Table 2.
Synaptic autoantibody targets and associated syndromes
| Antigen | Antigen function | Tumour association | Syndromes | Mechanisms | Prognosis |
|---|---|---|---|---|---|
| Intracellular antigens | |||||
| 65 kDa glutamic acid decarboxylase | Crucial for synthesis of GABA | Usually none; four of 61 had neuroendocrine tumours in one series35 | Most commonly stiff-person syndrome or cerebellitis Observed in many other syndromes | Evidence for both T-cell-mediated and antibody-mediated mechanisms Pathogenic role in other syndromes is not clear | Not known |
| Amphiphysin | Important for recycling of synaptic vesicles | Breast cancer (90%) | Stiff-person syndrome | Antibodies are directly pathogenic | Median time to death 33 months in one series38 |
| Extracellular antigens | |||||
| NMDAR | Crucial for learning and memory | Ovarian teratoma (frequency varies according to patient's age; rare in children) | Characteristic clinical syndrome | Antibodies disrupt NMDAR function by cross-linking and internalization of receptors | 75% of patients have good outcomes |
| Leucine-rich glioma-inactivated protein 1 | Secreted protein that regulates presynaptic Kv1 channels and postsynaptic AMPARs | Usually none | Limbic encephalitis, often with seizures, hyponatraemia, and/or myoclonus | Unknown | Approximately 80% of patients have good outcomes |
| Contactin-associated protein-like 2 | Organizes Kv1 channels on myelinated axons | Thymoma | Encephalitis and/or peripheral nerve hyperexcitability | Unknown | Approximately 80% of patients have good outcomes |
| GABAB receptor | Mediates inhibitory synaptic transmission | Small-cell lung cancer | Encephalitis with prominent and severe seizures | Unknown | Nine of 10 treated patients showed some improvement |
| AMPAR | Crucial for learning and memory | Lung, breast and thymic cancers | Limbic encephalitis | Antibodies cause cross-linking and internalization of AMPARs | Nine of 10 treated patients showed some improvement |
| P/Q-type voltage-gated calcium channels | Crucial for calcium influx into presynaptic terminals | Small-cell lung cancer | Lambert-Eaton myasthenic syndrome and/or cerebellitis | Antibodies block channels at presynaptic terminal of neuromuscular junction; possibly also pathogenic in CNS | Not known for CNS syndrome |
| Metabotropic glutamate receptor 1 | Crucial for cerebellar function | Hodgkin lymphoma | Cerebellitis | Unknown | Mixed response to treatment |
| Metabotropic glutamate receptor 5 | Crucial for hippocampal function | Hodgkin lymphoma | Ophelia syndrome | Unknown | Patients usually respond to treatment |
Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABA, γ-aminobutyric acid; NMDAR, N-methyl-d-aspartate receptor.