bims-meglyc 2023-05-07 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–05–07
ten papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review.
The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP).
The role of glucose in cardiac physiology and pathophysiology.
Application of machine learning tools and integrated OMICS for screening and diagnosis of inborn errors of metabolism.
Reduced O-GlcNAcylation diminishes cardiomyocyte Ca2+ dependent facilitation and frequency dependent acceleration of relaxation.
A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance.
Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development.
Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants.
Generalized low levels of serum N-glycans associate with better health status.
Inborn Errors of Immunity and Autoimmune Disease.

Front Pediatr. 2023 ;11 1150367

Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review.

Siliang Lu, Shuheng Liang, Yi Wu, Jinyi Liu, Lin Lin, Guosheng Huang, Huaijun Ning.

  We report the case of a 2-year-old girl who was diagnosed with Mannose-6-phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) and provide a review of the relevant literature. The young girl presented with recurrent unexplained diarrhea, vomiting, hypoproteinemia, and elevated liver transaminases. Whole-exome sequencing revealed that the patient had compound heterozygous mutations in the MPI gene (NM_0024). An exon 4 (c.455G > T, p.R152l) mutation was inherited from the mother and an exon 7 (c.884G > A, p.R295H) mutation from the father. One week after the start of mannose treatment, the vomiting and diarrhea symptoms disappeared completely and did not show any side effects. We also provide a brief review of the relevant literature. Including the present case, a total of 52 patients from hospitals across 17 countries were diagnosed with MPI-CDG. Age at disease onset ranged from birth to 15 years, with an onset under 2 years in most patients (43/50). Overall, patients presented with at least one or more of the following symptoms: chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14), and abnormally elevated leukocytes (5). None of the patients was reported to have an intellectual disability (0/28). The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration. Our findings suggest that MPI-CDG should be considered in children with unexplained recurrent digestive and endocrine systems involvement, and gene examination should be performed immediately to obtain a definite diagnosis in order to begin treatment in a timely manner.

Keywords:  CDG; MPI-CDG; carbohydrate deficient glycoprotein syndrome; congenital disorder of glycosylation; mannose phosphate isomerase

DOI:  https://doi.org/10.3389/fped.2023.1150367
J Pharmacokinet Pharmacodyn. 2023 May 02.

The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP).

Jeffrey S Barrett, Alexandre Betourne, Ramona L Walls, Kara Lasater, Scott Russell, Amanda Borens, Shlok Rohatagi, Will Roddy.

  Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and any data projecting likelihood of patient response to therapy including any genetic data. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. FDA intentions were clearly focused on improving the quality of rare disease regulatory applications by sponsors seeking to develop treatment options for various rare disease populations. As this initiative moves into its second year of operations it is envisioned that the increased connectivity to new and diverse data streams and tools will result in solutions that benefit the entire rare disease ecosystem and that the platform becomes a Collaboratory for engagement of this ecosystem that also includes patients and caregivers.

Keywords:  Data analytics; Digital research environment (DRE); Drug development; MIDD; Rare diseases

DOI:  https://doi.org/10.1007/s10928-023-09859-7
Curr Opin Clin Nutr Metab Care. 2023 May 04.

The role of glucose in cardiac physiology and pathophysiology.

Nikolaos Mylonas, Konstantinos Drosatos, Sobuj Mia.

PURPOSE OF REVIEW: Heart failure is one the major causes of death worldwide and continues to increase despite therapeutics and pharmacology advances. Fatty acids and glucose are used as ATP-producing fuels in heart to meet its energy demands. However, dysregulation of metabolites' use plays a pivotal role in cardiac diseases. How glucose becomes toxic or drives cardiac dysfunction is incompletely understood. In the present review, we summarize the recent findings on cardiac cellular and molecular events that are driven by glucose during pathologic conditions and potential therapeutic strategies to tackle hyperglycemia-mediated cardiac dysfunction.
RECENT FINDINGS: Several studies have emerged recently, demonstrating that excessive glucose utilization has been correlated with impairment of cellular metabolic homeostasis primarily driven by mitochondrial dysfunction and damage, oxidative stress, and abnormal redox signaling. This disturbance is associated with cardiac remodeling, hypertrophy, and systolic and diastolic dysfunction. Both human and animal heart failure studies, report that glucose is a preferable fuel at the expense of fatty acid oxidation during ischemia and hypertrophy, but the opposite happens in diabetic hearts, which warrants further investigation.
SUMMARY: A better understanding of glucose metabolism and its fate during distinct types of heart disease will contribute to developing novel therapeutic options for the prevention and treatment of heart failure.

