{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:57:07Z","timestamp":1786636627619,"version":"build-2736575974"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471352"],"award-info":[{"award-number":["82471352"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071408"],"award-info":[{"award-number":["82071408"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81920108017"],"award-info":[{"award-number":["81920108017"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023ZD0505200"],"award-info":[{"award-number":["2023ZD0505200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20191116"],"award-info":[{"award-number":["BK20191116"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction\/Aims<\/jats:title>\n                    <jats:p>Mitochondrial encephalomyopathies are multisystem disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome is a rare manifestation, often associated with\u00a0POLG\u00a0mutations. This study identifies a novel\u00a0POLG\u00a0mutation in a SANDO patient, validates its pathogenicity, and analyzes the molecular genetics of 61 reported\u00a0POLG\u2010SANDO cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After obtaining informed consent, the proband underwent neurological examination, electromyography, muscle\/nerve biopsies (histochemical\/ultrastructural analyses), and genetic testing (whole\u2010exome sequencing, mtDNA analysis). Pathogenicity of identified POLG variants was assessed in Cas9\u2010mediated primary neuronal models expressing mutant proteins by measuring reactive oxygen species (ROS) levels and mtDNA copy number (qRT\u2010PCR, ND1\/APP ratio). Literature searches (PubMed, CNKI, Wanfang, and ClinVar) identified reported\u00a0POLG\u00a0mutations and clinical features in SANDO.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinical and biopsy findings confirmed SANDO syndrome. Genetic analysis revealed compound heterozygous POLG mutations: a novel c.3297G&gt;C (p.W1099C) and a known c.1774C&gt;T (p.L592F). Neurons expressing either mutant exhibited elevated ROS levels (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and reduced mtDNA copy number compared with controls. Literature synthesis identified over 30 SANDO\u2010associated POLG mutations, with p.A467T (31.2%) and p.W748S (22.1%) being the most frequent. The mean age of onset was 31.6 years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identify a novel pathogenic\u00a0POLG\u00a0variant (p.W1099C) causing mitochondrial dysfunction via impaired mtDNA maintenance, expanding the SANDO genetic spectrum. Functional studies confirmed both mutations induce mitochondrial dysfunction (elevated ROS and decreased mtDNA Copy Number), validating their pathogenicity. The compiled mutation profile aids diagnosis of this phenotypically heterogeneous, frequently misdiagnosed disorder.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.71045","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T06:21:53Z","timestamp":1762928513000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4367-1648","authenticated-orcid":false,"given":"Fanjing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingzheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengnan","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinglong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"},{"name":"Department of Neurology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13508"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-14-105"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.12164"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.06.062"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2012.06.002"},{"key":"e_1_2_12_7_1","volume-title":"GeneReviews(\u00ae)","author":"Cohen B. 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