Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early
Xiaojing Wei1,2, Jianian Hu3,4,5, Liye Bao6
1Department of Neurology and Neuroscience Center, the First Affiliated Hospital of Jilin University, Changchun, Jilin, China.
Background:
The UNC13D 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, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized.
Case Report:
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 UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>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.
Discussion:
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.
