bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2024‒09‒08
six papers selected by
Silvia Radenkovic, UMC Utrecht
  1. Treatment of congenital disorders of glycosylation: An overview.
  2. Sensitivity of transferrin isoform analysis for PMM2-CDG.
  3. Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation.
  4. Identification of CNTN2 as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing in Drosophila.
  5. Development of new NGLY1 assay systems - toward developing an early screening method for NGLY1 deficiency.
  6. Development of a Multiplexed Sphingolipids Method for Diagnosis of Inborn Errors of Ceramide Metabolism.
  1. Mol Genet Metab. 2024 Aug 18. pii: S1096-7192(24)00451-7. [Epub ahead of print]143(1-2): 108567
    Treatment of congenital disorders of glycosylation: An overview.
    Dulce Quelhas, Jaak Jaeken.
      While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.
    Keywords:  Chaperones; Congenital disorders of glycosylation; Drug repurposing; Epalrestat; GLM101; Monosaccharide
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108567
  2. Mol Genet Metab. 2024 Aug 11. pii: S1096-7192(24)00448-7. [Epub ahead of print]143(1-2): 108564
    Sensitivity of transferrin isoform analysis for PMM2-CDG.
    Patrica L Hall, Kris Liedke, Coleman Turgeon, Amy White, Gesele Bentz Pino, Dawn Peck, April Studinski, Dimitar Gavrilov, Silvia Tortorelli, Devin Oglesbee, Dietrich Matern, Kimiyo Raymond, Matthew J Schultz.
      Transferrin isoform analysis is an established laboratory test for congenital disorders of glycosylation (CDG). Despite its long history of clinical use, little has been published about its empirical sensitivity for specific conditions. We conducted a retrospective analysis of ten years of testing data and report our experience with transferrin testing for type I profiles and its sensitivity for the most common congenital disorder of glycosylation, PMM2-CDG. The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly demonstrate two known, recurrent variants enriched in false positive cases highlighting an important limitation of the test. The data confirm the clinical validity of transferrin isotype analysis as a screening test for disorders of protein N-linked glycosylation and as functional test for PMM2 genotypes of uncertain significance.
    Keywords:  Biochemical testing; Carbohydrate deficient transferrin; Congenital disorders of glycosylation; PMM2-CDG; Test performance
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108564
  3. Mol Genet Metab. 2024 Aug 30. pii: S1096-7192(24)00455-4. [Epub ahead of print]143(1-2): 108571
    Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation.
    Livia Interdonato, Nastassja Himmelreich, Sven F Garbade, Dan Wen, Marina Morath, Rosanna Di Paola, Vittorio Calabrese, Christian Thiel, Verena Peters.
      Diagnosing Congenital Disorders of Glycosylation (CDG) is challenging due to clinical heterogeneity and the limited sensitivity of the classic serum transferrin isoelectric focusing (IEF) or capillary zone electrophoresis test. This study investigates the potential of using the glycoprotein carnosinase 1 (CN1) activity as a diagnostic marker for CDG patients. CN1 activity was measured photometrically in serum from 81 genetically confirmed CDG patients and healthy individuals. While the IEF transferrin method detected 77 patients, four remained undetected. In healthy individuals, serum CN1 activity ranged from 0.1 to 6.4 μmol/ml/h depending on age, with mean CN1 activities up to four-fold higher than in CDG patients. CDG patients´ CN1 activities never exceeded 2,04 μmol/ml/h. Using the 25th percentile to differentiate between groups, the test performance varied by age. For children over 10 years old, the sensitivity and specificity were 96 % and 83 %, respectively. For those under 10, sensitivity and specificity dropped to 71 % and to 64 %. However, CN1 activity successfully identified three of four patients with normal IEF patterns. Although mean CN1 activity in CDG patients is significantly lower than in healthy controls, the test's reliability for classic CDG diagnosis is limited, as the diagnosis is usually made at a young age. Nevertheless, it is a simple, cost-effective assay that can complement classic tests, especially in settings with limited access to complex methods or for patients with normal transferrin patterns but suspicious for CDG.
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108571
  4. bioRxiv. 2024 Aug 12. pii: 2024.08.12.607501. [Epub ahead of print]
    Identification of CNTN2 as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing in Drosophila.
    Holly J Thorpe, Brent S Pedersen, Miranda Dietze, Nichole Link, Aaron R Quinlan, Joshua L Bonkowsky, Ashley Thomas, Clement Y Chow.
