Genetic Variants and Clinical Phenotyping in 39 Pediatric Patients with Neuropathic Pain

Abstract

Introduction

Pathogenic variants in voltage-gated sodium channels (VGSCs) may cause disturbed sensory function, including small fiber neuropathy (SFN) in adults, but little is known about their role in children and adolescents.

Methods

A total of 39 prospectively enrolled children (age 12.03 ± 4.61 years) with abnormal pain sensation underwent detailed diagnostics including quantitative sensory testing (QST, if >5 years old), quality of life assessment, and genetic studies for VGSC variants and further etiologies.

Results

QST results were consistent with Aẟ- und C-fiber damage, including increased cold, warmth, and mechanical detection thresholds, higher thermal sensory limen, and allodynia. Intraepidermal nerve fiber densities were low in 9/18 children. This resulted in a great impact on physical quality of life and pain scales but not on social life. Five children showed heterozygous variants of unknown significance (VUS) in genes encoding VGSC (SCN9A, n = 2; SCN10A, n = 3) with maternal or paternal inheritance in two and one patients, respectively. Three further patients showed likely disease-associated variants in the HUWE1, TRIO, and PYGM genes.

Discussion

Despite a high disease burden and small fiber damage indicated by QST and skin histology, only VUS in VGSC and additional monogenic causes of pain symptoms outside of VGSC genes were identified. Genetic studies in affected children should therefore be comprehensive, not restricted to VGSC variants and be supplemented by a detailed clinical workup. In silico modeling and future functional studies might help to identify VUS that play a role in altered pain perception.

Keywords

voltage-gated sodium channels - small fiber neuropathy - children - neuropathic pain - in silico modeling

Ethical Publication Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Publication History

Received: 09 January 2025

Accepted: 23 April 2025

Accepted Manuscript online:
28 April 2025

Article published online:
20 May 2025

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