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. 2017 Mar 28;88(13):1235-1242.
doi: 10.1212/WNL.0000000000003778. Epub 2017 Mar 1.

Netrin-1 Receptor Antibodies in Thymoma-Associated Neuromyotonia With Myasthenia Gravis

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Free PMC article

Netrin-1 Receptor Antibodies in Thymoma-Associated Neuromyotonia With Myasthenia Gravis

Estefanía Torres-Vega et al. Neurology. .
Free PMC article

Abstract

Objective: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications.

Methods: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers).

Results: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma (p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome (p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus.

Conclusions: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis.

Classification of evidence: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).

Figures

Figure 1
Figure 1. Flowchart of the study
CRMP3 and CRMP5 = collapsin response mediator proteins 3 and 5.
Figure 2
Figure 2. Venn diagram of Netrin-1 receptor antibody–positive patients in clinical groups
Number of patients in blue; number of patients with Netrin 1 receptor antibodies in red. MG = myasthenia gravis; NMT = neuromyotonia.
Figure 3
Figure 3. Immunohistochemistry studies of thymomas
Immunohistochemical staining for contactin-associated protein-like 2 (Caspr2), deleted in colorectal carcinoma (DCC), uncoordinated-5A (UNC5A), cytokeratin (CK)-AE1/AE3, and CD3 on the thymoma samples of patients 2 (A–D) and 8 (E–H). CK-AE1/AE3 staining reveals a neoplastic epithelial cell network around CD3-positive T cells (thymocytes). Neoplastic epithelial thymoma cells were immunoreactive on the cell membrane, cytoplasm, or both for Caspr2, DCC, and UNC5A. Scale bars: 50 μm.

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