GUIDANCE FOR USE
The Syn-One Test® is a skin biopsy-based test intended to identify specific pathological markers located in cutaneous tissue to aid in the diagnosis of neurological disorders. The central diagnostic feature of Syn-One is the application of immunofluorescent techniques to identify and visualize phosphorylated alpha-synuclein co-located in cutaneous nerves to aid in the diagnosis of a synucleinopathy, a group of neurodegenerative disorders that includes Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD)*. An abnormal result that identifies phosphorylated alpha-synuclein is indicative of a synuclein pathology but cannot distinguish between the synucleinopathies. Clinicians should use the results from the synuclein assay of the Syn-One Test along with other clinical features to help make a more specific diagnosis.
Syn-One includes the application of an immunofluorescent protein gene product (PGP 9.5) stain that enables quantitative measurement of intraepidermal nerve fiber density (IENFD). A reduced IENFD is indicative of nerve degeneration as seen in some neurodegenerative diseases and peripheral neuropathies
Syn-One includes a Congo red stain for amyloid as a part of the neuropathologic assessment. The finding of amyloid deposits could indicate a potential cause for epidermal and autonomic nerve pathology, generalized peripheral neuropathy, autonomic dysfunction, and other multi-organ disorders and should prompt an evaluation for primary and secondary causes of amyloidosis.
Syn-One includes a hematoxylin and eosin (H&E) stain, which allows for the evaluation of dermatologic conditions that could mimic neuropathies and identify other benign and malignant skin abnormalities that may be present. The H&E results pertain only to the tissue biopsies taken for this test. Any clinically apparent lesions warrant separate analysis by a dermatologist.
Stability data is not available for tissue specimens kept in fixative for more than 120 hours. The stability of phosphorylated alpha-synuclein deposition has not been established for prolonged fixative times. Prolonged fixative time could result in an artificial decrease in the intraepidermal nerve fiber density.
*REM sleep behavior disorder (RBD) is considered a prodromal synucleinopathy. The sensitivity and specificity data of the Syn-One Test for the detection of phosphorylated alpha-synuclein in patients with RBD has not been established. Ongoing research is being conducted in patients with RBD.
References
For additional information on the skin biopsy technique and detection of phosphorylated alpha-synuclein see:
Gibbons CH, Levine T, Adler C, et al. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies. JAMA. Published online March 20, 2024. doi:10.1001/jama.2024.0792
Gibbons C, Wang N, Rajan S, et al. Cutaneous α-synuclein signatures in patients with multiple system atrophy and Parkinson disease. Neurology.2023; 100(15), e1529–e1539. doi: 10.1212/WNL.0000000000206772
Kim JY, Illigens BM, McCormick MP, Wang N, Gibbons CH. Alpha-synuclein in skin nerve fibers as a biomarker for alpha-synucleinopathies. J Clin Neurol. 2019 Apr;15(2):135-142. doi: 10.3988/jcn.2019.15.2.135
Gibbons CH, Garcia J, Wang N, Shih LC, Freeman R. The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease. Neurology. 2016 Aug 2;87(5):505-12. doi: 10.1212/WNL.0000000000002919
Provitera V, Gibbons CH, Wendelschafer-Crabb G, et al. A multi-center, multinational age- and gender-adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg. Eur J Neurol. 2016 Feb;23(2):333-8. doi: 10.1111/ene.12842
Freeman R, Gonzalez-Duarte A, Barroso F, et al. Cutaneous amyloid is a biomarker in early ATTRv neuropathy and progresses across disease stages. Ann Clin Transl Neurol. 2022; 9(9), 1370–1383. doi: 10.1002/acn3.51636
Cassard L, Honari G, and Tousi, B, The skin and Lewy body disease. Alzheimers Dis.2024. doi: 10.3233/JAD-240198
Niemann, N, Billnitzer, A, and Jankovic, J. Parkinson’s disease and skin.Parkinsonism Relat Disord. 2021 (82); 61-76. doi:10.1016/j.parkreldis.2020.11.017
Immunohistochemistry and immunofluorescence tests were developed, and their performance characteristics were determined, by CND Life Sciences, Scottsdale, AZ. They have not been cleared or approved by the U.S. Food and Drug Administration. CND Life Sciences, Inc. is accredited by the College of American Pathologists (CAP) and holds a Clinical Laboratory Improvement Amendments (CLIA) Certificate of Accreditation to perform high-complexity testing.