      Loss of function mutations in the X-linked PIGA gene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA S132C , an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carry PIGA S132C , but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using a Drosophila eye-based model of PIGA-CDG. We found that loss of CNTN2 , a predicted protective modifier, rescues loss of PIGA in Drosophila eye-based model, like what we predict in the family. Further testing found that loss of CNTN2 also rescues patient-relevant phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. By using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.
    DOI:  https://doi.org/10.1101/2024.08.12.607501
  5. Glycobiology. 2024 Aug 29. pii: cwae067. [Epub ahead of print]
    Development of new NGLY1 assay systems - toward developing an early screening method for NGLY1 deficiency.
    Hiroto Hirayama, Haruhiko Fujihira, Tadashi Suzuki.
      Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) is an amidase (EC:3.5.1.52) widely conserved in eukaryotes. It catalyzes the removal of N-glycans on glycoproteins, converting N-glycosylated Asn into Asp residues. This enzyme also plays a role in the quality control system for nascent glycoproteins. Since the identification of a patient with an autosomal recessive genetic disorder caused by NGLY1 gene dysfunction, known as NGLY1 deficiency or NGLY1 congenital disorder of deglycosylation (OMIM: 615273), in 2012, more than 100 cases have been reported worldwide. NGLY1 deficiency is characterized by a wide array of symptoms, such as global mental delay, intellectual disability, abnormal electroencephalography findings, seizure, movement disorder, hypolacrima or alacrima, and liver dysfunction. Unfortunately, no effective therapeutic treatments for this disease have been established. However, administration of adeno-associated virus 9 (AAV9) vector harboring human NGLY1 gene to an NGLY1-deficient rat model (Ngly1  -/- rat) by intracerebroventricular injection was found to drastically improve motor function defects. This observation indicated that early therapeutic intervention could alleviate various symptoms originating from central nervous system dysfunction in this disease. Therefore, there is a keen interest in the development of facile diagnostic methods for NGLY1 deficiency. This review summarizes the history of assay development for PNGase/NGLY1 activity, as well as the recent progress in the development of novel plate-based assay systems for NGLY1, and also discusses future perspectives.
    Keywords:  ELISA; FRET; Ngly1; luciferase assay; peptide:n-glycanase
    DOI:  https://doi.org/10.1093/glycob/cwae067
  6. Clin Chem. 2024 Aug 29. pii: hvae115. [Epub ahead of print]
    Development of a Multiplexed Sphingolipids Method for Diagnosis of Inborn Errors of Ceramide Metabolism.
    Seul Kee Byeon, Jinyong Kim, Peter Jared Wegwerth, Roman Zenka, John P George, Filippo Pinto E Vairo, Devin Oglesbee, Matthew J Schultz, Dietrich Matern, Akhilesh Pandey.
      BACKGROUND: Sphingolipids play a crucial role in cellular functions and are essential components of cell membranes, signaling molecules, and lipid metabolism. In particular, ceramide is a key intermediate in sphingolipid metabolism and defects in ceramide metabolism can lead to various inborn errors of metabolism, making ceramides important targets for clinical screening and diagnosis. Detecting altered concentration patterns of sphingolipids is desirable for distinguishing related inborn errors of metabolism for diagnosis and treatment monitoring.METHODS: We developed a liquid chromatography-tandem mass spectrometry method with a pathway-oriented approach to focus on sphingolipids involved in ceramide metabolism. A total of 47 sphingolipids bearing different head groups and side chains were targeted. Precision/reproducibility, linearity, and spike recovery extraction efficiency tests were performed on plasma and serum samples from confirmed cases of sphingolipidosis.
    RESULTS: Linearity of the method showed the coefficient of determination (r2) for all standards to be >0.99 with a slope of 1.00 ± 0.01. Intra- and interday reproducibility of standards spiked into plasma and serum revealed a coefficient of variation <20%. Spike and recovery assessment showed recovery values of 80%-120% for all standards. Altered levels of sphingolipids from patients with hereditary sensory and autonomic neuropathy caused by pathogenic variants in SPTLC2 and hypomyelinating leukodystrophy related to variants in DEGS1 were detected, in agreement with trends reported in earlier studies confirming the utility of this pathway-centric method.
    CONCLUSIONS: This method can serve as a useful tool to simultaneously monitor sphingolipids, enabling screening and diagnosis of inborn errors of ceramide metabolism.
    DOI:  https://doi.org/10.1093/clinchem/hvae115
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