Microtubule-associated protein 1B: Novel paraneoplastic biomarker

Avi Gadoth, Thomas J. Kryzer, Jim Fryer, Andrew B McKeon, Vanda A Lennon, Sean J Pittock

Research output: Contribution to journalArticle

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Abstract

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 response-mediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as anti-Hu; 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.

Original languageEnglish (US)
Pages (from-to)266-277
Number of pages12
JournalAnnals of Neurology
Volume81
Issue number2
DOIs
StatePublished - Feb 1 2017

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Biomarkers
Purkinje Cells
Autoantibodies
Antibodies
Immunoglobulin G
Cerebellar Ataxia
Small Cell Lung Carcinoma
Autoantigens
Cerebrospinal Fluid
Western Blotting
Serum
Semaphorin-3A
Dysarthria
Passive Cutaneous Anaphylaxis
Small Cell Carcinoma
microtubule-associated protein 1B
Brain Diseases
Peripheral Nervous System Diseases
Neurologic Manifestations
Nervous System Diseases

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Microtubule-associated protein 1B : Novel paraneoplastic biomarker. / Gadoth, Avi; Kryzer, Thomas J.; Fryer, Jim; McKeon, Andrew B; Lennon, Vanda A; Pittock, Sean J.

In: Annals of Neurology, Vol. 81, No. 2, 01.02.2017, p. 266-277.

Research output: Contribution to journalArticle

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abstract = "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 response-mediated protein 5 (CRMP5) IgG (26{\%}) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as anti-Hu; 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.",
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