Abstract
Background: Mutations in superoxide dismutase 1 gene (SOD1) are the most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) in the Chinese population. A detailed natural history of SOD1-mutated ALS patients will provide key information for ongoing genetic clinical trials. Methods: We screened for SOD1 mutations using whole exome sequencing (WES) in Chinese ALS cases from 2017 to 2021. Functional studies were then performed to confirm the pathogenicity of novel variants. In addition, we enrolled previously reported SOD1 mutations in our centers from 2007 to 2017. The SOD1 mutation spectrum, age at onset (AAO), diagnostic delay, and survival duration were analyzed. Results: We found two novel SOD1 variants (p.G17H and p.E134*) that exerted both gain-of-function and loss-of-function effects in vitro. Combined with our previous SOD1-mutated patients, 32 probands with 21 SOD1 mutations were included with the four most frequently occurring mutations of p.V48A, p.H47R, p.C112Y, and p.G148D. SOD1 mutations account for 58.9% of familial ALS (FALS) cases. The mean (SD) AAO was 46 ± 11.4 years with a significant difference between patients carrying mutations in exon 1 [n = 5, 34.6 (12.4) years] and exon 2 [n = 8, 51.4 (8.2) years] (p = 0.038). The mean of the diagnostic delay of FALS patients is significantly earlier than the sporadic ALS (SALS) patients [9.5 (4.8) vs. 20.3 (9.3) years, p = 0.0026]. In addition, male patients survived longer than female patients (40 vs. 16 months, p = 0.05). Conclusion: Our results expanded the spectrum of SOD1 mutations, highlighted the mutation distribution, and summarized the natural history of SOD1-mutated patients in southeastern China. Male patients were found to have better survival, and FALS patients received an earlier diagnosis. Our findings assist in providing a detailed clinical picture, which is important for ongoing genetic clinical trials.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the involvement of both upper and lower motor neurons in the spinal cord, brainstem, and motor cortex with or without cognitive dysfunction
The nonsense variant was not regarded as very strong evidence of pathogenicity because loss of function is not the primary mechanism in Superoxide dismutase 1 gene (SOD1)-related ALS
We previously reported 20 probands with SOD1 mutations in 36 unrelated FALS patients (Niu et al, 2011; Liu et al, 2014; Lin et al, 2019; Liu et al, 2019)
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the involvement of both upper and lower motor neurons in the spinal cord, brainstem, and motor cortex with or without cognitive dysfunction. The advancement of genetic technologies, such as whole exome sequencing (WES), has facilitated the identification of genes associated with ALS. Superoxide dismutase 1 gene (SOD1) was the first ALS-associated gene dating back to 1993 (Rosen et al, 1993) and led to engineering of the first transgenic model of SOD1-G93A mice (Gurney et al, 1994). It ushered in a new era of ALS research and set the stage for future genetic breakthroughs. Mutations in superoxide dismutase 1 gene (SOD1) are the most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) in the Chinese population. A detailed natural history of SOD1-mutated ALS patients will provide key information for ongoing genetic clinical trials
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