An emerging role for endothelial barrier support therapy for congenital disorders of glycosylation

Abstract

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.

P53 in the impaired lungs

“…The cellular cytoskeleton and glycocalyx regulate the morphology of the metabolically active endothelial cells [ [23] , [24] , [25] ]. The endothelium disruption may be due to the cytoskeletal reorganization and pathogen recognition by cellular receptors [ [26] , [27] , [28] , [29] ]. Lung endothelial hyperpermeability is the cause and consequence of inflammatory lung disease, including ALI or ARDS [ 30 , 31 ].…”

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

“…Our proteomics revealed multiple coagulation factor abnormalities. Thus, CHAPLE disease involves the pathological cross-talk of complement abnormalities on coagulation similar to glycosylation disorders that also present with lymphangiectasia and coagulation abnormalities 43 . Further studies are needed to understand the intersection of complement and coagulation pathways, especially in unexplained lymphangiectasia disorders.…”

The development of end stage renal disease in two patients with PMM2‐CDG

“…This patient was the subject of a previous report emphasizing perturbations in the vascular barrier that led to anasarca. 6 Other medical issues at the time of death included diffuse hypotonia, seizure disorder, hypoglycemia, neuromuscular scoliosis, thrombocytopenia, coagulopathy, and cortical vision impairment. PMM2 gene sequencing confirmed the following compound heterozygote variants: p. Gly42Arg and p. Pro113Leu.…”