What is the pathophysiology of stiff person syndrome?

Updated: Jun 14, 2018
  • Author: Nancy Theresa Rodgers-Neame, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Endocrinologists were excited by a discovery in the 1980s of an antibody to a 65-kd protein that was strongly associated with adult-onset diabetes mellitus and stiff person syndrome. It is found in a particularly large subset of patients with diabetes, and endocrinologists hoped that it would be the major breakthrough needed to cure this disease in millions of patients worldwide. They were disappointed to find that the 65-kd protein was GAD, an enzyme largely found in the central nervous system (CNS), and, unfortunately, the pathophysiologic link between diabetes and glutamic acid decarboxylase remains unclear.

Since that time, the antibody has been found in patients with a number of neurologic diseases, a scenario that is easier to understand because the pathophysiologic link to neurologic disease is easier to explain. The range of diseases encountered includes seizures, cerebellar dysfunction, cortical dysfunction, and myelopathy, but the association between function of the enzyme and the consequence of the disease is most clear in patients with stiff person syndrome.

In stiff person syndrome, spinal interneurons function to inhibit spontaneous discharges from spinal motor neurons, primarily through the action of glycine. However, this is only one inhibitory input for the motor pathway that includes GABA-mediated inhibition from the cortex, brain stem, and cerebellum. If GAD function is inhibited significantly, then GABA available for these functions is decreased and muscles become continuously stimulated by the motor neurons. Additional possible pathophysiologic etiologies in patients negative for GAD antibody include postsynaptic elements such as synaptophysin, amphiphysin, [24] gephyrin, [25] and GABA-transaminase.

Glutamate is an excitatory amino acid synthesized from glucose via the Krebs cycle. It has several fates within the cell. Glutamate can be packaged for release from synaptic clefts, and it can be acted on by several transaminases to transform it to either glutamine or GABA. Following release from the synapse, glutamate is absorbed either by reuptake mechanisms by the neurons or, more commonly, by astrocytes. GAD is nearly ubiquitous in the CNS and is located in or near the synaptic button. It is rate limited primarily by the availability of free glutamate. However, GAD is not the only source of GABA. The Krebs cycle also serves to synthesize GABA via GABA-transaminase.

However, GAD antibodies alone appear to be insufficient to cause stiff person syndrome, [3] and GAD antibodies are associated with a broad spectrum of disease; consequently, GAD clearly forms only part of the pathophysiology of stiff person syndrome. [26] Possibly, postsynaptic GABA-ergic mechanisms, such as the synaptobrevins involved in tetanus, are involved. Research continues to progress on this interesting subject. [5, 17, 21, 27, 7, 28] Some patients clearly have GAD antibody-negative disease and may also be negative for anti-amphiphysin but otherwise fit the clinical picture.


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