{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:01:59Z","timestamp":1784523719451,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>UNC13D<\/jats:italic>\n                      gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13\u20134 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed \u201cperforinopathy\u201c manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13\u20134 deficiency, its association with autoimmune neuropathy remains largely unrecognized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case report<\/jats:title>\n                    <jats:p>\n                      We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous\n                      <jats:italic>UNC13D<\/jats:italic>\n                      mutations: in Case 1, a nonsense (c.3193C&amp;gt;T; p.Arg1065*) and a missense (c.1135G&amp;gt;A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447\u00a0+\u00a01G&amp;gt;A) and a paternal missense mutation (c.1241G&amp;gt;T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1890404","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:27Z","timestamp":1784521227000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Munc13\u20134 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaojing","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Neurology and Neuroscience Center, the First Affiliated Hospital of Jilin University","place":["Changchun, Jilin, China"]},{"name":"Center for Rare Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianian","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neuology, Huashan Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Huashan Rare Disease Center, Huashan Hospital, Fudan University","place":["Shanghai, China"]},{"name":"National Center for Neurological Disorders","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liye","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Emergency, Changchun Hospital of Traditional Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Electrophysiology, The First Affiliated Hospital of University of Science and Technology of China","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuroscience Center, the First Affiliated Hospital of Jilin University","place":["Changchun, Jilin, China"]},{"name":"Center for Rare Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuroscience Center, the First Affiliated Hospital of Jilin University","place":["Changchun, Jilin, China"]},{"name":"Center for Rare Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neuology, Huashan Hospital, Fudan 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