| Neuroimmunology | Rare Neurological Diseases  

Neurology Update: Emerging Insights into the Pathogenesis and Management of Stiff Person Syndrome

Stiff Person Syndrome (SPS) is an autoimmune neurological disorder marked by rigidity, spasms, and heightened sensitivity to stimuli, often associated with high-titer GAD65 antibodies. A recent study of 72 GAD65-positive patients found that those with isolated cerebellar ataxia (pCA) were older and more often male than those with SPS spectrum disorders (SPSD), which include SPS-plus and PERM. While disability levels were similar, pCA patients showed more cerebellar dysfunction and atrophy, suggesting differing disease mechanisms. Complementing these findings, an immunogenetic study identified seven KLK10 gene variants uniquely present in 95% of SPS patients. KLK10, involved in immune signaling, may contribute to disease susceptibility. Additional immune-related genes (ORAI1, LILRA4) were also implicated, highlighting potential genetic drivers of SPS. At the synaptic level, new research shows glycine receptor autoantibodies—present in some SPS and PERM patients—disrupt both pre- and postsynaptic inhibition. Specifically, targeting of presynaptic GlyRα2 reduces glycinergic transmission, offering insight into the disorder’s clinical variability. Together, these studies underscore SPS as a complex, multifactorial condition involving immune, genetic, and synaptic dysfunctions.

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder characterized by muscle rigidity, painful spasms, heightened sensitivity to stimuli, and an association with high-titer autoantibodies, most notably against glutamic acid decarboxylase 65 (GAD65). Recent studies have advanced our understanding of the clinical, immunogenetic, and molecular mechanisms underlying SPS and its broader spectrum of disorders, including progressive encephalomyelitis with rigidity and myoclonus (PERM).

A large cohort study by Krett et al. analyzed 72 GAD65-antibody–seropositive patients with cerebellar dysfunction, either in isolation (pure cerebellar ataxia, pCA) or as part of the SPS spectrum disorders (SPSD) such as SPS-plus and PERM (1). Patients with pCA were typically older and more frequently male than those with SPSD. Despite similar overall disability as measured by the modified Rankin Scale, those with pCA showed a higher burden of cerebellar dysfunction on specific ataxia rating scales and MRI evidence of cerebellar atrophy. Interestingly, both groups had high GAD65 antibody titers, but cerebrospinal fluid (CSF) positivity was more frequent in SPSD cases. The study emphasizes the importance of cerebellar involvement in disease severity and suggests that structural neuroimaging and ataxia-specific scales may help refine prognosis and treatment approaches.

Complementing the clinical findings, immunogenetic studies have uncovered novel genetic markers that may underlie the pathogenesis of GAD-positive SPS. Whole-exome sequencing of patients revealed consistent polymorphisms in the KLK10 gene, identified in 95% of individuals with SPS but absent in controls and GAD-positive individuals without neurologic symptoms (2). KLK10 encodes a protease implicated in neuroinflammation and immune signaling, indicating a potential genetic predisposition contributing to autoimmunity in SPS. Additionally, immune-related genes such as ORAI1 and LILRA4, involved in calcium signaling and dendritic cell function respectively, were also overrepresented in SPS patients. These discoveries suggest a complex interplay between genetic susceptibility and immune dysregulation, offering potential targets for future therapeutic interventions.

On a molecular level, Wiessler et al. have shown that glycine receptor (GlyR) autoantibodies, present in subsets of SPS and PERM patients, affect not only postsynaptic but also presynaptic receptor function (3). Their experimental data demonstrate that autoantibody binding can impair glycinergic transmission by targeting GlyRα2 subunits located at presynaptic terminals, leading to a significant reduction in inhibitory neurotransmission. This newly recognized presynaptic pathology helps explain the variability in symptoms and treatment responses observed in GlyR-positive patients and suggests that broader synaptic mechanisms are at play than previously appreciated.

Together, these studies deepen our understanding of SPS as a heterogeneous disorder with diverse immunologic, genetic, and neurophysiologic underpinnings. They underscore the need for individualized diagnostic approaches and open new avenues for targeted therapies based on biomarker profiles and molecular pathways.
 

Key Points:

  1. pCA patients are older, more often male, and show greater cerebellar atrophy than SPSD patients and early immunotherapy plus GABAergic drugs improve patient outcomes.
  2. High serum GAD65 titers are common; CSF positivity is higher in SPSD.
  3. KLK10 variants are highly prevalent in GAD65-positive SPS patients.
  4. Variants in ORAI1 and LILRA4—genes regulating T cells and dendritic cells—suggest immune signaling dysfunction in SPS.
  5. GlyR autoantibodies impair presynaptic GlyRα2, reducing inhibitory signaling.

References:

  1. Krett JD, Wang Y, Miles A, Chen HR, Afshar H, Elfasi A, Lin DD, Newsome SD. Clinical Features and Outcomes of Glutamic Acid Decarboxylase-65 Antibody-Associated Pure Cerebellar Ataxia and Stiff Person Syndrome Spectrum Disorders: A Single-Center Cohort Study. Eur J Neurol. 2025 May;32(5):e70166. doi: 10.1111/ene.70166.
  2. Tsiortou P, Alexopoulos H, Kyriakidis K, Kosmidis M, Barba C, Akrivou S, Michalopoulos I, Politis P, Dalakas MC. Immunogenetic Studies in Patients With GAD-Positive Stiff-Person Syndrome Reveal Novel Lymphocytic Genes and KLK10-Gene Variants. Neurol Neuroimmunol Neuroinflamm. 2025 Mar;12(2):e200373. doi: 10.1212/NXI.0000000000200373.
  3. Wiessler AL, Zheng F, Werner C, Habib M, Tuzun E, Alzheimer C, Sommer C, Villmann C. Impaired Presynaptic Function Contributes Significantly to the Pathology of Glycine Receptor Autoantibodies. Neurol Neuroimmunol Neuroinflamm. 2025 Mar;12(2):e200364. doi: 10.1212/NXI.0000000000200364.

Publish on behalf of the Scientific Panel on Neuroimmunology

Back