Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center+, Maastricht, The Netherlands.
Department of Rehabilitation Medicine, Libra Revalidatie & Audiologie, Eindhoven, The Netherlands.
Mol Genet Genomic Med. 2022 Oct;10(10):e2026. doi: 10.1002/mgg3.2026. Epub 2022 Sep 16.
Voltage-gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Na 1.7, encoded by the SCN9A-gene, has been of special interest in the last decades because missense gain-of-function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).
In this case report, we present a 61-year-old woman who was referred to our tertiary referral center in a standard day care setting with suspicion of SFN. We performed additional investigations: skin biopsy to determine the intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST), and blood examination (including DNA analysis) for possible underlying conditions.
The patient showed a clinical picture that fulfilled the criteria of IEM, PEPD, and SFN. DNA analysis revealed the heterozygous variant c.554G > A in the SCN9A-gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions. Because its pathogenicity has never been functionally confirmed, the variant is classified as a variance of unknown significance (VUS)/risk factor. This suggests that another genetic and/or environmental substrate plays a role in the development of neuropathic conditions like described.
We have described this as the SCN9A-pain triangle phenomenon. Treatment should focus on pain management, genetic counseling, and improving/maintaining quality of life by treating symptoms and, if indicated, starting a rehabilitation program.
电压门控钠离子通道对于可兴奋细胞中电脉冲的产生和传导至关重要。SCN9A 基因编码的钠离子通道 Na 1.7 近几十年来引起了特别关注，因为错义获得性功能突变与一系列神经性疼痛疾病有关，包括遗传性红斑性肢痛症（IEM）、阵发性剧痛障碍（PEPD）和小纤维神经病（SFN）。
在本病例报告中，我们介绍了一位 61 岁女性，她在标准日间护理环境下被转诊至我们的三级转诊中心，疑似患有 SFN。我们进行了额外的检查：皮肤活检以确定表皮内神经纤维密度（IENFD）、定量感觉测试（QST）和血液检查（包括 DNA 分析）以确定可能的潜在疾病。
患者的临床表现符合 IEM、PEPD 和 SFN 的标准。DNA 分析显示 SCN9A 基因中的杂合变体 c.554G > A（OMIM 603415）。该变体已分别在所有三种人类疼痛疾病中被描述过，但从未在一个患者中同时出现这三种疾病的症状。由于其致病性从未被功能证实，该变体被归类为意义不明的变异（VUS）/风险因素。这表明在描述的神经性疾病的发展中，还有另一个遗传和/或环境因素起作用。
我们将此描述为 SCN9A 疼痛三角现象。治疗应侧重于疼痛管理、遗传咨询、通过治疗症状以及在有指征时开始康复计划来改善/维持生活质量。
