bims-meglyc 2024-03-10 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2024‒03‒10
eight papers selected by
Silvia Radenkovic, UMC Utrecht

A rare case report of type 1 congenital disorders of glycosylation with acute decompensated heart failure and the incidental discovery of congenital disorders of glycosylation associated dilated cardiomyopathy and acute myocarditis.
Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models.
Resilience in patients and family caregivers living with congenital disorders of glycosylation (CDG): a quantitative study using the brief resilience coping scale (BRCS).
Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation.
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation.
Does gene therapies clinical research in rare diseases reflects the competitivity of the country: Example of France.
Search progress of pyruvate kinase M2 (PKM2) in organ fibrosis.
Congenital Myasthenia Syndrome Due to a Novel DPAGT1 Gene Mutation - An Error of Glycosylation Masquerading as a Congenital Myopathy.

Eur Heart J Case Rep. 2024 Mar;8(3): ytae088

A rare case report of type 1 congenital disorders of glycosylation with acute decompensated heart failure and the incidental discovery of congenital disorders of glycosylation associated dilated cardiomyopathy and acute myocarditis.

Woo Sze Yang, Suchi Grover, Emma Smith, Joseph B Selvanayagam.

  Background: Congenital disorders of glycosylation (CDG) are rare genetically inherited defects leading to enzyme deficiency or malfunction in the glycosylation pathway. Normal glycosylation is essential to the development of normal cardiac anatomy and function. Congenital disorders of glycosylation-related cardiomyopathy are often the first manifestation detected in early life and may lead to sudden cardiac death. Approximately one-fifth of CDG types are related to cardiac diseases that include cardiomyopathy, rhythm disturbances, pericardial effusions, and structural heart disease.Case summary: We report a rare case of a 26-year-old lady with CDG-1 who presented with acute-onset dyspnoea. She had respiratory tract symptoms for the past 2 weeks. With the relevant clinical and biochemical findings, including supportive findings on echocardiogram and cardiac magnetic resonance imaging, we have managed to arrive at a diagnosis of severe pneumonia leading to acute decompensated heart failure, as well as the discovery of an underlying CDG-associated dilated cardiomyopathy (DCM) and acute myocarditis. Anti-failure medications and i.v. methylprednisolone were commenced, and she showed gradual clinical improvement with an increase of her left ventricular function. She was discharged home well with anti-failure therapy, prednisolone, and a follow-up echocardiogram with further review in the heart failure clinic.
Discussion: In conclusion, this case report highlights the need for accurate diagnosis and prompt management of CDG-associated DCM, leading to a successful recovery and discharge from hospital care. With this, we hope to add to the increasing number of reported cases of CDG-related cardiac disease in the medical literature to emphasize the importance of screening and follow-up for any underlying cardiac diseases in patients with CDG.

Keywords:  Acute myocarditis; Cardiac magnetic resonance; Case report; Congenital disorders of glycosylation; Dilated cardiomyopathy; Heart failure

DOI:  https://doi.org/10.1093/ehjcr/ytae088
Cell Rep. 2024 Mar 01. pii: S2211-1247(24)00211-0. [Epub ahead of print]43(3): 113883

Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models.

Silvia Radenkovic, Rohit Budhraja, Teun Klein-Gunnewiek, Alexia Tyler King, Tarun N Bhatia, Anna N Ligezka, Karen Driesen, Rameen Shah, Bart Ghesquière, Akhilesh Pandey, Nael Nadif Kasri, Steven A Sloan, Eva Morava, Tamas Kozicz.

  Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals. Utilizing multi-omics datasets from 3D human cortical organoids (hCOs) derived from PMM2-CDG individuals, we identify widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG, as well as impaired mitochondrial structure and abnormal glucose metabolism in PMM2-deficient hCOs, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in hCOs and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions.

Keywords:  CP: Neuroscience; congenital disorder of glycosylation; disease model; hiPSC-derived cortical organoids; hiPSC-derived iNeuronal networks; neurodevelopmental disorder; phosphomannomutase 2

DOI:  https://doi.org/10.1016/j.celrep.2024.113883
Orphanet J Rare Dis. 2024 Mar 04. 19(1): 98

Resilience in patients and family caregivers living with congenital disorders of glycosylation (CDG): a quantitative study using the brief resilience coping scale (BRCS).

Joana Poejo, Ana Isabel Gomes, Pedro Granjo, Vanessa Dos Reis Ferreira.

  BACKGROUND: Patients and family caregivers living with Congenital Disorders of Glycosylation (CDG) experience a heavy burden, which can impact their resiliency and quality of life. The study's purpose was to measure the resilience levels of patients and family caregivers living with CDG using the brief resilience coping scale.METHODS: We conducted an observational, cross-sectional study with 23 patients and 151 family caregivers living with CDG. Descriptive analyses were performed to characterize patients with CDG and family caregivers' samples. Additionally, we assessed correlations between resilience and specific variables (e.g., age, academic degree, time until diagnosis) and examined resilience differences between groups (e.g., sex, marital status, occupation, professional and social support).
RESULTS: GNE myopathy was the most prevalent CDG among patients, while in family caregivers was PMM2-CDG. Both samples showed medium levels of resilience coping scores. Individuals with GNE myopathy had significantly higher scores of resilience compared to patients with other CDG. Resilience was positively correlated with educational degree in patients with CDG. Family caregivers had marginally significant higher scores of resilience coping if they received any kind of professional support or had contact with other families or people with the same or similar disease, compared with unsupported individuals.
CONCLUSIONS: Despite the inherited difficulties of living with a life-threatening disease like CDG, patients and family caregivers showed medium resilient coping levels. Resilience scores changed significantly considering the CDG genotype, individual's academic degree and professional and social support. These exploratory findings can empower the healthcare system and private institutions by promoting the development of targeted interventions to enhance individuals` coping skills and improve the overall well-being and mental health of the CDG community.

