Over a dozen genes have been identified ( Darnell RB and Posner JB. N Engl J Med, 349:1543-1554, 2003.) by expression cloning and other means that encode onconeural antigens (a term we coined (Darnell RB. Proc Natl Acad Sci, USA, 93:4529-4536, 1996) to refer to the tumor-brain-specific expression of the PND antigens). At the same time, there is evidence that the full spectrum of onconeural antigens remains to be identified.

Paraneoplastic Cerebellar Degeneration

The cerebellar degeneration antigens are expressed by gynecologic tumors, are normally found in cerebellar Purkinje neurons, and cDNAs encoding them have been cloned. Two of these genes encode a family of proteins with extended leucine zipper motifs. We are currently studying these proteins as examples of cytoplasmic signal transduction antigens, and are evaluating proteins with which cdr antigens interact.

Paraneoplastic cerebellar degeneration (PCD) occurs in patients with breast or ovarian cancer. 55 patients with PCD have been described with these tumors who harbor an autoantibody termed Yo.

Paraneoplastic Opsoclonus Myoclonus Ataxia

This disease is seen in patients with lung cancer, gynecologic cancer, or, in children, neuroblastoma. Patients suffer from what is seen by neurologists as a lack of inhibition of brainstem and spinal motor neurons, and, in some cases, may go on to develop CNS signs (dementia). The target antigen, Nova, has been found to be encoded by two genes, one primarily expressed in the brainstem and spinal motor neurons (Nova1), and a second (Nova2) primarily expressed in the cortex, with some areas of overlap. The Nova genes encode neuron-specific RNA binding proteins involved in regulating alternative splicing of transcripts encoding synaptic proteins in the brain. These proteins share features in common with the FMRP protein, which is lost in patients with Fragile-X mental retardation, and they interact with a brain-specific homologue of the RNA binding protein brPTB.

Hu Encephalopathy/Subacute Sensory Neuronopathy

This multifocal disorder occurs primarily in patients with small cell lung cancer. Patients may have unifocal illness involving nearly any part of the central or peripheral nervous system (ranging from memory loss/limbic encephalopathy to sensory neuropathy/dorsal root ganglionopathy to pure autonomic neuropathy), or develop a devastating multifocal neurologic degeneration. The Hu antigens are encoded by three genes, HuB, HuC and HuD, which encode neuron-specific RNA binding proteins.