{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:00:21Z","timestamp":1785301221514,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2023JJ30963"],"award-info":[{"award-number":["2023JJ30963"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      To delineate the clinical features of\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      \u2010related developmental and epileptic encephalopathy (DEE) and explore its pathogenic mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole\u2010genome and blood transcriptome sequencing were performed in undiagnosed DEE patients. Patient\u2010derived skin fibroblasts were established for the analysis of RNA and protein expression as well as for mitochondrial functional assays, including OPA1 processing, mtDNA copy number, membrane potential, ATP production, mitochondrial morphology analysis, and mitochondrial stress testing. Additionally, published\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      \u2010related epilepsy cases were systematically reviewed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified four novel\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      variants in four DEE patients from two unrelated families, including splice\u2010site\/intronic variants in one family and exon\u2010deletion\/intronic variants in the other, fitting a recessive model of disease. In these patients, plus six additional previously reported DEE patients, symptoms included severe developmental delay, intractable seizures, microcephaly, generalized spasticity, and progressive cerebral atrophy. Transcriptome and fibroblast functional analyses revealed aberrant splicing, reduced\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      expression, defective OPA1 processing, decreased mtDNA content, impaired membrane potential and ATP production, fragmented mitochondrial networks, and diminished respiratory capacity, supporting a loss\u2010of\u2010function mechanism. Compared with spastic ataxia 5\u2014usually involving null\u2010missense or missense\u2010missense genotypes\u2014DEE predominantly features null\u2010null combinations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      We implicate\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      as a novel causative gene for DEE, likely through mitochondrial proteostasis failure and bioenergetic compromise, expanding the phenotypic and genotypic spectrum of\n                      <jats:italic>AFG3L2<\/jats:italic>\n                      \u2010related disorders.\n                    <\/jats:p>\n                  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