Abstract
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, characterized by a great variety of both clinical presentations and genetic causes. Previous studies had identified two different missense mutations in SOD1 (p.R116C and p.R116G) causing familial ALS. In this study, we report a novel heterozygous missense mutation in the SOD1 gene (p.R116S) in a family with inherited ALS manifested as fast-deteriorating pure lower motor neuron symptoms. The patient displayed similar clinical picture and prognostic value to previous reported cases with different R116 substitution mutations. Modeling of all R116 substitutions in the resolved SOD1 protein structure revealed a shared mechanism with destroyed hydrogen bonds between R116 and other two residues, which might lead to protein unfolding and oligomer formation, ultimately conferring neurotoxicity.
Highlights
Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disorder and the most common adult-onset motor neuron disease (MND), which causes muscle weakness and atrophy
Sensory and motor nerve conduction velocities were within normal ranges. 18F-FDG PET did not detect any hypometabolism at the motor and premotor cortices or frontal–temporal regions
We found a Chinese fALS family carrying a novel R116S change in SOD1
Summary
Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disorder and the most common adult-onset motor neuron disease (MND), which causes muscle weakness and atrophy. It is progressively fatal, and the majority of patients die within 3 years after onset of symptom (Turner et al, 2013). The majority of patients die within 3 years after onset of symptom (Turner et al, 2013) It is considered highly heterogeneous in nature, which displays a great variety of both clinical presentations and underlying pathogenic mechanisms. More than 180 distinct SOD1 mutations have been identified as genetic causes for ALS (Mathis et al, 2019) (https://alsod.ac.uk/). Other possible mechanisms include increased protein instability, protein aggregation, and probabilities of fibrillization (Wright et al, 2019)
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