This study constitutes the first direct comparison of mutational and clinical characteristics of Asian and Caucasian ALS patients with SOD1 mutations based on two large hospital-based registry cohorts. Overall, 150 patients carrying 69 distinct mutations, of which 7 mutations were found in both populations, did not show survival difference between the two populations.
Our findings demonstrate a significant lower age of onset in the Chinese SOD1-mutant patients compared with their German counterparts (43.9 vs 49.9 years). The Chinese age of onset was therefore also younger compared to SOD1-mutant patients from Canada (48.9 years)[15] and the United States (46.9–49.7 years) [16, 17]. A previous bi-ethnic comparison showed that an earlier age of onset in Chinese compared to German patients was also present and even more pronounced in sporadic ALS (51.0 vs 61.0, p < 0.0001)[10]. In the present study, both Chinese and German SOD1 patients featured a much higher proportion of young-onset cases (62.5% and 30.7%, respectively) compared to 10% in the overall ALS population[14]. Moreover, young-onset ALS was significantly more frequent in Chinese compared to German SOD1 patients (p < 0.001). An earlier age of onset is hypothesized to reflect a higher burden of genetic and environmental risk factors[18]. Our results of a generally young age of onset of SOD1-mutant patients are in line with the multistep model of ALS[19], which proposes that the number of steps in ALS was 2 in patients with SOD1 mutations, 3 in patients carrying C9orf72 expansions, and 6 in patients without known mutations. The age of onset in the whole ALS population varies between different ethnicities : In Asia (India: 46.2 years, China:52.4 years[20]), Africa (approximately 50 years[21]), and South America (Rio de Janeiro/Brazil: 53.6 years[22], Cuba and Uruguay: 54.4 and 59.5 years[23]) age of onset is younger compared to Europe (Germany: 61.0 years[10]; Ireland: 63.0 years[23]) and North America (US: 61.5 years[24]). A systematic review[25] of ALS cohorts showed considerable differences regarding the mean ages of onset among patients carrying distinct mutations: The youngest ages of onset were found in patients with VCP (11.6 years), hnRNPA1 (33 years), ALS2 (37.4 years), and FUS (41.8 years) mutations, the oldest in Fig. 4 (61.3 years), TUBA4A (59.6 years), and TBK1 (59.5 years). Therefore, our results confirm SOD1-specific features (SOD1-mutant patients featuring a younger age of onset in both cohorts compared to the overall ALS population) while at the same time also displaying ethnicity-specific features known from sporadic ALS (younger age of onset in Chinese compared to German patients).
A striking 95% of SOD1 cases in the present study displayed spinal onset which is significantly higher compared to the prevalence of spinal onset in the whole ALS population, which is about 70%-80%[25] and consistent across both countries. In the whole ALS population, a lower proportion (16%) of bulbar onset is present in patients with young onset (< 41 years) compared to older onset (> 70 years, 43%)[26]. Thus, the high share of young onset ALS in our cohort could partly explain the high proportion of spinal onset. Consistent with previous findings of spinal onset constituting a positive prognostic factor in the whole ALS population, we found a significant difference regarding survival between spinal-onset and bulbar-onset patients carrying SOD1 mutations (p = 0.001).
A notable proportion of 20% of cases in our cohort featured pure LMN signs. Several ALS-associated genes have been described to be associated with a proportion of > 20% of patients with pure or predominant LMN signs (hnRNPA1, SETX, SOD1, and TBK1)[25]. On the other hand, both juvenile ALS, usually caused by mutations of FUS, ALS2, SETX (ALS4), and ALS5 genes, and young-onset ALS have been found to feature predominantly UMN rather than LMN dysfunction[14]. For SOD1, specific mutations have been reported to result in severe LMN phenotypes. The mutation A4V (p.Ala5Val according to former nomenclature), accounting for up to 50% of SOD1-related fALS cases in the United States, causes a rapidly progressive form of pure LMN presentation with a median survival of 1.2 years[17]. This is also the case in the Chinese patient carrying an A4V mutation in our study. A p.D12Y mutation also caused an LMN-predominant presentation[27]. Interestingly, in SOD1-mutant patients, pathological signatures of SOD1 protein inclusion staining have been mainly found in LMN rather than UMN[28].
The finding of significantly lower BMIs of Chinese SOD1-mutant patients compared to their German counterparts (mean 22.78 vs 26.00, p < 0.001) is consistent with previous findings in sporadic ALS (mean 23.0 vs 24.5, p < 0.0001)[10]. BMI is an indicator of nutritional status, and malnutrition is a prognostic factor of survival in ALS patients[29]. In the whole Caucasian ALS population, patients with below-normal BMI have a shorter median survival compared to those with normal BMI[24]. Metabolic changes have increasingly been recognized in ALS, and hypermetabolism has been identified as the potential main reason for loss of body weight[30]. Experimentally, mutant SOD1 protein can cause mitochondrial dysfunction and metabolic imbalance[31].
We have confirmed several previous known prognostic factors in this SOD1 cohort, i.e., site of onset (spinal vs bulbar) and disease progression rate (especially late progression rate). Of note, some known prognostic factors in the whole ALS population, including BMI and age of onset, were not associated with survival, indicating that the spectrum of disease-modifying factors may be different from sporadic ALS. Another possibility is that there is not a simple linear relationship between BMI, age of onset, and survival in patients carrying SOD1 mutations. Interestingly, in SOD1-G93A murine models of different genetic backgrounds (C57BL/6J and 129S2/Sv), animals carrying the same mutation and expressing the same amount of mutant SOD1-G93A protein have been found to feature significantly different disease progression rates and survival[32], highlighting a set of potential key genes and molecular pathways acting as disease modifiers and possibly contributing to the heterogeneity of ALS phenotypes[33]. It is therefore reasonable to assume that both known specific mutations and unknown susceptibility genes might interact with environmental factors to modulate disease phenotypes and prognosis.
Sex has been reported as an independent factor affecting ALS vulnerability and phenotypes. In our cohorts, female patients showed significantly longer survival compared to male patients, especially in the Chinese population. In a Dutch case-control study, a longer exposition to estrogen was significantly correlated with a longer survival in female ALS patients[34]. A negative association between incidence of ALS and a dose-dependent use of hormonal contraception also highlighted a possible protective role of estrogen and progestogen[35]. A very recent study from an Italian register cohort suggested an influence of sex, together with age and gene variants, on ALS phenotypes[36]. Evidence from SOD1 transgenic mice [37, 38] and rat models [39][39][39][39][39] also demonstrated that female animals displayed extended lifespan and delayed onset compared to their male counterparts.
Limitations
Our study is not without limitations. First, our hospital-based cohorts may imply a selection bias compared to population-based studies, i.e., patients of hospital-based registries are known to be younger, predominantly male, and feature a lower share of bulbar onsets[10]. Second, cognitive status was not included in this study, despite that few cases carrying SOD1 mutations have been reported to feature cognitive dysfunction[25]. Third, potential modifier genes were not analyzed. However, it is not common in SOD1-mutant patients to carry another causative gene mutation[40, 41]. On the other hand, we regard the existence of large synchronized databases and that patients were derived from specialized ALS centers in both countries as main strengths of our study.