Objective: To evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-syn) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls.

Background: In 2004 we described the E46K mutation in the alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of the myocardium. The skin has become a target for the development of biomarkers in PD, and sudomotor function can be affected since early stages of the disease.

Method: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure (PAF), 1 PD and 1 asymptomatic), 2 PARK2 carriers and one healthy control to quantify intraepidermal nerve fiber density and p-syn deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-syn) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan).

Results: All E46K-SNCA carriers had moderate to severe p-syn deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with predominant autonomic features (PAF), while p-syn aggregates where absent in the healthy control and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035).

Conclusion: E46K-SNCA mutation is a suitable model to study small fiber neuropathy in Lewy body diseases and small fiber neuropathy is a good marker of peripheral disease in synucleinopathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autonomic-features-in-e46k-snca-carriers/