DOI: https://doi.org/10.1097/MCO.0000000000000943
Metabolomics. 2023 May 03. 19(5): 49

Application of machine learning tools and integrated OMICS for screening and diagnosis of inborn errors of metabolism.

Ganni Usha Rani, Srilatha Kadali, Banka Kurma Reddy, Dudekula Shaheena, Shaik Mohammad Naushad.

   INTRODUCTION: Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility.
METHODS: TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling.
RESULTS: This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00).
CONCLUSION: Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates.

Keywords:  Cut-off values; Inborn errors of metabolism; Integrated OMICS; Machine learning; Newborn screening; Tandem mass spectrometry

DOI:  https://doi.org/10.1007/s11306-023-02013-x
J Mol Cell Cardiol. 2023 Apr 28. pii: S0022-2828(23)00079-2. [Epub ahead of print]180 10-21

Reduced O-GlcNAcylation diminishes cardiomyocyte Ca2+ dependent facilitation and frequency dependent acceleration of relaxation.

Andrew R Ednie, Chiagozie D Paul-Onyia, Eric S Bennett.

  Ca2+ dependent facilitation (CDF) and frequency dependent acceleration of relaxation (FDAR) are regulatory mechanisms that potentiate cardiomyocyte Ca2+ channel function and increase the rate of Ca2+ sequestration following a Ca2+-release event, respectively, when depolarization frequency increases. CDF and FDAR likely evolved to maintain EC coupling at increased heart rates. Ca2+/calmodulin-dependent kinase II (CaMKII) was shown to be indispensable to both; however, the mechanisms remain to be completely elucidated. CaMKII activity can be modulated by post-translational modifications but if and how these modifications impact CDF and FDAR is unknown. Intracellular O-linked glycosylation (O-GlcNAcylation) is a post-translational modification that acts as a signaling molecule and metabolic sensor. In hyperglycemic conditions, CaMKII was shown to be O-GlcNAcylated resulting in pathologic activity. Here we sought to investigate whether O-GlcNAcylation impacts CDF and FDAR through modulation of CaMKII activity in a pseudo-physiologic setting. Using voltage-clamp and Ca2+ photometry we show that cardiomyocyte CDF and FDAR are significantly diminished in conditions of reduced O-GlcNAcylation. Immunoblot showed that CaMKIIδ and calmodulin expression are increased but the autophosphorylation of CaMKIIδ and the muscle cell-specific CaMKIIβ isoform are reduced by 75% or more when O-GlcNAcylation is inhibited. We also show that the enzyme responsible for O-GlcNAcylation (OGT) can likely be localized in the dyad space and/or at the cardiac sarcoplasmic reticulum and is precipitated by calmodulin in a Ca2+ dependent manner. These findings will have important implications for our understanding of how CaMKII and OGT interact to impact cardiomyocyte EC coupling in normal physiologic settings as well as in disease states where CaMKII and OGT may be aberrantly regulated.

Keywords:  Ca(2+)-induced Ca(2+) release; CaMKII; O-GlcNAcylation; Voltage-gated Ca(2+) channel

DOI:  https://doi.org/10.1016/j.yjmcc.2023.04.007
Orphanet J Rare Dis. 2023 May 05. 18(1): 106

A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance.

Isabel C Hageman, Iris A L M van Rooij, Ivo de Blaauw, Misel Trajanovska, Sebastian K King.

  Patient registries serve to overcome the research limitations inherent in the study of rare diseases, where patient numbers are typically small. Despite the value of real-world data collected through registries, adequate design and maintenance are integral to data quality. We aimed to describe an overview of the challenges in design, quality management, and maintenance of rare disease registries.A systematic search of English articles was conducted in PubMed, Ovid Medline/Embase, and Cochrane Library. Search terms included "rare diseases, patient registries, common data elements, quality, hospital information systems, and datasets". Inclusion criteria were any manuscript type focused upon rare disease patient registries describing design, quality monitoring or maintenance. Biobanks and drug surveillances were excluded.A total of 37 articles, published between 2001 and 2021, met the inclusion criteria. Patient registries covered a wide range of disease areas and covered multiple geographical locations, with a predisposition for Europe. Most articles were methodological reports and described the design and setup of a registry. Most registries recruited clinical patients (92%) with informed consent (81%) and protected the collected data (76%). Whilst the majority (57%) collected patient-reported outcome measures, only few (38%) consulted PAGs during the registry design process. Few reports described details regarding quality management (51%) and maintenance (46%).Rare disease patient registries are valuable for research and evaluation of clinical care, and an increasing number have emerged. However, registries need to be continuously evaluated for data quality and long-term sustainability to remain relevant for future use.

