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Review
. 2012 Dec;25(6):689-700.
doi: 10.1097/WCO.0b013e32835a3efb.

How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?

Marka van Blitterswijk  1 , Mariely DeJesus-Hernandez, Rosa Rademakers
Affiliations
Review

How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?

Marka van Blitterswijk et al. Curr Opin Neurol. 2012 Dec.

Abstract

Purpose of review: The aim of this review is to describe disease mechanisms by which chromosome 9 open reading frame 72 (C9ORF72) repeat expansions could lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and to discuss these diseases in relation to other noncoding repeat expansion disorders.

Recent findings: ALS and FTD are complex neurodegenerative disorders with a considerable clinical and pathological overlap, and this overlap is further substantiated by the recent discovery of C9ORF72 repeat expansions. These repeat expansions are currently the most important genetic cause of familial ALS and FTD, accounting for approximately 34.2 and 25.9% of the cases. Clinical phenotypes associated with these repeat expansions are highly variable, and combinations with mutations in other ALS-associated and/or FTD-associated genes may contribute to this pleiotropy. It is challenging, however, to diagnose patients with C9ORF72 expansions, not only because of large repeat sizes, but also due to somatic heterogeneity. Most other noncoding repeat expansion disorders share an RNA gain-of-function disease mechanism, a mechanism that could underlie the development of ALS and/or FTD as well.

Summary: The discovery of C9ORF72 repeat expansions provides novel insights into the pathogenesis of ALS and FTD and highlights the importance of noncoding repeat expansions and RNA toxicity in neurodegenerative diseases.

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Conflict of interest statement

Disclosure statement: No actual or potential conflicts of interest have been reported.

Figures

Figure 1
Figure 1
C9ORF72 mutation frequencies worldwide. Percentages reported in (A) familial ALS patients, (B) familial FTD patients, (C) sporadic ALS patients, and (D) sporadic FTD patients. Cohorts of less than ten subjects were not included. Only reported subjects with more than 29 repeat expansions were considered to have a C9ORF72 mutation. In general, error bars represent 95% confidence intervals, as calculated with the Wald method. If multiple studies were conducted for one country, then error bars represent standard errors. For these countries the average of all conducted studies was calculated, applying equal weight to all of them. The same method was used to calculate an average for all reported countries in Europe, countries in North America, other countries (Other), and an overall average (World). Graphpad Prism version 5.04 (http://www.graphpad.com) was used to perform these analyses. When mutation frequencies of other genes were reported, they were incorporated, to give a better impression of the actual mutation percentage in the general ALS/FTD population. If authors stated that the same (sub)group was used in multiple studies, then this (sub)group was only included in one of the studies. Majounie et al. [47**], Chio et al. [49*], and Renton et al. [19**], however, did include the same subset of 29 familial ALS samples without specification, and therefore, this relatively small amount of samples could not be excluded. More details about the studies included in our comparison can be found in Supplementary Table 1.
Figure 1
Figure 1
C9ORF72 mutation frequencies worldwide. Percentages reported in (A) familial ALS patients, (B) familial FTD patients, (C) sporadic ALS patients, and (D) sporadic FTD patients. Cohorts of less than ten subjects were not included. Only reported subjects with more than 29 repeat expansions were considered to have a C9ORF72 mutation. In general, error bars represent 95% confidence intervals, as calculated with the Wald method. If multiple studies were conducted for one country, then error bars represent standard errors. For these countries the average of all conducted studies was calculated, applying equal weight to all of them. The same method was used to calculate an average for all reported countries in Europe, countries in North America, other countries (Other), and an overall average (World). Graphpad Prism version 5.04 (http://www.graphpad.com) was used to perform these analyses. When mutation frequencies of other genes were reported, they were incorporated, to give a better impression of the actual mutation percentage in the general ALS/FTD population. If authors stated that the same (sub)group was used in multiple studies, then this (sub)group was only included in one of the studies. Majounie et al. [47**], Chio et al. [49*], and Renton et al. [19**], however, did include the same subset of 29 familial ALS samples without specification, and therefore, this relatively small amount of samples could not be excluded. More details about the studies included in our comparison can be found in Supplementary Table 1.
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References

    1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377:942–955. This review summerizes the etiology of amyotrophic lateral sclerosis, its clinical characteristics, its diagnosis, its prognosis, and its management.

    1. Graff-Radford NR, Woodruff BK. Frontotemporal dementia. Semin Neurol. 2007;27:48–57. - PubMed
    1. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456–2477. - PMC - PubMed
    1. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76:1006–1014. - PMC - PubMed
    1. The Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1994;57:416–418. - PMC - PubMed

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