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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.
The proband (III-7) …
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