Immunofluorescence analysis of skin biopsies from 17 small-fiber neuropathy patients (8 idiopathic) found no alpha-synuclein deposition in PGP9.5-positive nerve terminals, suggesting synucleinopathy is not common in idiopathic SFN.

This negative pilot finding reduces the likelihood that peripheral skin alpha-synuclein is a broadly useful biomarker or target in idiopathic SFN and implies peripheral synuclein pathology may be specific to systemic synucleinopathies, informing biomarker strategies and patient selection for…

INTRODUCTION/AIMS: Small-fiber neuropathy (SFN) is a heterogeneous disorder with many established causes, but around half of all cases are idiopathic after extensive investigation. Recent pathologic studies in Parkinson disease have revealed deposition of ⍺-synuclein in small sensory and autonomic nerve terminals in skin biopsy specimens, suggesting that ⍺-synuclein deposition may cause SFN in patients with systemic synucleinopathies. Our aim was to investigate whether ⍺-synuclein deposition may also underlie cases of SFN previously classified as idiopathic. METHODS: We co-stained skin biopsy specimens of 17 patients with SFN (8 idiopathic and 9 symptomatic) for ⍺-synuclein and protein gene product 9.5 (PGP 9.5). Specimens had been previously obtained for clinical diagnostic purposes and were recut in 10 μm sections on a freezing sliding microtome and mounted on slides followed by staining. Specimens were viewed under a Zeiss fluorescent microscope. RESULTS: We found PGP 9.5-positive nerve terminals in all specimens, but none demonstrated positive staining for ⍺-synuclein. DISCUSSION: This suggests that ⍺-synuclein deposition is not a common underlying cause of idiopathic SFN and may be specific to systemic synucleinopathies. As no neurodegenerative causes of idiopathic SFN have yet been identified, further research is needed to investigate novel causes of this common condition that is often associated with pain, autonomic dysfunction, and diminished quality of life.