Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Dana Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.
J Inherit Metab Dis. 2020 Jul;43(4):880-890. doi: 10.1002/jimd.12225. Epub 2020 Feb 27.
Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.
先天性糖基化障碍 (CDG) 是一组临床异质性疾病，其特征是生物分子的寡糖修饰能力下降。蛋白质识别、相互作用、结合和锚定的关键中断导致广泛的生理效应。患者表现为内分泌异常、免疫缺陷、肝损伤、凝血障碍和神经发育障碍。患者可能会因休克生理而出现死亡率/发病率，这种休克通常培养阴性且对标准治疗反应不佳。水肿、胸腔和心包积液、腹水、蛋白尿和蛋白丢失性肠病伴有过度炎症反应。血清蛋白稳态的负平衡是多种机制导致的，包括肝合成和分泌减少、消耗增加和外渗。糖萼（一层覆盖在内皮细胞表面的糖基化蛋白，可防止血栓形成和外渗）的破坏被认为是 CDG 患者内皮功能障碍的一个可疑原因。我们对过去 2 年在我们机构因急性病住院的 CDG 患者进行了回顾性研究。在患病和康复期间收集的纵向临床和实验室数据用于评估炎症标志物和干预措施的疗效。确定了 6 名患者，代表 4 种 CDG 亚型和 14 次住院治疗。急性疾病时观察到 D-二聚体升高、蛋白尿、血清总蛋白水平、凝血蛋白和白蛋白降低。输注新鲜冷冻血浆，在某些情况下输注蛋白 C 浓缩物，与临床和生物标志物改善相关。在治疗与未治疗患者的个体内比较中，这一点尤为明显。内皮屏障支持治疗的使用可以通过恢复调节性血清蛋白稳态和支持糖萼来减少内皮通透性，这可能是该人群治疗的关键组成部分。
