We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10–20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Background Geographical differences in amyotrophic lateral sclerosis (ALS) incidence have been reported in the literature, but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled-analysis of European population-based ALS registries. Methods All new incident ALS cases in subjects 18 years old and older were identified prospectively in six population-based registries in three European countries (Ireland, United Kingdom, Italy) in the two year period 1998-1999 with a reference population of almost 24 million. Results Based on 1,028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100,000 person-years; 95% CI 2.0-2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100,000 person-years; 95% CI = 2.8 to 3.3) than among women (2.4 per 100,000 person-years; 95% CI=2.2 to 2.6). Spinal onset ALS was more common among men compared to women, particularly in the 70-80 year age group. Disease occurrence decreases rapidly after 80 years of age. Conclusions ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among males and the age-related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of aging.

We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.