Objective:

The Synuclein-One study is an NIH-funded 30-site trial that included 33 participants with pure autonomic failure (PAF). We report the detection and quantitation of cutaneous phosphorylated alpha-synuclein (P-SYN) in patients with suspected PAF. 

Background:

PAF is a peripheral neurodegenerative disease associated with the deposition of P-SYN.  The differential diagnoses include peripheral autonomic neuropathies, ganglionopathies and other neurodegenerative diseases.  Up to 10% of patients per year phenocovert to a central synucleinopathy.  No diagnostic test exists to confirm the underlying pathology, to predict phenoconversion risk or the central synucleinopathy subtype.

Design/Methods:

After consent, participants with PAF (or healthy controls) completed neurologic examinations, medical history review, cognitive evaluation, orthostatic vital signs and neurodegenerative disease questionnaires.  All participants underwent blinded review by a panel of experts to confirm a diagnosis of PAF.  Skin biopsies at the distal leg, distal thigh and posterior cervical sites were performed on all participants with quantitation of P-SYN.

Results:

120 controls and 33 PAF participants were enrolled.  The expert panel excluded 11 patients with PAF (8 phenoconverted to another synucleinopathy and 3 with peripheral autonomic neuropathy).  Of the 22 with confirmed PAF, P-SYN was detected in 22/22 (100%) and in 8/8 (100%) of those who had phenoconverted to another synucleinopathy. Of the 3 with suspected peripheral autonomic neuropathy, 3/3 (100%) had peripheral neuropathy on skin biopsy, but 2/3 (66%) also had evidence of P-SYN on skin biopsy.  Of the 120 controls, P-SYN was detected in 4/120 (3.7%).

Conclusions:

Cutaneous P-SYN testing is sensitive and specific for detection of P-SYN in patients with suspected PAF.  The presence of misfolded synuclein should be considered in the differential diagnosis of peripheral autonomic neuropathies.  Phenoconversion to another synucleinopathy was noted in 25% of enrolled subjects.  Longitudinal studies with serial skin biopsies and topographic analysis may offer insight into phenoconversion risk and synucleinopathy subtype.