Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting from loss of motor neurons in the motor cortex, brainstem and spinal cord. Despite a characterised rapidly progressive clinical course with upper and lower motor neuron signs and symptoms in classical ALS, unusual presentations can restrict to a specific spinal or bulbar segment for several years. Flail leg syndrome (FLS) is an atypical variant of ALS characterised by progressive distal onset weakness and atrophy of lower limbs with reduced or absent reflexes. Patients should not present with significant weakness or wasting in upper limbs and bulbar within 12 months after onset.1 Mutations in more than 20 genes have been linked to ALS.2 However, genetic cause familial FLS has never been reported. We have identified a missense mutation in PFN1 gene in a FLS family by whole-exome sequencing (WES). The proband (III-7) of the FLS pedigree was chosen for WES using the Illumina Hiseq sequencing platform and screening for presence of the GGGGCC expansions in the C9orf72 gene. All three exons of the PFN1 (NM_005022) gene were amplified by PCR and directly sequenced (online supplementary file 1) in additional 15 patients with familial ALS (FALS) indexes and 275 patients with sporadic ALS (SALS) (173 male, 117 female, mean age of onset±SD 55.3±11.6 years) referred to Fujian Medical Union Hospital and Henan Provincial People's Hospital between January 2017 and December 2018. A diagnosis of definite, probable or laboratory supported probable ALS was established using the revised El Escorial criteria. Blood samples were collected after the individuals had signed an informed consent document. ### Supplementary data [jnnp-2019-321366supp001.pdf] The proband (III-7) …

中文翻译：

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由PFN1突变引起的家族fl腿ALS。

肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，由运动皮层，脑干和脊髓中的运动神经元丢失引起。尽管在典型的ALS中有特征性的快速进展的临床过程，包括上，下运动神经元体征和症状，但异常表现可能会限制到特定的脊柱或延髓段数年。il腿综合征（FLS）是ALS的一种非典型变体，其特征是进行性远端发作无力和下肢萎缩，反射减少或缺失。发病后12个月内，患者不应出现明显的无力或上肢和延髓消瘦。1ALS中有20多个基因的突变与之相关。2然而，遗传原因家族性FLS尚未见报道。我们已通过全外显子组测序（WES）在FLS家族中鉴定了PFN1基因的错义突变。使用Illumina Hiseq测序平台选择FLS谱系的先证者（III-7）进行WES，并筛选C9orf72基因中GGGGCC扩增的存在。通过PCR扩增了PFN1（NM_005022）基因的所有三个外显子，并直接对其测序（在线补充文件1），分别用于另外15例具有家族性ALS（FALS）指数的患者和275例散发性ALS（SALS）的患者（男性173例，女性117例）。平均发病年龄为±SD 55.3±11.6岁）于2017年1月至2018年12月间转诊至福建省医协医院和河南省人民医院。采用修订后的El Escorial标准对明确，可能或实验室支持的ALS进行了诊断。在个人签署知情同意文件后收集血液样本。###补充数据[jnnp-2019-321366supp001.pdf]先证者（III-7）…