BACKGROUND Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. OBJECTIVES To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. METHODS Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. RESULTS Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. CONCLUSION This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

中文翻译：

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FIG4突变导致帕金森氏症和CMT4J与YunisVarón综合征之间的表型连续体。

背景技术4J型Charcot-Marie-Tooth病（CMT4J）起源于FIG4基因的突变并导致远端肌肉无力。FIG4的两个无效等位基因导致YunisVarón综合征，伴有严重的中枢神经系统受累，颅骨畸形，拇指和幻觉缺失以及早期死亡。目的分析FIG4相关疾病的表型谱，探讨残余FIG4蛋白的作用。方法对五名与FIG4相关疾病的新患者进行表型分析。来自患者成纤维细胞的FIG4的蛋白质印迹分析。结果下一代测序揭示了5例患者中图4中的化合物杂合变异体。所有5例患者均出现周围神经病变，各种程度的异形性以及包括帕金森病的中枢神经系统受累，其中3/5例，小脑性共济失调（1/5），下肢痉挛（1/5），癫痫症（1/5）和/或认知缺陷（2/5）。在第一个和第七个十年之间发作。在四名分析患者的成纤维细胞中没有检测到残留的FIG4蛋白。结论本研究将FIG4相关疾病的表型谱扩展为帕金森病，并证明了CMT4J和尤尼斯·瓦隆综合征之间连续体的新表型。