Mutations in approximately thirty genes have been uncovered as a cause of familial amyotrophic lateral sclerosis (ALS), and several others have been identified as phenotype modifiers.1 These discoveries have advanced our understanding of this rare and fatal neurodegenera-tive disease and paved the way for targeted therapeutics. In particular, these advances have redefined ALS as a multisystem disorder involving degeneration of the pyramidal motor system and the frontal cortices.Despite these advances, genetic factors account for only a portion of the clinical and pathological heterogeneity observed in ALS. Estimates of ALS heritability suggest that genetic factors can explain only half to two-thirds of the disease occurrence.2 Furthermore, penetrance of ALS-causing mutations' is incomplete and highly variable even among family members carrying an identical mutation.3 Taken together, the evidence suggests that other factors such as epigenetics and environment might be influencing ALS occurrence and clinical phenomenology. These mechanisms could even converge in a multi-step process that ultimately leads to neurodegeneration.
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