{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T18:14:31Z","timestamp":1790964871947,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G&gt;A, p.Trp105* and c.1192G&gt;C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.<\/jats:p>","DOI":"10.3390\/cells10123481","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:52:32Z","timestamp":1639086752000},"page":"3481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0737-6142","authenticated-orcid":false,"given":"Adela","family":"Della Marina","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Arlt","sequence":"additional","affiliation":[{"name":"Institute of Clinical Genetics and Tumor Genetics Bonn, 53111 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Depienne","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gangfu\u00df","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-7053","authenticated-orcid":false,"given":"Heike","family":"K\u00f6lbel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Freier","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Kohlschmidt","sequence":"additional","affiliation":[{"name":"Institute of Clinical Genetics and Tumor Genetics Bonn, 53111 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Weis","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Aachen, RWTH-Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Czech","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7928-5613","authenticated-orcid":false,"given":"Anika","family":"Gr\u00fcneboom","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"},{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s00415-017-8689-3","article-title":"Congenital 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