SPS patients have GAD antibodies, compared with about one percent of the general population. The overwhelming majority of people who have GAD antibodies do not develop SPS, indicating that systemic synthesis of the antibody is not the sole cause of SPS. GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect SPS patients are not known. Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP). Autoantibodies against amphiphysin and gephyrin are also sometimes found in SPS patients. The antibodies appear to interact with antigens in the brain neurons and the spinal cord synapses, causing a functional blockade of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This leads to GABA impairment, which probably causes the stiffness and spasms that characterize SPS. There are low GABA levels in the motor cortexes of SPS patients. It is not known why GAD autoimmunity occurs in SPS patients, and whether SPS qualifies as a neuro-autoimmune disorder has been questioned. It is also unknown whether these antibodies are pathogenic. The level of GAD antibody titers found in SPS patients does not correlate with disease severity, indicating that these titer levels do not need to be monitored. It has not been proven that GAD antibodies are the sole cause of SPS, and the possibility exists that they are a marker or an epiphenomenon of the condition's cause. In SPS patients, motor unit neurons fire involuntarily in a way that resembles a normal contraction. Motor unit potentials fire while the patient is at rest, particularly in the muscles which are stiff. The excessive firing of motor neurons may be caused by malfunctions in spinal and supra-segmental inhibitory networks that utilize GABA. Involuntary actions show up as voluntary on EMG scans: even when the patient tries to relax, there are agonist and antagonist contractions. In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplastically as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have GAD antibodies. Passive transfer of SPS by plasma injection has been demonstrated in paraneoplastic SPS but not in classical SPS. There is evidence of genetic influence on SPS risk. The HLA class II locus makes patients susceptible to the