Keywords:  Brief resilience coping scale (BRCS); Congenital disorders of glycosylation (CDG); Mental health; Rare diseases; Resilience

DOI:  https://doi.org/10.1186/s13023-024-03043-x
Mol Genet Metab Rep. 2024 Jun;39 101067

Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation.

Dan Zhong, Xiujuan Huang, Taoshan Feng, Jieqing Zeng, Shanshan Gu, Fan Ning, Yue Yang, Jinyuan Zhu, Yajun Wang, Riling Chen, Guoda Ma.

  Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C > G (p.F221L) mutation and loss of exon 2. Further analysis revealed that the enzymatic activity of the mutant PMM2 protein was significantly reduced by 44.97% (p < 0.05) compared to the wild-type protein.

Keywords:  Cerebellar dysplasia; Congenital disorder of glycosylation type Ia; Liver injury; Phosphomannomutase 2

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101067
Biochimie. 2024 Mar 06. pii: S0300-9084(24)00049-X. [Epub ahead of print]

Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation.

Maria Monticelli, Bruno Hay Mele, Demi Marie Wright, Simone Guerriero, Giuseppina Andreotti, Maria Vittoria Cubellis.

  PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.

Keywords:  CeTSA; Phosphomannomutase-2; Protein stability; Protein-ligand binding; ReBaTSA In silico docking

DOI:  https://doi.org/10.1016/j.biochi.2024.02.011
Therapie. 2024 Feb 15. pii: S0040-5957(24)00028-3. [Epub ahead of print]

Does gene therapies clinical research in rare diseases reflects the competitivity of the country: Example of France.

Karyna Lutsyk, Tristan Gicquel, Lucas Cortial, Sylvain Forget, Serge Braun, Pierre-Olivier Boyer, Vincent Laugel, Olivier Blin.

  Rare diseases are chronic, serious and generally genetic conditions affecting a small number of people, and their therapeutic management is a real challenge. They represent a considerable burden for patients, caregivers and society alike. Compared with existing symptomatic treatments, gene therapies represent a promising new approach aimed at treating these diseases by replacing a defective gene, or by abolishing or reviving a gene-derived function. France is considered one of the leading countries in the research and development of drugs for rare diseases, yet the position of French public and private stakeholders in the research and development of gene therapies for rare diseases at global and European level remains unclear. To answer this question, we used the GENOTRIAL FR database developed by OrphanDev to clarify France's involvement and competitiveness in this field. The results show that France is actively involved in gene therapy clinical trials, with a dense international collaboration network and solid expertise. However, the French medical infrastructure is mainly involved in clinical research on gene therapy candidates sponsored by several foreign countries. To a lesser extent, French public and private entities are also developing their own gene therapy candidates for various rare diseases, some of which have already reached advanced clinical phases. In conclusion, a number of technical and financial challenges need to be overcome if France is to maintain its position as a European and world leader and increase its contribution to reducing the economic and social burden of rare diseases by developing revolutionary and effective new therapies.

Keywords:  France; Gene therapy; R&D; Rare diseases; State of the art 2023

DOI:  https://doi.org/10.1016/j.therap.2024.01.007
Mol Biol Rep. 2024 Mar 06. 51(1): 389

Search progress of pyruvate kinase M2 (PKM2) in organ fibrosis.

Shumei Lv, Mengfei Cao, Jie Luo, Kewei Fu, Wei Yuan.

  Fibrosis is characterized by abnormal deposition of the extracellular matrix (ECM), leading to organ structural remodeling and loss of function. The principal cellular effector in fibrosis is activated myofibroblasts, which serve as the main source of matrix proteins. Metabolic reprogramming, transitioning from mitochondrial oxidative phosphorylation to aerobic glycolysis, is widely observed in rapidly dividing cells such as tumor cells and activated myofibroblasts and is increasingly recognized as a fundamental pathogenic basis in organ fibrosis. Targeting metabolism represents a promising strategy to mitigate fibrosis. PKM2, a key enzyme in glycolysis, plays a pivotal role in metabolic reprogramming through allosteric regulation, impacting both metabolic and non-metabolic pathways. Therefore, metabolic reprogramming induced by PKM2 activation is involved in the occurrence and development of fibrosis in various organs. A comprehensive understanding of the role of PKM2 in fibrotic diseases is crucial for seeking new anti-fibrotic therapeutic targets. In this context, we summarize PKM2's role in glycolysis, mediating the intricate mechanisms underlying fibrosis in multiple organs, and discuss the potential value of PKM2 inhibitors and allosteric activators in future clinical treatments, aiming to identify novel therapeutic targets for proliferative fibrotic diseases.

Keywords:  Aerobic glycolysis; Myofibroblasts; Organ fibrosis; PKM2

DOI:  https://doi.org/10.1007/s11033-024-09307-w
Neurol India. 2024 Jan 01. 72(1): 175-177

Congenital Myasthenia Syndrome Due to a Novel DPAGT1 Gene Mutation - An Error of Glycosylation Masquerading as a Congenital Myopathy.

Aakash Mahesan, Gautam Kamila, Richa Tiwari, Sumanta Das, Mehar C Sharma, Prashant Jauhari, Biswaroop Chakrabarty, Sheffali Gulati.

DOI: https://doi.org/10.4103/neurol-india.Neurol-India-D-23-00582