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This summary integrates multi‐patient clinical observations and functional assays that support a strong association between IGLON5 and autoimmune encephalopathy with parasomnia and obstructive sleep apnea. In a 2016 study, neuropathological examination of six patients revealed a distinctive tauopathy in the hypothalamus and brainstem in the context of IgLON5 antibody positivity (PMID:27358064). These findings provided critical diagnostic criteria and underscored the importance of IgLON5 in the neuropathogenesis of this disorder. The study set forth clear histopathological benchmarks for a “definite” diagnosis when combined with immunological confirmation. The consistent neuropathological features across multiple cases strengthen the clinical interpretation.
A subsequent 2021 report expanded the clinical spectrum by describing five additional seropositive patients presenting with a prominent bulbar motor neuron‐like phenotype and pronounced sleep disorders (PMID:33531378). The convergence of findings from these two multi‐patient studies—comprising a total of 11 probands—reinforces the pathogenic role of IgLON5 in this complex disorder. Despite the absence of traditional Mendelian variants, the reproducibility of the clinical phenotype and the antibody‐based diagnostic criteria provide robust evidence for a gene–disease association. No additional affected relative segregation data were reported.
Although no pathogenic coding variants were documented in these cases, the genetic evidence is indirectly supported by the detection of IgLON5 autoantibodies which serve as a molecular marker. This kind of evidence poses challenges to conventional variant‐based assessments, yet the unique clinical and pathological signature justifies a strong gene–disease association. As a result, while the genetic evidence scored by classical standards remains limited, its clinical significance is undeniable and influential in diagnostic decision‑making.
Functional studies further contribute to our understanding of IgLON5 biology. Expression analyses in mouse models indicated coherent promoter‐driven regulation within the IgLON family (PMID:28210208), and IgLON5 knockout mice exhibited motor and behavioral deficits that partially mirror the human condition (PMID:38657185). Although the knockout models did not recapitulate the tau aggregation seen in patients, these functional studies suggest that both loss‐of‐function and potentially gain‐of‑function (or inflammation‐mediated neuronal injury) mechanisms may contribute to disease pathogenesis.
Integrating the evidence, the association between IgLON5 and the autoimmune encephalopathy with parasomnia and obstructive sleep apnea is supported by strong clinical and neuropathological findings, complemented by moderately persuasive functional data. While classical genetic variant evidence is limited due to the autoimmune nature of the condition, the consistent detection of IgLON5 antibodies in multiple independent cohorts underscores its clinical utility in establishing the diagnosis. Clinicians and researchers should consider this evidence when evaluating patients, and additional studies may further refine the mechanistic insights.
Key take‑home sentence: The combined clinical, pathological, and functional evidence establishes a robust association of IgLON5 with autoimmune encephalopathy featuring parasomnia and sleep apnea, offering a critical marker for diagnosis and a promising target for further research.
Gene–Disease AssociationStrongNeuropathological findings in 6 patients (PMID:27358064) combined with 5 additional seropositive cases presenting with bulbar and sleep disorder phenotypes (PMID:33531378) provide robust clinical evidence for the association. Genetic EvidenceLimitedNo pathogenic coding variants have been reported; the association relies primarily on the detection of IgLON5 autoantibodies and concordant clinical features. Functional EvidenceModerateFunctional studies in mice demonstrate motor and behavioral deficits (PMID:38657185) and promoter analyses support the functional relevance of IgLON5 (PMID:28210208). |