bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2023–06–11
ten papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium



  1. Glob Med Genet. 2023 Jun;10(2): 105-108
      Congenital disorder of glycosylation (CDG) is an autosomal recessively inherited disorder. Hypotonia, stroke-like episodes, and peripheral neuropathy are also associated with the condition that typically develops during infancy. The patient, a 12-year-old girl born to healthy consanguineous parents, was diagnosed with cerebral palsy as a child. The affected patient has hypotonia, inadequate speech, strabismus, and developmental delay with mild mental retardation, which are key symptoms of CDG. Whole-exome sequencing (WES) identified the known missense pathogenic variant PMM2 c.710 C > T, p.T237M in the patient coding for the phosphomannomutase 2 (PMM2) confirming molecular testing of CDG. The patient's parents carried heterozygous PMM2 c.710 C > T variants. This study highlights the importance of WES in patients with a developmental disability or other neurological conditions, which is also useful in screening risk factors in couples with infertility or miscarriage issues.
    Keywords:  PMM2 -CDG ; South India; cerebral palsy; mutation
    DOI:  https://doi.org/10.1055/s-0043-1769494
  2. Biotechnol Adv. 2023 Jun 06. pii: S0734-9750(23)00091-5. [Epub ahead of print] 108184
      Glycosylation is how proteins and lipids are modified with complex carbohydrates known as glycans. The post-translational modification of proteins with glycans is not a template-driven process in the same way as genetic transcription or protein translation. Glycosylation is instead dynamically regulated by metabolic flux. This metabolic flux is determined by the concentrations and activities of the glycotransferase enzymes, which synthesise glycans, the metabolites that act as their precursors and transporter proteins. This review provides an overview of the metabolic pathways underlying glycan synthesis. Pathological dysregulation of glycosylation, particularly increased glycosylation occurring during inflammation, is also elucidated. The resulting inflammatory hyperglycosylation acts as a glycosignature of disease, and we report on the changes in the metabolic pathways which feed into glycan synthesis, revealing alterations to key enzymes. Finally, we examine studies in developing metabolic inhibitors targeting these critical enzymes. These results provide the tools for researchers investigating the role of glycan metabolism in inflammation and have helped to identify promising glycotherapeutic approaches to inflammation.
    Keywords:  Glycan synthesis; Glycosylation; Inflammation; Metabolic flux
    DOI:  https://doi.org/10.1016/j.biotechadv.2023.108184
  3. Carbohydr Res. 2023 May 31. pii: S0008-6215(23)00120-9. [Epub ahead of print]530 108858
      Terminal N-acetylglucosamine (GlcNAc) N-linked glycosylation is a truncated N-glycosylated modification that has been reported to be involved in various diseases, such as autoimmune diseases, cancers, and neurodegenerative diseases. New and simple tools will be always valuable for further characterization of the functions of this kind of glycosylation. Our previous paper proved that an optimized lectin created from Agrocybe aegerita GlcNAc selective lectin (AANL) named AANL6, can effectively identify O-GlcNAcylation, which is terminal GlcNAc O-linked glycosylation. We speculated that AANL6 could also be used to identify terminal GlcNAc N-linked glycosylation. Using therapeutic monoclonal antibodies as a model of terminal GlcNAc N-glycosylated proteins, we proved that AANL6 could selectively identify terminal GlcNAc N-linked glycosylation. The ratio of terminal GlcNAc N-linked glycosylation was increased by enrichment with AANL6 in human serum. Using cell membrane proteins as a complex sample, we found that AANL6 bound to the sperm surface, which expresses abundant terminal GlcNAc N-glycans, but did not bind to some tumor cell surfaces such A549 and MCF-7 cells, which is rich in high mannose glycoforms. In conclusion, AANL6 was identified as a powerful tool to probe terminal GlcNAc N-linked glycosylation and would be valuable for uncovering the function of this glycosylation.
