Objective: To assess how skin biopsy detection of phosphorylated alpha-synuclein (P-SYN) and its distribution pattern impact the diagnosis of synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) at a tertiary academic center.

Background: Synucleinopathies are characterized by P-SYN deposition in the central and peripheral nervous systems and are difficult to diagnose due to overlapping symptoms and lack of objective diagnostic tools. Recently, skin biopsy detection of P-SYN and analysis of its deposition patterns have been implicated as a reliable tool in diagnosing synucleinopathies. Regarding P-SYN deposition, patients with PD display a proximal to distal deposition pattern with small fiber neuropathy (SFN), while patients with MSA have similar deposition between both proximal and distal sites without SFN. In DLB, P-SYN is seen proximally and distally but with severe SFN.

Method: Patients who underwent skin biopsy detection of P-SYN were selected. Patients first underwent clinical examination and were diagnosed with possible PD, DLB, MSA, and/or other diagnosis (secondary parkinsonism, essential tremor [ET], etc). They then underwent skin biopsy at posterior cervical, distal thigh, and distal leg sites. Biopsy data was analyzed by expert review and used to establish the diagnosis of a specific synucleinopathy, secondary parkinsonism, or other disorder.

Results: Of the 25 patients who received skin biopsies, 17 patients (68%) were diagnosed with a specific synucleinopathy (PD, DLB, or MSA), and eight patients (32%) were diagnosed with secondary parkinsonism or other disorder (copper dysmetabolism, SFN, ET, or progressive supranuclear palsy [PSP]). In two cases of synucleinopathy, the clinical presentation did not directly match pathologic parkinsonism subtype interpretation on skin biopsy. However, 88% of skin biopsies positive for P-SYN matched the clinical phenotype.

Conclusion: Presence of P-SYN and its deposition pattern on skin biopsy may be utilized to confirm a suspected diagnosis of PD, DLB, or MSA, while absence of P-SYN deposition may be used to distinguish between synucleinopathy mimics such as secondary parkinsonism or PSP. Overall, skin biopsy helped provide a specific diagnosis in 23 of 25 (92%) of patients without the need for invasive procedures.

References: Gibbons CH, Levine T, Adler C, et al. Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. JAMA. 2024;331(15):1298–1306. doi:10.1001/jama.2024.0792

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-skin-biopsy-detection-of-phosphorylated-alpha-synuclein-and-its-distribution-patterns-on-the-diagnosis-of-synucleinopathies/