Abstract: In his accounts “On longevity and shortness of life”, Aristotle considered how diseased states could be interchangeably associated with long and short lifespans. He believed that the presence of opposite elements and the environment were the sole determinants of this variability. Nowadays, also struck by the same phenomenon observed by the Greek philosopher, human geneticists are still trying to define the etiological basis of the phenotypic plasticity in neurodegenerative disorders. Among such diseases, amyotrophic lateral sclerosis (ALS) stands out as a highly heterogeneous condition. Patients affected by ALS commonly start manifesting symptoms such as weakness in the upper or lower limbs, difficulty in climbing stairs, fasciculations and loss of muscular mass. As the disease progresses, patients become wheelchair-bound and bulbar signs such as dysarthria and dysphagia become more pronounced. Death occurs on average after 3 years of onset, mainly due to respiratory failure (Renton et al., 2014). However, this canonical course is frequently variable, with a myriad of phenotypic alterations (Swinnen and Robberecht, 2014). Here, we describe different aspects of amyotrophic lateral sclerosis type 8 (ALS8) clinical variability, both in terms of clinical manifestations and in rate of disease progression. Then, we outline our recent work on ALS8 patients (Oliveira et al., 2020), in which we tried to address the molecular underpinnings of clinical progression variation in the patients we studied. We were able to rule out well-described genetic modifiers, such as EPHA4 and UNC13A, and potential copy number variation alterations. Interestingly, both cell death rates and energetic metabolism appeared to be different among the severe ALS8, mild ALS8 and controls, suggesting an attenuation of pathological process in the less affected patients. Whole transcriptomic analysis of induced pluripotent stem cells (iPSCs)-derived motor neurons pointed that both “mild patients” presented 43 upregulated and 66 downregulated genes, when compared to controls and the “severe” group. Interestingly, most of the identified genes were associated with protein synthesis and protein targeting to endoplasmic reticulum (ER). Expression of protein translation markers’ pMTOR, 4EBP1 and RPS6 were found to be high in the mild ALS8 individuals, when compared to both controls and the severe group. To sum up, our data point that mitigating factors are most likely preventing neurodegeneration in ALS8 through maintenance of protein synthesis. Further studies, assessing the relationship among these potential genetic modifiers and the pathophysiology in ALS8, are fundamental. They might shed light on venues for treatment of this devastating disease.