    Keywords:  AANL; AANL6; Glycosylation; N-acetylglucosamine; Tool
    DOI:  https://doi.org/10.1016/j.carres.2023.108858
  4. Front Sociol. 2023 ;8 1122488
      Having worked with two large population sequencing initiatives, the separation between the potential for genomics in precision medicine and the current reality have become clear. To realize this potential requires workflows, policies, and technical architectures that are foreign to most healthcare systems. Many historical processes and regulatory barriers currently impede our progress. The future of precision medicine includes genomic data being widely available at the point of care with systems in place to manage its efficient utilization. To achieve such vision requires substantial changes in billing, reimbursement, and reporting as well as the development of new systemic and technical architectures within the healthcare system. Clinical geneticist roles will evolve into managing precision health frameworks and genetic counselors will serve crucial roles in both leading and supporting precision medicine through the implementation and maintenance of precision medicine architectures. Our current path has many obstacles that hold us back, leaving preventable deaths in the wake. Reengineering our healthcare systems to support genomics can have a major impact on patient outcomes and allow us to realize the long-sought promises of precision medicine.
    Keywords:  bioinformatics; genetic testing; genomics; implementation science; population health genomics; precision medicine; reimbursement; whole genome sequencing
    DOI:  https://doi.org/10.3389/fsoc.2023.1122488
  5. Antioxid Redox Signal. 2023 Jun 08.
       SIGNIFICANCE: Nicotinamide adenine dinucleotide (NAD+) participates in redox reactions and NAD+-dependent signaling processes, which couples the enzymatic degradation of NAD+ to post-translational modifications of proteins or the production of second messengers. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with acute and chronic neuronal dysfunction.
    RECENT ADVANCES: A decline in NAD+ has been observed during normal aging and since aging is the primary risk factor for many neurological disorders; NAD+ metabolism has become a promising therapeutic target and prolific research field in recent years.
    CRITICAL ISSUES: In many neurological disorders, either as a primary feature or as consequence of the pathological process, neuronal damage is accompanied by dysregulated mitochondrial homeostasis, oxidative stress or metabolic reprograming. Modulating NAD+ availability appears to have a protective effect against such changes observed in acute neuronal damage and age-related neurological disorders. Such beneficial effects could be, at least in part, due to the activation of NAD+-dependent signaling processes.
    FUTURE DIRECTIONS: While in many instances the protective effect has been ascribed to the activation of sirtuins; approaches that directly test the role of sirtuins or that target the NAD+ pool in a cell type-specific manner may be able to provide further mechanistic insight. Likewise, these approaches may afford greater efficacy to strategies aimed at harnessing the therapeutic potential of NAD+-dependent signaling in neurological disorders.
    DOI:  https://doi.org/10.1089/ars.2023.0241
  6. Afr J Lab Med. 2023 ;12(1): 1946
      Inborn errors of metabolism (IEM) are a group of genetically derived diseases that are individually rare but collectively common and can be very severe. While high-income countries usually employ modern scientific technologies like tandem mass spectrometry for IEM investigation, these disorders are, in contrast, only rarely screened for in developing countries due to misconceptions that the required facilities are beyond the reach of these countries. This paper attempts to educate scientists and clinicians in developing countries on low-technology IEM screening methods that only require moderate facilities. Although a definitive diagnosis of IEM may require specialised laboratory investigations and attendant interpretation, in most cases, the basic facilities available in the average clinical chemistry laboratory in developing countries can allow the early detection of IEM. This early detection would facilitate critical early decision making, thus leading to better management, optimised treatment, and reduced morbidity and or mortality of IEM in these resource-limited countries. With this approach, a few referral centres for confirmatory investigation, comparable to those existing in developed countries, could be established. This can be integrated into creative health education for healthcare professionals and families who have individuals with IEM.
    What this study adds: IEMs are important enough that every country, developed or developing, should have screening plans and basic laboratory facilities that are adequate for initial IEM diagnosis. No country should therefore give up on testing for IEMs on the excuse of a paucity of advanced facilities.
