{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T22:48:35Z","timestamp":1771541315781,"version":"3.50.1"},"reference-count":0,"publisher":"Bentham Science Publishers Ltd.","issue":"16","content-domain":{"domain":["eurekaselect.com"],"crossmark-restriction":true},"short-container-title":["EMIDDT"],"published-print":{"date-parts":[[2024,7,11]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction::<\/jats:title>\n                    <jats:p>Mitochondrial oxidative phosphorylation (OXPHOS) diseases are\nchallenging both from clinical and therapeutic perspectives. The advent of next-generation sequencing\n(NGS) boosted the discovery of new genetic defects affecting OXPHOS, with pathogenic\nvariants identified in &gt;350 genes to date [1]. However, in many patients, novel variants of unknown\nclinical significance are found. Subsequent functional studies may clarify its pathogenic\nconsequences and modify the variant\u2019s classification, establishing a genetic diagnosis [2, 3].<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods::<\/jats:title>\n                    <jats:p>Analysis of data obtained from patients (P1-P5) with novel genetic causes and functional\ngenomics\u2019 studies performed, namely OXPHOS respiratory\/glycolytic rates (Seahorse\nXF), enzymatic activity and assembly (BN-page), protein levels (SDS-WB), single muscle fiber\nassay, NGS and bioinformatics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results\/Case Report::<\/jats:title>\n                    <jats:p>P1-Leigh syndrome (40y, male); Complex IV activity deficiency (full\nassembly absent), homozygous deletion (c.-11_13del, SURF1), not detected by NGS[2]. P2-\nEpileptic encephalopathy (8y, male); homozygous c.882-1G&gt;A, FASTKD2; OXPHOS decrease;\nreduced FASTKD2 expression and abnormal respiratory\/glycolytic rates. P3-Cardiomyopathy\/\nnephropathy (39y, male); c.29G&gt;C, FASTKD2; OXPHOS decrease; reduced FASTKD2 levels.\nP4-CPEO (62y, female); multiple OXPHOS deficiency; mtDNA alterations (m.7486G&gt;A, MTTS1;\n4,977bp del); higher levels of mutant mtDNA alterations in COX-deficient fibers [3]. P5-\nPolyneuropathy (15y, female); heterozygous c.1437C&gt;A, POLG; combined def. or normal\nOXPHOS activity\/respiratory capacity (tissue variable), raised CI assembly; normal POLG levels.\nAlso, proteins\u2019 expression levels were reduced (P1-4), confirming pathogenicity. In P5, data\ndo not support pathogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion::<\/jats:title>\n                    <jats:p>If specific functional results are similar to controls, one might inquire about the\npathogenicity of the studied variant and more genetic or bioinformatics analyses and family investigations\nare needed. There are also limitations of NGS in mutation detection that Sanger\nsequencing can overcome (P1). When performed first, the OXPHOS activity may guide to genetic\nscreening or interpretation, concordant to later assembly results. All cases were solved and\ndata may be crucial for genetic counseling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2174\/0118715303273290231211062420","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:15:00Z","timestamp":1702944900000},"page":"9-9","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Challenges in Genetic Diagnosis of Mitochondrial Diseases: What Can\nFunctional Genomics' Studies Do?"],"prefix":"10.2174","volume":"24","author":[{"given":"Marta","family":"Sim\u00f5es","sequence":"first","affiliation":[{"name":"Laboratory of MitochondrialBiomedicine and Theranostics, CNC - Center for Neuroscience and Cell Biology, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"},{"name":"FCTUC -Faculty of Sciences and Technology, University of Coimbra"}]},{"given":"Maria Jo\u00e3o","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of MitochondrialBiomedicine and Theranostics, CNC - Center for Neuroscience and Cell Biology, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"},{"name":"FMUC - Faculty of Medicine, University of Coimbra"}]},{"given":"Sara","family":"Martins","sequence":"additional","affiliation":[{"name":"Laboratory of MitochondrialBiomedicine and Theranostics, CNC - Center for Neuroscience and Cell Biology, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"},{"name":"IIIUC - Institute for Interdisciplinary Research, University of Coimbra"}]},{"given":"Maria do Carmo","family":"Mac\u00e1rio","sequence":"additional","affiliation":[{"name":"Laboratory of MitochondrialBiomedicine and Theranostics, CNC - Center for Neuroscience and Cell Biology, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"},{"name":"Centro de Refer\u00eancia de Doen\u00e7as Heredit\u00e1riasdo Metabolismo, MetabERN, CHUC - Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, Coimbra"}]},{"given":"Jo\u00e3o","family":"Dur\u00e3es","sequence":"additional","affiliation":[{"name":"Centro de Refer\u00eancia de Doen\u00e7as Heredit\u00e1riasdo Metabolismo, MetabERN, CHUC - Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, Coimbra"},{"name":"FMUC - Faculty of Medicine, University of Coimbra"}]},{"given":"Lu\u00edsa","family":"Diogo","sequence":"additional","affiliation":[{"name":"Centro de Refer\u00eancia de Doen\u00e7as Heredit\u00e1riasdo Metabolismo, MetabERN, CHUC - Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, Coimbra"},{"name":"FMUC - Faculty of Medicine, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"}]},{"given":"Jo\u00e3o Paulo","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Service ofMedical Genetics, Centro Hospitalar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Porto, Portugal"}]},{"given":"Jos\u00e9 Carlos","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Service of Pediatric Neurology,Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal"}]},{"given":"Manuela","family":"Grazina","sequence":"additional","affiliation":[{"name":"Laboratory of MitochondrialBiomedicine and Theranostics, CNC - Center for Neuroscience and Cell Biology, University of Coimbra"},{"name":"CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra"},{"name":"FMUC - Faculty of Medicine, University of Coimbra"},{"name":"FMUC - Faculty of Medicine, University of Coimbra"}]}],"member":"965","container-title":["Endocrine, Metabolic &amp; 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