METHODS: The clinical features of patients with FEPS3 were summarized in a large autosomal dominant family. Sural nerve biopsies were conducted in two patients. Whole exome sequencing (WES) was performed in the index patient. Sanger sequencing was used to analyze family co-segregation.
RESULTS: Fourteen members exhibited typical and uniform clinical phenotypes characterized by length-dependent and age-dependent severe episodic pain affecting the distal extremities, which can be relieved with anti-inflammatory medicine. The WES revealed a heterozygous mutation c.665G > A (p.R222H) in the SCN11A gene, which was co-segregated with the clinical phenotype in this family. A sural biopsy in patient V:1, who was experiencing episodic pain at 16 years old, showed normal structure, while the sural nerve in patient IV:1, whose pain attack had completely diminished at 42 years old, displayed a decrease of the density of unmyelinated axons with the axonal degeneration.
CONCLUSIONS: The clinical phenotype of FEPS3 showed distinctive characteristics that likely arise from dysfunctional nociceptive neurons that lack detectable pathological alterations in the nerve fibers. Nevertheless, long-term dysfunction of the Nav1.9 channel may cause degeneration of the unmyelinated fibers in FEPS3 patient with pain remission.
方法:在一个常染色体显性遗传家族中总结了FEPS3患者的临床特征。对两名患者进行了腓肠神经活检。在索引患者中进行全外显子组测序(WES)。Sanger测序用于分析家庭共分离。
结果:14名成员表现出典型和统一的临床表型,其特征是影响四肢远端的长度依赖性和年龄依赖性严重的阵发性疼痛,可以用消炎药缓解。WES显示杂合突变c.665G>A(p。R222H)在SCN11A基因中,与该家族的临床表型共分离。患者V:1的腓肠活检,在16岁时经历了偶发性疼痛,显示正常结构,而患者IV:1的腓肠神经,其疼痛发作在42岁时完全减弱,显示轴突变性的无髓鞘轴突密度降低。
结论:FEPS3的临床表型显示出独特的特征,这些特征可能是由神经纤维中缺乏可检测的病理改变的功能失调的伤害性神经元引起的。然而,Nav1.9通道的长期功能障碍可能导致疼痛缓解的FEPS3患者的无髓纤维变性。