Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor

There are many types of cerebellar ataxia, including ataxia due to congenital or metabolic disorders and a paraneoplastic form in patients with gynecologic cancer, breast cancer, lung cancer, or Hodgkin's disease.1 This paraneoplastic syndrome is the only type of cerebellar ataxia associated with autoantibodies against neuronal antigens. Often, the neuronal antigens are aberrantly expressed by the tumor cells.2-4 The antineuronal autoantibodies are believed to cause cerebellar ataxia, but this is unproved.5,6 In Hodgkin's disease, the lymphoma precedes the ataxia by months to years in 80 percent of patients, and ataxia often occurs during a prolonged complete remission.4 Among patients with this type of ataxia, 30 percent have anti–Purkinje-cell antibodies, some of which have the features of the neuronal antibody anti-Tr.4,7 We identified a new autoantibody in two patients with severe cerebellar ataxia that developed while they were in remission from Hodgkin's disease. The antibody reacts specifically with the metabotropic glutamate receptor mGluR1 in mouse brain. Metabotropic glutamate receptors belong to a large family of cell-surface receptors that transmit signals into the cell by coupling to guanine nucleotide-binding proteins (G proteins) in the cytoplasm. Purified IgG from the serum of both patients blocked the glutamate-stimulated formation of inositol phosphates in Chinese-hamster-ovary (CHO) cells that expressed mGluR1α, and the injection of IgG from serum or cerebrospinal fluid into the cerebellar subarachnoid space of mice caused severe, reversible ataxia. These results indicate that antineuronal autoantibodies can cause disease of the central nervous system by blocking neuronal receptors.