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Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma.

ABSTRACT: We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal-expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two-pore-domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A-purified antibodies reproduced the hippocampal immunolabeling of all patients' antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune-mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies.

SUBMITTER: Vitaliani R

PROVIDER: S-EPMC2245881 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma.

Vitaliani Roberta R Mason Warren W Ances Beau B Zwerdling Theodore T Jiang Zhilong Z Dalmau Josep J

Annals of neurology 20051001 4

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling ...[more]

PMID: 16178029

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Project description:OBJECTIVE:To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis. METHODS:Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR). RESULTS:Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. INTERPRETATION:Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.

Project description:Mature ovarian teratoma is considered to be a parthenogenetic tumor that arises from a single oocyte/ovum. Conversely, complete hydatidiform mole (CHM) is androgenetic in origin: classic CHM arises from a single or two sperm. Since mature ovarian teratoma and CHM have only maternal and paternal genomes, respectively, their genome imprinting is theoretically reverse, but this has yet to be investigated. Genome imprinting in struma ovarii, a special form of mature teratoma, remains unclear. Although a mature teratoma can rarely arise in extragonadal sites, its genome imprinting, as well as cell origin, is poorly understood. One of the most important mechanisms of genome imprinting is DNA methylation. To investigate the methylation profile of imprinted genes, we performed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of 21 imprinting control region (ICRs) of 9 imprinted genes/gene clusters in formalin-fixed, paraffin-embedded samples obtained from 12 mature ovarian teratomas, 6 struma ovarii, 10 CHMs, and 7 extragonadal (1 sacrococcygeal, 6 mediastinal) mature teratomas of females. In mature ovarian teratomas, ICRs of maternally and paternally imprinted genes showed high and low levels of methylation, respectively, and this pattern was almost reverse in CHMs. In CHMs, however, some ICRs showed aberrant methylation. The methylation profile of struma ovarii was comparable to that of mature ovarian teratomas, except for an adenomatous tumor. In extragonadal mature teratomas, the methylation pattern was somatic or irregular. In conclusion, mature ovarian teratomas/struma ovarii, CHMs, and extragonadal mature teratomas showed distinct methylation profiles of imprinted genes. Ovarian teratomas and CHMs are most likely to inherit their methylation profiles from their ancestral germ cells, although some aberrant methylation suggests a relaxation of imprinting in CHMs and a subset of struma ovarii. Extragonadal mature teratomas may carry a methylation profile of misplaced primordial germ cells or possibly somatic cells that have been reprogrammed in vivo.

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Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma.

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Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma.

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