Yilei Zheng1, Pengcheng Huang1, Shumeng Li1, Kaiyan Jiang1, Binbin Zhou1, Xin Fang1, Meihong Zhou1, Daojun Hong1,2, Min Zhu3,4. 1. Department of Neurology, The First Affiliated Hospital of Nanchang University, Yong Wai Zheng Street 17#, Nanchang, China. 2. Department of Medical Genetics, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China. 3. Department of Neurology, The First Affiliated Hospital of Nanchang University, Yong Wai Zheng Street 17#, Nanchang, China. zhumin1@126.com. 4. Department of Medical Genetics, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China. zhumin1@126.com.
Abstract
BACKGROUND: Familial episodic pain syndrome type 3 (FEPS3) is an inherited disorder characterized by the early-childhood onset of severe episodic pain that primarily affects the distal extremities. As skin biopsy has revealed a reduction in intraepidermal nerve fiber density and degeneration of the unmyelinated axons, it remains unclear whether FEPS3 patients have pathological changes in the peripheral nerve. 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.
BACKGROUND: Familial episodic pain syndrome type 3 (FEPS3) is an inherited disorder characterized by the early-childhood onset of severe episodic pain that primarily affects the distal extremities. As skin biopsy has revealed a reduction in intraepidermal nerve fiber density and degeneration of the unmyelinated axons, it remains unclear whether FEPS3 patients have pathological changes in the peripheral nerve. 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.
Authors: Nyamkhishig Sambuughin; Mingqiang Ren; John F Capacchione; Ognoon Mungunsukh; Kevin Chuang; Iren Horkayne-Szakaly; Francis G O'Connor; Patricia A Deuster Journal: Case Rep Genet Date: 2018-11-07