Amphiphysin autoimmunity: Paraneoplastic accompaniments

Pittock, Sean J.; Lucchinetti, Claudia F.; Parisi, Joseph E.; Benarroch, Eduardo E.; Mokri, Bahram; Stephan, Christina; Kim, Kwang Kuk; Kilimann, Manfred W.; Lennon, Vanda A.

doi:10.1002/ana.20529

Cited by 316 publications

(199 citation statements)

References 36 publications

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“…Its expression in mature synapses plausibly explains the staining of the neuropil noted throughout the mouse nervous system and is reminiscent of that seen with amphiphysin and CRMP5. 5,41,42 The widespread distribution of MAP1B throughout the central and peripheral nervous systems is consistent with the diverse and multifocal neurologic impairment observed with PCA-2 autoimmunity. 40 Amino acid sequence homologies of MAP1A and MAP1B (see Supplementary Table 1) would account for the reactivity of patient IgG with MAP1A protein in some cases.…”

Section: Discussionsupporting

confidence: 62%

Microtubule‐associated protein 1B: Novel paraneoplastic biomarker

Gadoth¹,

Kryzer²,

Fryer³

et al. 2017

Annals of Neurology

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Objective: To report the identification of microtubule-associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA-2) antibody, its frequency, and clinical, oncological, and serological associations. Methods: Archival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA-2-IgG-seropositive patients identified during 1993-2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments. Results: IgG in 95 of 96 patients' serum or CSF (but in none of 98 healthy or disease control subjects' serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients' IgG also bound to MAP1A. PCA-2 was often accompanied by additional neural autoantibody markers of small-cell carcinoma, including collapsin responsemediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as antiHu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small-cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA-2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA-2 (also known as anti-Ri; 0.016%) and PCA-Tr (also known as delta/notch-like epidermal growth factor-related receptor [DNER]; 0.006%). Interpretation: MAP1B, the PCA-2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. ANN NEUROL 2017;81:266-277 I n 2000, Vernino and Lennon 1 reported 10 patients with neurological autoimmunity, 9 of whom had imaging or histopathologic evidence of lung cancer (8 biopsyproven small-cell lung carcinoma [SCLC]). Their serum IgG bound to a protein of 280kDa mass in both rodent brain and a SCLC line and yielded a characteristic staining pattern on rodent neural tissues. The autoantibody was named Purkinje cell cytoplasmic antibody type 2 (PCA-2), to distinguish it from a biomarker of ovarian and breast cancer-related cerebellar degeneration, PCA-1 (also known as anti-Yo). 2 The neurological associations initially reported for PCA-2 were mixed, of subacute onset and predominantly central (brainstem and limbic encephalitis, cerebellar ataxia), but some patients had peripheral manifestations (Lambert-Eaton myasthenic syndrome [LEMS] or autonomic or motor neuropathy). 1 Our study extends the immunochemical characteristization of PCA-2 IgG an...

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Section: Discussionsupporting

confidence: 62%

Microtubule‐associated protein 1B: Novel paraneoplastic biomarker

Gadoth¹,

Kryzer²,

Fryer³

et al. 2017

Annals of Neurology

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“…Amphiphysin autoantibody was associated with ANNA-1 or CRMP5 more frequently than hypothesized. It is recognized, for men, that small cell lung carcinoma is the cancer encountered most frequently with amphiphysin autoantibody, regardless of coexisting autoantibodies (10). In this study, amphiphysin-IgG was detected in 7 male patients; the 4 for whom histories were available, all had small cell lung carcinoma regardless of coexisting autoantibodies.…”

Section: Clinical Implications Of Neural Autoantibody Clustersmentioning

confidence: 64%

Neural Autoantibody Clusters Aid Diagnosis of Cancer

Horta¹,

Lennon

Lachance

et al. 2014

Clinical Cancer Research

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Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer.Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil).Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumorassociated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin responsemediator protein-5 autoantibodies).Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type.

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“…Anti-CRMP5/CV2 antibodies are usually associated with SCLC, neuroendocrine tumors, and thymoma. Antiamphiphysin antibodies are associated with multifocal paraneoplastic encephalomyelitis, and symptoms often include sensory or sensorimotor neuropathy [34,81,82]. Associated tumors (mostly limited) are mainly SCLC, breast cancer, and melanoma.…”

Section: Antineuronal Antibodiesmentioning

confidence: 99%