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A subset of MCDs, including focal cortical dysplasia type II, tuberous sclerosis complex, and hemimegalencephaly, shares characteristic histopathological features and somatic mutations in genes within the Phosphoinositide 3\u2010kinase (PI3K)\u2013AKT\u2013mechanistic target of rapamycin (mTOR) signaling cascade, and is collectively termed mTORopathies. However, mechanisms driving epileptogenesis and drug\u2010resistant seizures remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed integrated genomic, transcriptomic, and proteomic analyses of 56 surgical brain specimens from 41 patients with MCDs and 15 with mesial temporal lobe epilepsy. Targeted genomic sequencing identified 19 somatic mutations in PI3K\u2013AKT\u2013mTOR pathway genes, including novel variants in\n                      <jats:italic>AKT3<\/jats:italic>\n                      (L51H) and\n                      <jats:italic>MTOR<\/jats:italic>\n                      (A512T).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>RNA sequencing with independent cohort comparison identified 160 consistently differentially expressed genes. Downregulated genes were enriched in oxidative phosphorylation (OXPHOS) and mitochondrial metabolic pathways, whereas upregulated genes were associated with developmental process. Proteomic analysis revealed directionally concordant reductions in several mitochondrial proteins, and pathway\u2010level alterations in some biological cellular processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This study provides a patient\u2010matched, multi\u2010omics dataset of human mTOR\u2010related epilepsies from a single\u2010institution cohort. Integrated transcriptomic and proteomic analyses suggested impaired OXPHOS as a molecular hallmark, potentially contributing to focal hypometabolism in mTOR\u2010related epilepsy. These findings offer mechanistic insights into epileptogenesis and provide a resource for understanding molecular pathologies and developing mechanism\u2010based therapies for mTOR\u2010related epilepsy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70514","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:27:35Z","timestamp":1791818855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive transcriptomic and proteomic profiling of\n                    <scp>mTOR<\/scp>\n                    \u2010related epilepsy"],"prefix":"10.1002","author":[{"given":"Kaiyuan","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"},{"name":"Department of NCNP Brain Physiology and Pathology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3421-2477","authenticated-orcid":false,"given":"Satoshi","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6249-7732","authenticated-orcid":false,"given":"Keiya","family":"Iijima","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Yagita","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6333-9468","authenticated-orcid":false,"given":"Tomoo","family":"Owa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumi","family":"Shimaoka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao K. N.","family":"Tabe","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"},{"name":"Department of NCNP Brain Physiology and Pathology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minami","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"},{"name":"Department of NCNP Brain Physiology and Pathology Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Biomolecular Science, Faculty of Science Toho University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayane","family":"Hosaka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of 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