Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia

Jennifer C Schymick,Bryan J Traynor

doi:10.1186/alzrt133

Jennifer C Schymick, Bryan J Traynor

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading to death from respiratory failure
De ning the overlap between ALS and frontotemporal lobar degeneration (FTLD): a necessary rst step in unraveling the genetics of both conditions Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, uniformly fatal, neurodegenerative disease. e annual incidence of ALS is reported to be 1.5 to 2.7 per 100,000 in Western countries [1,2]. ere is currently no cure for ALS, and approximately 6,500 individuals die from the disease each year in the United States, making it the most common adult-onset form of motor neuron disease, and the third most common form of neurodegeneration [3]
The traditional view has been that cognition remains intact in the majority of ALS patients except for a small proportion who developed florid dementia. is view has only relatively recently been challenged and the current consensus is that ALS and frontotemporal lobar degeneration (FTLD) form part of a continuum of neurological disease: patients with familial and sporadic ALS exhibit signs of frontal lobe degeneration, including language dysfunction, changes in personality and executive function with relative sparing of memory [6,7,8,9]

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading to death from respiratory failure. In 2009, aggregations of the fused in sarcoma protein (FUS) were demonstrated in a subset of ALS and FTLD patients with TDP-43-negative neuronal inclusions (representing approximately 5% of cases) [12]. These include the identifi cation of mutations in the SOD1 gene in 1993, which account for approximately 12% of familial ALS cases in population-based studies [14,15].

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