Stratifying Sporadic Amyotrophic Lateral Sclerosis Patients by Metabotype — First Steps Towards Developing Personalized Precision Medicine for Effective New Therapies

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Amyotrophic lateral sclerosis (ALS) is a dreadful motor neuron disease characterized by progressive death of upper and lower motor neurons and breathing failure within 3-5 years. There are two recognized forms of ALS: familial ALS (mostly arising from SOD1 mutations) with ≈10% overall prevalence, and sporadic ALS (sALS) which comprises ≈90% of cases. There is no recognized molecular understanding of ALS and biomarkers for sALS are sorely lacking. We hypothesized that sALS is a heterogenous disease that can be stratified into multiple types that can be treated with optimal pharmacotherapies. To test this, we performed untargeted metabolite profiling to assess potential differences in fibroblast cell lines grown from sALS vs. control subjects.  Results demonstrate at least three distinct sALS metabotypes. Our findings provide the first evidence for sALS as a group of distinct diseases that can be distinguished metabotypically and provide a potential mechanistic basis for the development of personalized medicine.