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About 95% of patients develop limbic, diencephalic and/or brainstem encephalopathy. The resulting clinical picture often combines short-term memory loss, seizures, confusion, excessive daytime sleepiness (sometimes narcolepsy-cataplexy), hypothalamic-hormonal deficits, and vertical gaze paralysis that may progress to total ophthalmoplegia. Accompanying symptoms may include parkinsonism, hypokinesis and cerebellar ataxia. Figure 1 shows the three areas of the nervous system involved in 34 patients with anti-Ma2 antibodies.
Figure 1: Distribution of Predominant Syndromes in 34 Patients with anti-Ma2 Encephalitis
In a study of 38 patients with anti-Ma2 antibodies, 34 had pathologically
demonstrated cancer (see table 1). Three of the 4 patients without pathological
demonstration of cancer had clinical or radiological features suggesting
an underlying cancer; the fourth patient is lost to follow-up.
*2 breast, 1 parotid gland, 1 ovary, 1 colon, 1 kidney, 1 lymphoma,
1 metastatic extragonadal choriocarcinoma, 1 metastasis of unknown primary.
Using immunohistochemistry on frozen brain sections (human, rabbit, rat, mouse) the anti-Ma2 antibodies show reactivity with a discrete number of subnuclear structures, in a pattern of dot-like reactivity. Large neurons of the brainstem or deep cerebellar nuclei may show additional reactivity with the cytoplasm in a pattern of ~1-4 large dots of reactivity (Figure 2).
Immunoblot of recombinant Ma2 protein. Immunoblot of human neuronal proteins (Figure 3).
Figure 3: Immunoblot of Neuronal Proteins with Sera of Patients with Antibodies to Ma1 and Ma2.
Anti-Ma2 antibodies may develop in association with antibodies to Ma1 and/or Ma3. These antibodies can be identified with immunoblots of neuronal proteins or recombinant Ma1 and Ma3. Because all patients with anti-Ma1 or Ma3 antibodies harbor anti-Ma2 antibodies the immunohistochemical pattern of reactivity is similar to that described with anti-Ma2 antibodies. Compared with patients who harbor only anti-Ma2 antibodies, patients with additional antibodies to Ma1 or Ma3 develop more extensive brainstem or cerebellar dysfunction and the cancer is less likely to be in the testis.
The Ma2 protein is member of a family of proteins expressed in brain and the cancers of patients with paraneoplastic syndromes. Other Ma proteins include Ma1 and Ma3. Ma1 is expressed in brain and testis, and Ma3 has mild expression in other systemic tissues. In immunoblots of human neuronal proteins the Ma1 and Ma2 proteins migrate as a cluster of bands ~39-42 kDa (Figure 2); reactivity with Ma3 (~53 kDa) is variable and difficult to visualize. The sera and CSF of all patients with immunity to Ma proteins react with Ma2 and therefore, this protein is the main autoantigen of the disorder. About 38% of patients with anti-Ma2 antibodies harbor additional antibodies to Ma1 or Ma3. The function of the Ma proteins is unknown, but the pattern of expression in neurons and testis as well as analysis of protein motifs suggests that they are involved in the biogenesis of mRNA.
1. -Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001;50:339-348.
2. -Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, Posner JB et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 1999;340:1788-1795.
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Updated 2009-09-15
