학술논문
ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD
Document Type
article
Author
Mandel‐Brehm, Caleigh; Benson, Leslie A; Tran, Baouyen; Kung, Andrew F; Mann, Sabrina A; Vazquez, Sara E; Retallack, Hanna; Sample, Hannah A; Zorn, Kelsey C; Khan, Lillian M; Kerr, Lauren M; McAlpine, Patrick L; Zhang, Lichao; McCarthy, Frank; Elias, Joshua E; Katwa, Umakanth; Astley, Christina M; Tomko, Stuart; Dalmau, Josep; Seeley, William W; Pleasure, Samuel J; Wilson, Michael R; Gorman, Mark P; DeRisi, Joseph L
Source
Annals of Neurology. 92(2)
Subject
Language
Abstract
ObjectiveRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.MethodsImmunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively.ResultsAutoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed.InterpretationOur results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.