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Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1\u20133.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1\u20132 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting &amp;gt;4 years and \u223c9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention.<\/jats:p>","DOI":"10.1093\/brain\/awac185","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T11:55:50Z","timestamp":1653047750000},"page":"3500-3508","source":"Crossref","is-referenced-by-count":63,"title":["Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-5135","authenticated-orcid":false,"given":"Michael","family":"Benatar","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Miami , Miami, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6519-7225","authenticated-orcid":false,"given":"Volkan","family":"Granit","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Miami , Miami, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0094-5429","authenticated-orcid":false,"given":"Peter M","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Neurosciences, Ume\u00e5 University , Ume\u00e5 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Grignon","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Miami , Miami, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0103-8580","authenticated-orcid":false,"given":"Caroline","family":"McHutchison","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Edinburgh , Edinburgh , UK"},{"name":"Euan MacDonald Center for MND Research, University of Edinburgh , Edinburgh , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[{"name":"Department of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Wuu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Miami , Miami, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"2022102119175673700_awac185-B1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/21678421.2016.1267768","article-title":"Amyotrophic lateral sclerosis\u2014Frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria","volume":"18","author":"Strong","year":"2017","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2022102119175673700_awac185-B2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/ana.25276","article-title":"Neurofilament light: A candidate biomarker of pre-symptomatic ALS and phenoconversion","volume":"84","author":"Benatar","year":"2018","journal-title":"Ann Neurol"},{"key":"2022102119175673700_awac185-B3","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1080\/21678421.2019.1646769","article-title":"Neurofilaments in pre-symptomatic ALS and the impact of 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