Objective: To report the first case of OVERLAP SYNDROME of Stiff-Person Syndrome (SPS) with anti-HMGCR Immune-mediated necrotizing myopathy.

Background: Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder primarily associated with anti-GAD antibodies, characterized by progressive muscle stiffness, axial rigidity, and painful spasms. The loss of GABAergic inhibition by GAD65 leads to neuronal hyperexcitability and continuous motor unit activity. However, immune-mediated necrotizing myopathy (IMNM) causes proximal muscle weakness, muscle fiber necrosis, markedly elevated creatine kinase levels, and a minimal inflammatory infiltrate. In the anti-HMGCR subtype, autoantibodies continuously target regenerating muscle fibers, perpetuating a cycle of immune-mediated necrosis. Anti-GAD-associated SPS and anti-HMGCR-positive IMNM coexist in a combination not previously reported.

Method: A 51-year-old male with a past medical history of 2 years of anxiety disorder alongside lumbar radiculopathy presented to the clinic with six months of progressive axial and limb stiffness, severe fatigue, painful muscle spasms, proximal weakness, dysphagia, foot drop, severe thenar and interosseous atrophy, and the inability to perform their activities. Physical examination revealed bradykinesia, diffuse fasciculations, reduced muscle strength, hyperekplexia, dysmetria, and positive bilateral jaw-jerk reflexes, Hoffman’s, Marinescu’s, and Steinner’s reflexes. Brain MRI demonstrated mild cerebellar atrophy, and electromyography showed continuous motor unit activity with features suggestive of motor neuron involvement. Laboratory findings showed elevated CPK (468 U/L) and ESR (19 mm/h), with positive anti-HMGCR (257.08) and anti-GAD (13.30) antibodies.

Results: Patient received treatment with IV high-dose methylprednisolone followed by rituximab. Along with oral baclofen and a prednisone taper, which resulted in progressive clinical improvement across both motor and myopathic domains.

Conclusion: This case is the first case report of overlap syndrome of anti-GAD65 SPS and anti-HMGCR IMNM, demonstrating that distinct autoimmune processes can create  ALS mimics. Extended serological profiling beyond conventional panels is essential in atypical neuromuscular presentations, to guide therapeutic strategy, diagnostic reasoning, and long-term clinical outcome.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/too-weak-to-stand-too-stiff-to-fall-overlap-syndrome-of-stiff-person-syndrome-and-anti-hmgcr-necrotizing-myopathy-case-report/