To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

ImportanceClinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics.ObservationsBy restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale–Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome.Conclusions and RelevanceIt is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

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