Cutaneous alpha‐synuclein deposition in postural tachycardia patients

Abstract

Objective To report a case series of patients with neuropathic POTS and cutaneous phosphorylated alpha‐synuclein (P‐SYN) deposition on skin biopsy and compare these to neuropathic POTS patients without P‐SYN deposition. Methods The medical history, physical examination findings, autonomic function testing, and skin biopsy neuropathology of patients under the age of 50 with a postural tachycardia and a diagnosis of POTS were retrospectively reviewed. Included patients completed the composite autonomic severity score (COMPASS 31), the Wood Mental Fatigue Inventory, the Epworth Sleepiness scale, the REM Behavior Disorder Questionnaire, the Patient‐Reported Outcomes Measurement Information System (PROMIS‐10), and the Gastroparesis Cardinal Symptom Index. Results Of 296 patients seen with POTS, 22 patients with suspected neuropathic POTS had skin biopsies performed during their evaluation. Seven of 22 patients had P‐SYN present on skin biopsy, while 15 individuals did not. Those with P‐SYN on biopsy: (1) were more likely to be male; (2) had features of REM sleep behavioral disorder; (3) reported less sleepiness and cognitive impairment; and (4) noted greater symptoms of gastroparesis. On autonomic testing, the group with P‐SYN deposition was more likely to have a hypertensive response to tilt‐table testing and abnormal QSART responses. Interpretation Phosphorylated alpha‐synuclein deposition is present in some postural tachycardia patients with neuropathic features. Individuals with a postural tachycardia and cutaneous phosphorylated alpha‐synuclein deposition may be distinguished from other patients with neuropathic POTS.

Diagnosis and management of postural orthostatic tachycardia syndrome

“…35 Clinical features of small fibre neuropathy have traditionally been used to diagnose a partial autonomic neuropathy. Some patients with POTS have phosphorylated α-synuclein in skin biopsies, 36 suggesting a neuropathic mechanism that may be shared with Parkinson disease and pure autonomic failure.…”

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

“…We collect three 3-mm skin punch samples at the following sites from both patients: 10 cm above the lateral malleolus, 10 cm above the lateral knee, and 3 cm lateral to the C7 vertebral prominence [ 34 ]. Briefly, tissues are fixed in Zamboni’s fixative for 24 h and frozen and cut into 50 μm sections.…”

“…Emerging molecular diagnostic tests warrant mention. Skin biopsy for α-synuclein immunohistochemistry and assessment of nerve fiber density is now commercialized based on high sensitivity and specificity to distinguish synucleinopathy from other proteinopathies [ 34 ], with alpha-synuclein deposition predominating in somatosensory versus sympathetic adrenergic fibers in MSA versus PD, respectively [ 35 , 36 ]. Seed amplification assays (SAA) including real-time quaking-induced conversion (RT-QuiC) or protein misfolding cyclic amplification (PMCA) of amyloidogenic alpha-synuclein conformers from cerebrospinal fluid [ 37 ] may distinguish PD from MSA and have also recently been commercialized [ 38 ].…”

A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS

“…In one small cohort of one of the authors (C.G. ), cutaneous p-syn was reported on skin biopsy in 7/22 (32%) of POTS patients prior to the COVID-19 pandemic [ 7 ]. Those with a hypertensive response on HUT, as all of our patients had, were more likely to be p-syn positive.…”