Familial versus sporadic amyotrophic lateral sclerosis--a false dichotomy?

Historically, there has been a surprising level of uncertainty about whether amyotrophic lateral sclerosis (ALS), in its typical form, has a genetic basis. No less a figure than Jean-Martin Charcot (1825–93), at least initially, held the view that the disease he first named was never familial (Charcot and Joffroy, 1869). Some years earlier, in fact, familial cases of progressive muscular atrophy, a disorder that is now generally considered to be part of the same clinicopathological spectrum as ALS, were clearly described (Aran, 1850). Twenty years after Charcot, William Osler (1849–1919) reported typical ALS with autosomal dominant inheritance in a family from Vermont, which in the modern era, has been shown to have a mutation in SOD1 (Osler, 1880; Rouleau and Meijer, 2007). The view that the genetic contribution to ALS as a whole is relatively insignificant prevailed in the first half of the 20th century, but the development of modern molecular biology was a major impetus to the collection of familial kindreds with ALS in the 1980s and 1990s, leading ultimately to the identification in 1993 of mutations in SOD1 using classical linkage analysis (Rosen et al ., 1993). In recent years, the genetic landscape of ALS has been transformed. TDP43 has emerged as a signature protein in ALS and frontotemporal dementia (FTD) pathology (Neumann et al ., 2006) but also as a gene in which mutations have been found in 3–4% of familial ALS patients (Sreedharan et al ., 2008). In the last 2 years a further five genes have been associated with classical ALS ( FUS , OPTN , ANG , VCP and most recently UBQL2 : Greenway et al ., 2006; Vance et al ., …