Keywords:  Data quality; Design; Maintenance; Patient registry; Rare disease

DOI:  https://doi.org/10.1186/s13023-023-02719-0
Innov Clin Neurosci. 2023 Jan-Mar;20(1-3):20(1-3): 25-31

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development.

Joan Busner, Gahan Pandina, Simon Day, Atul Mahableshwarkar, Lucas Kempf, Maria Sheean, Judith Dunn.

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.

Keywords: CNS orphan drug development; CNS pediatric drug development; CNS rare disease drug development; Patient centricity
BMC Cardiovasc Disord. 2023 04 29. 23(1): 223

Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants.

Alessandra Granata.

  Stroke is an important disease with unmet clinical need. To uncover novel paths for treatment, it is of critical importance to develop relevant laboratory models that may help to shed light on the pathophysiological mechanisms of stroke. Induced pluripotent stem cells (iPSCs) technology has enormous potential to advance our knowledge into stroke by creating novel human models for research and therapeutic testing. iPSCs models generated from patients with specific stroke types and specific genetic predisposition in combination with other state of art technologies including genome editing, multi-omics, 3D system, libraries screening, offer the opportunity to investigate disease-related pathways and identify potential novel therapeutic targets that can then be tested in these models. Thus, iPSCs offer an unprecedented opportunity to make rapid progress in the field of stroke and vascular dementia research leading to clinical translation. This review paper summarizes some of the key areas in which patient-derived iPSCs technology has been applied to disease modelling and discusses the ongoing challenges and the future directions for the application of this technology in the field of stroke research.

Keywords:  Disease modeling; Genetic risk variant; Genome editing; Induced pluripotent stem cells; Small vessel disease; Stroke

DOI:  https://doi.org/10.1186/s12872-023-03227-6
Aging Cell. 2023 May 02. e13855

Generalized low levels of serum N-glycans associate with better health status.

Jiteng Fan, Jichen Sha, Shuwai Chang, Huijuan Zhao, Xiaoyun Niu, Yong Gu, Jianxin Gu, Shifang Ren.

  Caloric restriction (CR) can prolong life and ameliorate age-related diseases; thus, its molecular basis might provide new insights for finding biomarker and intervention for aging and age-related disease. Glycosylation is an important post-translational modification, which can timely reflect the changes of intracellular state. Serum N-glycosylation was found changed with aging in humans and mice. CR is widely accepted as an effective anti-aging intervention in mice and could affect mouse serum fucosylated N-glycans. However, the effect of CR on the level of global N-glycans remains unknown. In order to explore whether CR affect the level of global N-glycans, we performed a comprehensive serum glycome profiling in mice of 30% calorie restriction group and ad libitum group at 7 time points across 60 weeks by MALDI-TOF-MS. At each time point, the majority of glycans, including galactosylated and high mannose glycans, showed a consistent low level in CR group. Interestingly, O-acetylated sialoglycans presented an upward change different from other derived traits, which is mainly reflected in two biantennary α2,6-linked sialoglycans (H5N4Ge2Ac1, H5N4Ge2Ac2). Liver transcriptome analysis further revealed a decreased transcriptional level of genes involved in N-glycan biosynthesis while increased level of acetyl-CoA production. This finding is consistent with changes in serum N-glycans and O-acetylated sialic acids. Therefore, we provided one possible molecular basis for the beneficial effect of CR from N-glycosylation perspective.

Keywords:  N-glycans; O-acetylation; caloric restriction; liver; serum; transcriptome

DOI:  https://doi.org/10.1111/acel.13855
J Allergy Clin Immunol Pract. 2023 Apr 27. pii: S2213-2198(23)00458-0. [Epub ahead of print]

Inborn Errors of Immunity and Autoimmune Disease.

Paul Edgar Gray, Clementine David.

  Autoimmunity may be a manifestation of inborn errors of immunity (IEI) specifically as part of the subgroup of primary immunodeficiency (PID) known as primary immune regulatory disorders (PIRD). However, while making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes and inheritance of autoimmunity associated with PIRD, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunological features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. Additionally, there will be a review of autoimmunity in non-genetically defined PID such as common variable immunodeficiency (CVID), and of instances where primary autoimmunity can result in clinical phenocopies of IEI.

Keywords:  Autoimmune disease; Autoimmune phenocopy; Inborn errors of immunity; Monogenic autoimmunity; Primary immune regulatory disorders; Somatic autoimmunity

DOI:  https://doi.org/10.1016/j.jaip.2023.04.018