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Is ALS simply a collection of single, unique rare diseases with a discrete monogenetic cause, or is it a diagnostic continuum with a complex contribution of thousands of genetic and environmental factors? This is one of the most fundamental questions that are still unanswered in ALS
Five to 10% of patients have ‘familial’ amyotrophic lateral sclerosis (ALS), with at least one other first-degree or second-degree relative also affected with ALS. The remainder of patients is considered to have ‘sporadic’ ALS, although the exact definition of familial is unclear.1 Twin studies have shown that there is a considerable contribution of ALS genes to risk of 61%.2 The classical view is to distinguish familial ALS as Mendelian disease with mutations that always lead to disease from sporadic ALS as complex genetic disease with many small-effect genetic risk factors interacting with environmental factors.
Nevertheless, it has been well established that even a modest decrease in penetrance (ie, the chance a person gets a disease when carrying a specific genetic mutation) can very likely lead to the observation of sporadic disease.3 In that original study, for example, if one considers a mutation with 80% penetrance, with a family size …
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