Amyotrophic lateral sclerosis (ALS) is usually considered to begin when the first symptoms develop; an example is the onset of distal weakness and atrophy in an upper limb, often with fasciculation in a more widespread distribution.1 This definition of disease onset follows an understanding of the pattern of onset in other acquired neurological diseases and is rooted in the history of neurology. However, neurodegenerative disorders as a group seem characteristically to begin gradually and subclinically without a clearly defined moment of onset. Obvious examples are Alzheimer-type dementia, Huntington disease, Parkinson disease, and many peripheral neuropathies, whether genetic or acquired, such as diabetic neuropathy. Even monogenetic disorders such as Huntington disease or the Charcot-Marie-Tooth syndromes exhibit gradual and indefinable onset patterns. Because the onset of ALS, as distinct from its diagnostic clinical features, cannot be defined, the question arises whether there is a long preclinical phase of accumulation of pathology or toxic metabolites in the cytosol. This concept is presently undefined and virtually unstudied, at least in human ALS,2 although it may be possible to address it in transgenic rodent models. In sporadic ALS, there is accumulation of cytosolic TDP43 (transactive response DNA binding protein 43 kDa), a protein derived from RNA metabolism; this protein is also found in other recognized forms of mutation-related ALS, although not in superoxide dismutase–related ALS. The variation in age at onset and clinical phenotype of ALS suggests a possible analogy with the inverse relationship between birth weight and the risk of cerebrovascular disease and type 2 diabetes mellitus, which is sometimes termed the metabolic syndrome X.3
Swash M. Diet and Risk of Amyotrophic Lateral Sclerosis: Is Lifestyle Important? JAMA Neurol. 2014;71(9):1085–1086. doi:10.1001/jamaneurol.2014.1894
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