SOD1 Mutation Spectrum and Natural History of ALS Patients in a 15-Year Cohort in Southeastern China

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.

Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis

“…Among the ALS patients, nearly 90%–95% belong to sporadic ALS (sALS) most with unknown etiology 2 , while approximately 5%–10% is familial ALS (fALS) 3 associated with known gene mutations. Cu/Zn superoxide dismutase 1 (SOD1) is the leading cause for ALS in China, and account for 25.3% of Chinese fALS cases 4 , 5 . Although a number of candidates have been shown to delay disease progression in preclinical trials, riluzole and edaravone are only two drugs approved by US Food and Drug Administration for ALS treatment.…”

Cellular analysis of SOD1 protein-aggregation propensity and toxicity: a case of ALS with slow progression harboring homozygous SOD1-D92G mutation

“…It has been demonstrated that the clinical phenotype and prognosis of FALS harboring mutant SOD1 were closely related to the mutated site of the gene 20 . Most SOD1 mutations are heterozygous, but there have been reports that homozygous SOD1 mutations showed juvenile-onset and rapid progression, such as a French case of FALS harboring SOD1-L84F mutation 21 , a juvenile-onset Pakistani case of FALS harboring SOD1-N86S 22 , and a Japanese case of FALS carrying SOD1-L126S 23 .…”

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

“…Although the potential mechanisms of the toxicity of mutated SOD1 in motor neurons are still not fully understood, the SOD1 gene itself marked the beginning of a new era of research on ALS. This is due to the fact that it was used to create the first SOD1-G93A transgenic mice model, which is still used in clinical trials [ 79 , 87 , 88 , 89 ].…”