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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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
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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