The modifiers of amyotrophic lateral sclerosis survival and clinical trial design

Amyotrophic lateral sclerosis (ALS) patients with different median survival also show a different progression speed. Genetic studies identified several genes associated with an increased risk and/or shorter survival of ALS. In the present review, we discuss some issues critical for the definition of survival and identification of prognostic factors of ALS. More studies are needed to exclude confounds and find the true intrinsic risk factors affecting the disease onset and/or the prognosis of this disease. We propose that some mutated genes may act more as survival modifiers than as risk factors. Recruiting a homogeneous group of patients based on their genetic background is another approach that should be considered when drafting the inclusion criteria during the trial design. This approach may facilitate the development of therapies for ALS. Abbreviations: ALS: Amyotrophic lateral sclerosis; NIPPV: Noninvasive Positve Pressure Ventilation; C90rf72: Chromosome 9 open reading frame72; TARDBP: TAR DNA-binding protein 43 gene; FUS: Fused in Sarcoma gene; SOD1: Superoxide dismutase 1; KIFAP3: Kinesin-associated protein 3; CX3CR1: C-X3-C Motif Chemokine Receptor 1; UNC13A: Unc-13 homolog A; CAMTA1: calmodulin binding transcription activator 1; SMN1: Survival Motor Neuron 1; ATAXN2: gene encoding protein Ataxin-2; ALSFRS-R: ALS Functional Rating Scale-Revised; PEG: percutaneous endoscopic gastrostomy; SNV: single nucleotide variation