Background & Aims

In the realm of peripheral neuropathies, the urgent need for reliable biomarkers has become increasingly apparent. The complexities of painful idiopathic small fiber neuropathy (PiSFN) and SCN9A-related painful neuropathy (NavNP) pose diagnostic challenges, aggravated by overlapping clinical features that often confound accurate recognition using available diagnostic tools. Emerging evidence suggests that patients with specific characteristics, such as genetic background, respond differently to currently available therapies. Accurate phenotyping is crucial for optimizing treatment efficacy. This study employs advanced proteomic profiling on skin biopsy specimens to unveil unique molecular signatures associated with PiSFN and NavNP, aiming to identify tissue-specific biomarkers that will enhance diagnostic precision and, hopefully, guide tailored local treatment strategies that maximize therapeutic efficacy.

Methods

All included subjects underwent neurological exams with blood sampling for genetic analysis and skin biopsy sampling for intraepidermal nerve fiber density (IENFD) analysis. Unbiased mass-spectrometry proteomic analysis was conducted on the epidermis, the tissue hosting small nerve fibers, dissected from archived skin biopsy specimens of 11 patients with PiSFN, 6 patients with NavNP, and 9 controls. Only proteins that were found in at least 70% of one sample group were included in the analysis. After relative quantification analysis, significantly altered proteins were further elaborated using pathway enrichment analysis using distinct sources (KEGG Database, ClueGO, String, Reactome) to investigate potentially affected pathways and molecular functions associated with clinical phenotype.

Results

After quality filters, 3483 proteins were subsequently analyzed. The most significant data emerged when comparing PiSFN and NavNP. Namely, 264 proteins resulted statistically differentially expressed (limma p. value<0.05), with 14 proteins surviving the Benjamini–Hochberg correction. Pathway and molecular function enrichment analysis revealed that proteins involved in programmed cell death, inflammation, and extracellular matrix were upregulated in painful idiopathic SFN, while proteins driving vesicle-mediated transport, membrane trafficking, metabolism, and DNA and RNA repair were upregulated in SCN9A-related channelopathy.

Conclusions

Our study has successfully identified distinct proteomic patterns in two patient cohorts, shedding light on unique pathways and molecular processes within the epidermis, considered a polymodal nociceptor. These findings need to be further validated in independent cohorts and employing different approaches to provide a comprehensive understanding of the underlying processes and facilitate the identification of druggable targets. However, this innovative approach demonstrates the wide utility of archived skin biopsy specimens and their suitability for advanced profiling techniques. This approach opens new avenues for clinical research and enhances our ability to explore molecular mechanisms in complex neurological disorders.

References

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2.Sommer C. Exploring pain pathophysiology in patients. Science. Nov 04 2016;354(6312):588-592. doi:10.1126/science.aaf8935
3.de Greef BTA, Hoeijmakers JGJ, Geerts M, et al. Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial. Brain. 02 01 2019;142(2):263-275. doi:10.1093/brain/awy329
4.Labau JIR, Estacion M, Tanaka BS, et al. Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy. Brain. 03 01 2020;143(3):771-782. doi:10.1093/brain/awaa016
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Presenting Author

Mirna Andelic

Poster Authors

Mirna Andelic

MSc

IRCCS Neurological Institute Carlo Besta, Milan

Lead Author

Andrea Gelemanovic

Biology of Robustness Group, Mediterranean Institute for Life Sciences (MedILS), 21000 Split, Croatia

Lead Author

Raffaella Lombardi

Msc

Lead Author

Grazia Devigili

MD

Lead Author

Daniele Cartelli

PhD

Lead Author

Stefania Marcuzzo

PhD

Lead Author

Erika Salvi

PhD

Lead Author

Margherita Marchi

MSc

Lead Author

Linda Maldera

Msc

Lead Author

Elkadia Mehmeti

Msc

Lead Author

Ilaria D'Amato

Msc

Lead Author

Daniele Cazzato

MD

Lead Author

Eleonora Dalla Bella

IRCCS Foundation “Carlo Besta " Neurological Institute

Lead Author

Janneke G.J. Hoeijmakers

MD

Lead Author

Catharina G. Faber

MD

Lead Author

Topics

  • Assessment and Diagnosis