A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer

N Engl J Med. 1999 Jun 10;340(23):1788-95. doi: 10.1056/NEJM199906103402303.


Background: In patients with cancer, symptoms of limbic and brain-stem dysfunction may result from a paraneoplastic disorder. Paraneoplastic limbic or brain-stem encephalitis occurs more frequently with testicular cancer than with most other cancers. We sought antineuronal antibodies that might be used in a diagnostic test for this syndrome.

Methods: Immunohistochemical and immunoblotting techniques were used to detect serum and cerebrospinal fluid antibodies. Serologic screening of a complementary DNA library and Northern blotting were used to clone the target antigen and determine which tissues expressed it.

Results: Of 13 patients with testicular cancer and paraneoplastic limbic or brain-stem encephalitis (or both), 10 had antibodies in serum and cerebrospinal fluid against a 40-kd neuronal protein. These antibodies were used to clone a gene that we call Ma2, which codes for a protein (Ma2) that was recognized by serum from the 10 patients, but not by serum from 344 control subjects. Ma2 was selectively expressed by normal brain tissue and by the testicular tumors of the patients. Ma2 shares homology with Ma1, a "brain-testis-cancer" gene related to other paraneoplastic syndromes and tumors.

Conclusions: The serum of patients with subacute limbic and brain-stem dysfunction and testicular cancer contains antibodies against a protein found in normal brain and in testicular tumors. Detection of these antibodies supports the paraneoplastic origin of the neurologic disorder and could be of diagnostic importance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens / analysis
  • Antigens / genetics
  • Antigens / immunology*
  • Antigens, Neoplasm / immunology
  • Autoantibodies / blood*
  • Biomarkers / blood
  • Brain Chemistry
  • Brain Stem / immunology
  • DNA, Complementary / genetics
  • Encephalitis / diagnosis*
  • Encephalitis / etiology
  • Encephalitis / immunology
  • Female
  • Hippocampus / immunology
  • Humans
  • Limbic System / immunology
  • Male
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / immunology*
  • Paraneoplastic Syndromes / diagnosis*
  • Paraneoplastic Syndromes / etiology
  • Paraneoplastic Syndromes / immunology
  • RNA, Messenger / analysis
  • Rats
  • Testicular Neoplasms / complications*
  • Testicular Neoplasms / immunology
  • Testicular Neoplasms / pathology


  • Antigens
  • Antigens, Neoplasm
  • Autoantibodies
  • Biomarkers
  • DNA, Complementary
  • Ma1 antigen
  • Nerve Tissue Proteins
  • RNA, Messenger