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Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ABSTRACT: ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

SUBMITTER: Alharbi H

PROVIDER: S-EPMC10047170 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

Alharbi Hana H Daniel Earnest James Paul EJP Thies Jenny J Chang Irene I Goldner Dana L DL Ng Bobby G BG Witters Peter P Aqul Amal A Velez-Bartolomei Frances F Enns Gregory M GM Hsu Evelyn E Kichula Elizabeth E Lee Esther E Lourenco Charles C Poskanzer Sheri A SA Rasmussen Sara S Saarela Katelyn K Wang YunZu M YM Raymond Kimiyo M KM Schultz Matthew J MJ Freeze Hudson H HH Lam Christina C Edmondson Andrew C AC He Miao M

Journal of inherited metabolic disease 20230129 2

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. ...[more]

PMID: 36651831

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Project description:The Atherogenic Index of Plasma (AIP), calculated by log (Triglycerides/HDL-C), has been proposed as a marker of atherogenic and cardiovascular risk. Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) share some pathogenic features and may be considered clinical manifestations of Metabolic Syndrome. In this study, we aimed to investigate the role of increased AIP as a putative metabolic biomarker for MASLD. 1,496 individuals (49% males and 51% females) underwent clinical examination for Metabolic Syndrome at Internal Medicine Division "C. Frugoni" of University Hospital of Bari, Italy in the period between January 2016 and April 2024. Clinical history was recorded, and physical examination, anthropometric measures, biochemical assessment, and abdomen ultrasound were performed. In the overall population, AIP significantly correlated with fasting glycemia (FPG, r = 0.26, p < 0.0001), HbA1c (r = 0.20, p < 0.0001), LDL (r = 0.11, p < 0.0001) and total cholesterol (r = 0.09; p < 0.0001), and anthropometric measures of obesity BMI (r = 0.37, p < 0.0001) and Waist Circumference (r = 0.44; p < 0.001). We then investigated AIP values in patients with and without dysmetabolic conditions, finding that AIP significantly increased as steatosis worsened (p < 0.001). ROC curves identified an optimal cut-off of 0.31 for accurately diagnosing severe steatosis and AIP values above this cut-off discriminated patients with significantly increased (p < 0.0001) fasting glycemia, LDL, and waist circumference, and were strongly associated (p < 0.0001) with MASLD (LLR 85.3), type 2 diabetes (LLR 85.5), abdominal obesity (LLR 72.9), overweight (LLR 151.8), and systemic obesity (LLR 178.4). The risk for being diagnosed with such conditions was found to be even higher in the subpopulation of patients with severe liver steatosis. To validate our findings, we considered another cohort of patients with and without biopsy-proven liver steatosis (public dataset GSE89632), confirming that a significant increase (p < 0.001) in AIP values could be found in patients with liver steatosis compared to healthy controls. AIP can be considered a specific biomarker of fatty liver disease with high sensitivity for the diagnosis of the severe form of liver steatosis. Considering AIP in the evaluation of patients with liver steatosis may augment the accuracy for diagnosing metabolic impairment and MASLD.

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Dataset Information

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

Publications

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

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