation. The complex defect involving abnormal concentrations of activated sugars leads to hypoglycemia and two major phenotypic presentations, one with primary muscle involvement and the other with severe multisystem disease. The multisystem phenotype includes growth delay and malformations, like cleft palate or uvula, and liver, endocrine and heart function with possible cardiomyopathy. The patients have normal intelligence. Decreased transferrin galactosylation is a characteristic finding on mass spectrometry. Previous in vitro studies in patient fibroblasts showed an improvement of glycosylation on galactose supplements. Four patients with PGM1 deficiency have been trialed on d-galactose (compassionate use), and showed improvement of serum transferrin hypoglycosylation. There was a parallel improvement of liver function, endocrine abnormalities and a decrease in the frequency of hypoglycemic episodes. No side effects have been observed. Galactose supplementation didn't seem to resolve all clinical symptoms. Adding complex carbohydrates showed an additional clinical amelioration. Based on the available clinical data we suggest to consider the use of 0.5-1g/kg/day d-galactose and maximum 50 g/day oral galactose therapy in PGM1-CDG. The existing data on galactose therapy have to be viewed as preliminary observations. A prospective multicenter trial is ongoing to evaluate the efficacy and optimal d-galactose dose of galactose supplementation.
我们最近重新定义了磷酸葡萄糖变位酶 1 缺乏症，不仅将其视为一种涉及正常糖原代谢的酶缺陷，也将其视为一种蛋白质糖基化的先天性错误。磷酸葡萄糖变位酶 1 是糖酵解和糖生成过程中的关键酶，通过催化葡萄糖位 1 到 6 上的磷酸的双向转移。葡萄糖-1-P 和 UDP-葡萄糖与半乳糖代谢密切相关。正常的 PGM1 活性对于空腹时有效的糖酵解很重要。激活的葡萄糖和半乳糖对于正常的蛋白质糖基化至关重要。涉及异常激活糖浓度的复杂缺陷导致低血糖和两种主要表型表现，一种主要涉及肌肉，另一种涉及严重的多系统疾病。多系统表型包括生长迟缓、畸形，如腭裂或悬雍垂，以及肝、内分泌和心脏功能，可能伴有心肌病。患者智力正常。转铁蛋白半乳糖基化程度降低是质谱分析的一个特征性发现。以前在患者成纤维细胞中的体外研究表明，在半乳糖补充剂的作用下，糖基化得到改善。有 4 名 PGM1 缺乏症患者接受了 d-半乳糖（同情使用）治疗，显示血清转铁蛋白低血糖的改善。肝功能、内分泌异常和低血糖发作频率降低均得到改善。未观察到副作用。半乳糖补充似乎没有解决所有临床症状。添加复合碳水化合物显示出额外的临床改善。基于现有的临床数据，我们建议在 PGM1-CDG 中考虑使用 0.5-1g/kg/天 d-半乳糖和最大 50g/天口服半乳糖治疗。对半乳糖治疗的现有数据应视为初步观察。正在进行一项前瞻性多中心试验，以评估半乳糖补充的疗效和最佳 d-半乳糖剂量。
