{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:54Z","timestamp":1787028234506,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T00:00:00Z","timestamp":1688256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012352","name":"University of Milan","doi-asserted-by":"publisher","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012352","name":"University of Milan","doi-asserted-by":"publisher","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}]},{"name":"Italian Ministry of Health","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}]},{"name":"Mariani Foundation","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}]},{"name":"Mariani Foundation","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}]},{"name":"Italian Ministry of Health","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}]},{"name":"Italian Ministry of Health","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}]},{"name":"European Reference Network","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}]},{"name":"European Reference Network","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}]},{"name":"Associazione Centro Dino Ferrari","award":["PSR2017_DIP_009_Ghezzi"],"award-info":[{"award-number":["PSR2017_DIP_009_Ghezzi"]}]},{"name":"Associazione Centro Dino Ferrari","award":["ERP-2019\u201323671045"],"award-info":[{"award-number":["ERP-2019\u201323671045"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction\/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.<\/jats:p>","DOI":"10.3390\/genes14071393","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:34:08Z","timestamp":1688344448000},"page":"1393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and\/or HyperCKemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-0152","authenticated-orcid":false,"given":"Federica","family":"Invernizzi","sequence":"first","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5785-5016","authenticated-orcid":false,"given":"Rossella","family":"Izzo","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-9417","authenticated-orcid":false,"given":"Isabel","family":"Colangelo","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Legati","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4323-9145","authenticated-orcid":false,"given":"Barbara","family":"Garavaglia","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5090-6028","authenticated-orcid":false,"given":"Eleonora","family":"Lamantea","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6175-025X","authenticated-orcid":false,"given":"Lorenzo","family":"Peverelli","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ardissone","sequence":"additional","affiliation":[{"name":"Child Neurology Unit\u2014Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Moroni","sequence":"additional","affiliation":[{"name":"Child Neurology Unit\u2014Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0932-5173","authenticated-orcid":false,"given":"Lorenzo","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8823-6821","authenticated-orcid":false,"given":"Silvia","family":"Bonanno","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fiori","sequence":"additional","affiliation":[{"name":"UOS di Malattie Metaboliche e Nutrizione, Ospedale dei Bambini Vittore Buzzi, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Velardo","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Magri","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo P.","family":"Comi","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-3766","authenticated-orcid":false,"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"},{"name":"Lab of Neurogenetics and Mitochondrial Disorders, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1001\/jama.1973.03230130024009","article-title":"Serum enzyme alterations in neuromuscular disorders","volume":"226","author":"Munsat","year":"1973","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s004150200010","article-title":"Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels","volume":"249","author":"Prelle","year":"2002","journal-title":"J. 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