Table 1.

Neuronal nonsynaptic autoantibody targets and associated syndromes

Antigen	Antigen function	Tumour association	Syndromes	Mechanisms	Prognosis
Hu proteins (primarily HuD, but also HuC, Hel-N1 and Hel-N2)112	HuD is important for neuronal RNA handling, cell-cycle regulation and cell development113,114	Small-cell lung cancer115	Neuropathy (often purely sensory), cerebellitis, limbic encephalitis, autonomic dysfunction and/or brainstem encephalitis	Antibodies are not directly pathogenic; possibly T-cell-mediated	20% survival at 3 years (encephalitis is slightly more likely to cause death than is cancer)
Collapsin response mediator protein 5	Regulation of neurite outgrowth, and neurogenesis116	Small-cell lung cancer and thymoma117	Neuropathy, uveoretinal symptoms, ataxia or limbic encephalitis117	Possibly T-cell-mediated22	Longer survival than with anti-Hu syndromes (48 versus 11 months)117
Ma1118	Promotion of apoptosis	Diverse (lung, skin, gastrointestinal and renal)	Limbic encephalitis, cerebellitis, brainstem encephalitis or polyneuropathy	Probably T-cell-mediated rather than antibody-mediated21	In a series of 13 patients, nine deteriorated, three stabilized and one improved119
Ma2 (also known as Ta)118	Not known	Germ cell tumours (especially in young men)	Limbic encephalitis, brainstem encephalitis, polyneuropathy or cerebellitis119	Not known	In a case series 33% improved, 21% stabilized and 46% deteriorated119
Yo proteins (also known CDR1 and CDR2)	CDR1 is strongly expressed in Purkinje cells; function unknown120 CDR2 may be involved in cell cycle regulation, mitosis, and transcriptional regulation121	Specific to women Almost all are eventually diagnosed with breast or gynaecological cancer122	Paraneoplastic cerebellar degeneration	Conflicting data in patients regarding a role for T cells27,28 Antibodies trigger neuronal cell death in slice culture29	Tumours may respond, but neurological symptoms are often unresponsive122
Ri proteins (also known as Nova-1 and Nova-2)	Nova-1 is an RNA-binding protein expressed by subcortical neurons Function of Nova-2 is not known	Breast cancer	Nova-1: cerebellar degeneration, encephalitis, myelitis, opsoclonus myoclonus123,124 Nova-2: paraneoplastic opsoclonus myoclonus ataxia,125 myoclonus, encephalitis, cerebellar degeneration and myelitis	Antibodies may prevent binding of Nova-1 to RNA126 Unclear whether antibodies are pathogenic; comorbid antibodies are common and can occur in asymptomatic cancer patients127	Three of six patients improved; median survival >69 months in one series123
Tr	Found in Purkinje neurons;128 function not known	Hodgkin lymphoma	Paraneoplastic cerebellar degeneration129	Not known	Relatively good: median survival >113 months123
Zinc finger protein ZIC 4	Important for brain development	Small-cell lung cancer	Paraneoplastic cerebellar degeneration130	Antibodies may not be pathogenic; 80% of patients have other antibodies as well	Not known
Gephyrin and GABARAP	Associated with GABAergic transmission	Gephyrin: mediastinal carcinoma GABARAP: not known	Stiff-person syndrome131,132	Not known	Not known

Abbreviations: GABA, γ-aminobutyric acid; GABARAP, GABA receptor-associated protein.