A Natural History Comparison of SOD1-mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

Tang, Lu; Dorst, Johannes; Chen, Lu; Liu, Xiaolu; Ma, Yan; Günther, Klaus Peter; Michels, Sebastian; Müller, Kathrin; Freischmidt, Axel; Weishaupt, Jochen H.; Ludolph, Albert C.

doi:10.21203/rs.3.rs-603164/v1

Cited by 2 publications

(5 citation statements)

References 30 publications

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“…Previous studies have suggested higher penetrance of SOD1 mutations in men [6,9]. However, in our cohort we found no evidence of an effect of sex on penetrance, at least in the most frequent mutations.…”

Section: Discussioncontrasting

confidence: 89%

“…Interestingly, the age of onset and disease progression were found to vary in patients carrying the same SOD1 mutation but different haplotypes [30], and co‐mutations have been described in patients harbouring SOD1 mutations [31], suggesting that polygenic, epigenetic and environmental factors may also have a role in the disease onset and progression of SOD1 patients. Previous studies have suggested higher penetrance of SOD1 mutations in men [6, 9]. However, in our cohort we found no evidence of an effect of sex on penetrance, at least in the most frequent mutations.…”

Section: Discussioncontrasting

confidence: 85%

“…This effect on DPR and survival was not found when the whole cohort was assessed. Interestingly, another work found worse survival in male SOD1 patients [9], again suggesting a differential effect of sex on the prognosis according to the underlying mutation. Furthermore, older patients showed faster DPR and shorter survival, independent of the underlying mutation, as has also been found in sALS.…”

Section: Discussionmentioning

confidence: 99%

“…Each mutation is associated with different clinical characteristics regarding penetrance, age of onset, progression rate and survival [6,7]. However, despite some attempts [8,9], little is known about the effect of other variables such as age and sex on the prognosis of SOD1 ALS patients.…”

Section: Introductionmentioning

confidence: 99%

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Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Vázquez-Costa

Borrego-Hernández

Paradas

et al. 2023

Euro J of Neurology

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Background and purpose The aim of this study was to describe the frequency and distribution of SOD1 mutations in Spain, and to explore factors contributing to their phenotype and prognosis. Methods Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. Results In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of SOD1, including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months). Conclusions These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Vázquez-Costa

Borrego-Hernández

Paradas

et al. 2023

Euro J of Neurology

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“…C9ORF72 gene‐associated ALS is generally characterized by a later onset and faster disease progression [32]. Amongst SOD1 gene patients, a greater heterogeneity has been reported, which is strongly linked to the specific mutation [33]. Specifically, patients with A4V mutations show fast disease progression [34], whilst the D91A and L118V mutations are associated with a comparatively benign disease course and longer survival [35].…”

Section: Discussionmentioning

confidence: 99%

Mutation‐specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis

Xia

Witzel

et al. 2022

Euro J of Neurology

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Background and purpose Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage. Methods A total of 60 presymptomatic ALS mutation carriers and 70 age‐ and gender‐matched controls (non‐mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high‐density lipoprotein (HDL) and low‐density lipoprotein. Results All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 (C9ORF72) gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6–26.1 kg/m2 vs. 24.9, IQR 22.7–30.5 kg/m2; p = 0.007), lower systolic blood pressure (120, IQR 110–130 mmHg vs. 128, IQR 120–140 mmHg; p = 0.02), lower fasting serum glucose (89.0, IQR 85.0–97.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl; p = 0.005) and higher HDL (1.6, IQR 1.3–1.8 mmol/l vs. 1.2, IQR 1.0–1.4 mmol/l; p = 0.04). However, presymptomatic superoxide dismutase 1 (SOD1) gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0, IQR 26.1–31.5 kg/m2 vs. 24.9, IQR 22.7–30.5 kg/m2; p = 0.02), higher fasting serum glucose (100.0, IQR 94.0–117.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl; p = 0.04) and lower HDL (1.2, IQR 1.0–1.4 mmol/l vs. 1.4, IQR 1.2–1.7 mmol/l; p = 0.01). These features were most prominent in patients carrying SOD1 gene mutations associated with slow disease progression. Conclusions This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

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A Natural History Comparison of SOD1-mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

Cited by 2 publications

References 30 publications

Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Mutation‐specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis

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