Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases

Misra, Kaalindi; Ślęczkowska, Milena; Santoro, Silvia; Gerrits, Monique M.; Mascia, Elisabetta; Marchi, Margherita; Salvi, Erika; Smeets, Hubert J. M.; Hoeijmakers, Janneke G. J.; Martinelli Boneschi, Filippo Giovanni; Filippi, Massimo; Lauria Pinter, Giuseppe; Faber, Catharina G.; Esposito, Federica

doi:10.3390/ijms25137248

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Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases

by

Kaalindi Misra

^1,†,

Milena Ślęczkowska

^2,3,†

,

Silvia Santoro

¹,

Monique M. Gerrits

⁴

,

Elisabetta Mascia

¹,

Margherita Marchi

⁵

,

Erika Salvi

⁵,

Hubert J. M. Smeets

²,

Janneke G. J. Hoeijmakers

³

,

Filippo Giovanni Martinelli Boneschi

^6,7

,

Massimo Filippi

^8,9,10,11

,

Giuseppe Lauria Pinter

^5,12,

Catharina G. Faber

³

and

Federica Esposito

^1,8,*

¹

Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20132 Milan, Italy

²

Department of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The Netherlands

³

Department of Neurology, Mental Health and Neuroscience Research Intsitute, Maastricht University Medical Centre+, 6229 ER Maastricht, The Netherlands

⁴

Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 HX Maastricht, The Netherlands

⁵

Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy

⁶

Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy

⁷

Clinical Neurology Unit, Azienda Socio-Sanitaria Territoriale Santi Paolo e Carlo and Department of Health Sciences, University of Milan, 20142 Milan, Italy

⁸

Neurology and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

⁹

Vita-Salute San Raffaele University, 20132 Milan, Italy

¹⁰

Neurophysiology Service, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

¹¹

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

¹²

Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, 20157 Milan, Italy

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^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2024, 25(13), 7248; https://doi.org/10.3390/ijms25137248

Submission received: 30 May 2024 / Revised: 25 June 2024 / Accepted: 28 June 2024 / Published: 30 June 2024

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Chronic Pain)

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Abstract

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the “Nicotinic acetylcholine receptor signaling pathway”. Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.

Keywords: Small-Fiber Neuropathy; Early-Onset; whole-exome study; neuropathic pain; genetics

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MDPI and ACS Style

Misra, K.; Ślęczkowska, M.; Santoro, S.; Gerrits, M.M.; Mascia, E.; Marchi, M.; Salvi, E.; Smeets, H.J.M.; Hoeijmakers, J.G.J.; Martinelli Boneschi, F.G.; et al. Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases. Int. J. Mol. Sci. 2024, 25, 7248. https://doi.org/10.3390/ijms25137248

AMA Style

Misra K, Ślęczkowska M, Santoro S, Gerrits MM, Mascia E, Marchi M, Salvi E, Smeets HJM, Hoeijmakers JGJ, Martinelli Boneschi FG, et al. Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases. International Journal of Molecular Sciences. 2024; 25(13):7248. https://doi.org/10.3390/ijms25137248

Chicago/Turabian Style

Misra, Kaalindi, Milena Ślęczkowska, Silvia Santoro, Monique M. Gerrits, Elisabetta Mascia, Margherita Marchi, Erika Salvi, Hubert J. M. Smeets, Janneke G. J. Hoeijmakers, Filippo Giovanni Martinelli Boneschi, and et al. 2024. "Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases" International Journal of Molecular Sciences 25, no. 13: 7248. https://doi.org/10.3390/ijms25137248

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Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases

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