Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

Objective In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1 . This study aimed to summarize the genotype–phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor. Methods A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members. Results A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2–5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1 V48A fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder. Conclusions Our study expanded the understanding of the genotype–phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.

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H46R SOD1 mutation is consistently associated with a relatively benign form of amyotrophic lateral sclerosis with slow progression

Zou

Liu

2016

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Over 60% of patients die from respiratory failure within three years of presentation. We report two ALS patients carrying the p.H46R missense mutation in the SOD1 gene presented with a characteristic clinical phenotype of very slow progression. We also reviewed the 13 pedigrees harbouring the p.H46R mutation reported previously. SOD1 p.H46R mutation is consistently associated with a specific phenotype, i.e. lower limb onset with rare bulbar involvement, and a slow progression with longer survival. It is important to recognize the typical clinical picture of the SOD1 p.H46R mutation, and SOD1 sequencing may be necessary to give the patient correct diagnosis and prognosis.

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Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

Cited by 5 publications

References 20 publications

Hereditary motor neuron disease in a large Norwegian family with a “H46R” substitution in the superoxide dismutase 1 gene

Hereditary motor neuron disease in a large Norwegian family with a “H46R” substitution in the superoxide dismutase 1 gene

Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants

H46R SOD1 mutation is consistently associated with a relatively benign form of amyotrophic lateral sclerosis with slow progression

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