    Keywords:  basic laboratory investigations; developing countries; health education; inborn errors of metabolism; optimisation of treatment
    DOI:  https://doi.org/10.4102/ajlm.v12i1.1946
  7. Orphanet J Rare Dis. 2023 Jun 07. 18(1): 140
       BACKGROUND: Rare diseases present a challenge to guideline implementation due to a low prevalence in the general population and the unfamiliarity of healthcare professionals. Existing literature in more common diseases references barriers and facilitators to guideline implementation. This systematic review aims to identify these barriers and facilitators in rare diseases from existing literature.
    METHODS: A multi-stage strategy included searching MEDLINE PubMed, EMBASE Ovid, Web of Science and Cochrane library from the earliest date available to April 2021, Orphanet journal hand-search, a pearl-growing strategy from a primary source and reference/citation search was performed. The Integrated Checklist of Determinants of Practice which comprises of twelve checklists and taxonomies, informed by 57 potential determinants was selected as a screening tool to identify determinants that warrant further in-depth investigation to inform design of future implementation strategies.
    RESULTS: Forty-four studies were included, most of which were conducted in the United States (54.5%). There were 168 barriers across 36 determinants (37 studies) and 52 facilitators across 22 determinants (22 studies). Fifteen diseases were included across eight WHO ICD-11 disease categories. Together individual health professional factors and guideline factors formed the majority of the reported determinants (59.5% of barriers and 53.8% of facilitators). Overall, the three most reported individual barriers were the awareness/familiarity with the recommendation, domain knowledge and feasibility. The three most reported individual facilitators were awareness/familiarity with the recommendation, agreement with the recommendation and ability to readily access the guidelines. Resource barriers to implementation included technology costs, ancillary staff costs and more cost-effective alternatives. There was a paucity of studies reporting influential people, patient advocacy groups or opinion leaders, or organisational factors influencing implementation.
    CONCLUSIONS: Key barriers and facilitators to the implementation of clinical practice guidelines in the setting of rare diseases were at the individual health professional and guideline level. Influential people and organisational factors were relatively under-reported and warrant exploration, as does increasing the ability to access the guidelines as a potential intervention.
    DOI:  https://doi.org/10.1186/s13023-023-02667-9
  8. Front Cardiovasc Med. 2023 ;10 1110119
       Introduction: Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies for energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood.
    Methods: In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases (|log2FC| ≥ 0.28 and BH adjusted p-val 0.1) and performed gene set analysis (GSA) using the PAGE statistics on KEGG pathways.
    Results: Our analysis demonstrates that genes in arachidonic acid metabolism (AA) are significantly perturbed across cardiomyopathies. In particular, the arachidonic acid metabolism gene PLA2G2A interacts with fibroblast marker genes and can potentially influence fibrosis during cardiomyopathy.
    Conclusion: The profound significance of AA metabolism within the cardiovascular system renders it a key player in modulating the phenotypes of cardiomyopathies.
    Keywords:  GSA; arachidonic acid; cardiomyopathies; heart failure; metabolism; transcriptome
    DOI:  https://doi.org/10.3389/fcvm.2023.1110119
  9. Neurotherapeutics. 2023 Jun 06.
      MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6 months in doses up to 1.5 g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6 months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of "much improved" or better). Twelve patients (aged 5-28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6 months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV - 3.19 [- 0.84; - 5.6]), social communication (mean SCQ - 2.08 [- 0.63; - 4.90]), and executive function (BRIEF-2 inhibit - 5.2 [- 1.23; - 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Our results suggest that supplementation with D-galactose in patients with MOGHE is safe and well tolerated and, although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.
    Keywords:  Developmental and epileptic encephalopathy; Genetic epilepsy; Neurogenetics; SLC35A2; Somatic mutation
    DOI:  https://doi.org/10.1007/s13311-023-01395-z
  10. Free Radic Biol Med. 2023 Jun 02. pii: S0891-5849(23)00473-2. [Epub ahead of print]205 77-89
      NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.
    Keywords:  Carnitine; Cysteine; Metabolomics; NAD(+) precursors; Serine; Systems medicine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.032