Blood biomarker fingerprints in a cohort of patients with CHRNE-related congenital myasthenic syndrome

Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.

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Acta Neuropathologica Communications
Published
2025-02-13
DOI
https://doi.org/10.1186/s40478-025-01946-9
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1
Primary Topic
Myasthenia Gravis and Thymoma
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article
Field-Weighted Citation Impact
1.39

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article

Blood biomarker fingerprints in a cohort of patients with CHRNE-related congenital myasthenic syndrome

Andrie Koutsoulidou, Kristia Georgiou, Leonidas A. Phylactou, Ulrike Schara‐Schmidt et al.
1 citations
Acta Neuropathologica Communications
Myasthenia Gravis and Thymoma
1.39
article

Blood biomarker fingerprints in a cohort of patients with CHRNE-related congenital myasthenic syndrome

Andrie Koutsoulidou, Kristia Georgiou, Leonidas A. Phylactou, Ulrike Schara‐Schmidt, Lars‐Oliver Tykocinski, Andreas Hentschel, Tobias Ruck, Adela Della Marina, Andreas Roos, C. Ortez, A. Nascimento, Hanns Lochmüller, Marios Tomazou, Basant Kumar Thakur, Heike Kölbel, Daniel Natera‐de Benito, D. D. Kale, Andreas Laner, Angela Abicht
article en
1 citations

Abstract

Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.

Acta Neuropathologica CommunicationsVol. 13(1)
Hospital Sant Joan de Déu Barcelona (ES), University of Ottawa (CA), Heidelberg University (DE), Children's Hospital of Eastern Ontario (CA), Ottawa Hospital (CA), Instituto de Salud Carlos III (ES), University Hospital Heidelberg (DE), Düsseldorf University Hospital (DE), Centre for Biomedical Network Research on Rare Diseases (ES), Medical Genetics Center (DE), Essen University Hospital (DE), Leibniz Institute for Analytical Sciences - ISAS (DE), Friedrich Baur Stiftung (DE), BG University Hospital Bergmannsheil Bochum (DE), Centro Nacional de Análisis Genómico (ES), Institut de Recerca Sant Joan de Déu, Heinrich Heine University Düsseldorf (DE), Cyprus Institute of Neurology and Genetics (CY), University of Duisburg-Essen (DE), Ludwig-Maximilians-Universität München (DE)
Universitätsklinikum Essen, Government of Canada, European Commission, Canada Research Chairs, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Muskelkranke, Stiftung Universitätsmedizin Essen, Canada First Research Excellence Fund, Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, Canadian Institutes of Health Research, Instituto de Salud Carlos III, European Regional Development Fund
Good health and well-being
Openalex Percentile: Top 24%
Myasthenia Gravis and Thymoma
1.39
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