Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis

Byrne, Susan; Walsh, Cathal; Lynch, Catherine; Bede, Peter; Elamin, Marwa; Kenna, Kevin P.; McLaughlin, Russell L.; Hardiman, Orla

doi:10.1136/jnnp.2010.224501

Cited by 303 publications

(210 citation statements)

References 70 publications

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“…With minimal knowledge of the causes of sporadic ALS (and hence, at least until recently, no ability to identify people at risk), attention has understandably focused on the genetic etiology of fALS, which accounts for 5%-10% of all cases of ALS. 28,29 SOD1 mutations, responsible for ϳ14%-20% of fALS 28,30 (and therefore 1%-2% of all ALS cases), were the first identified. For almost 15 years, SOD1 remained virtually the only known cause of ALS.…”

Section: Environmental Risk Factorsmentioning

confidence: 99%

Presymptomatic studies in ALS

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Wuu

2012

Neurology

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It is now well-established that the disease process in many neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Huntington disease, begins many years before the appearance of typical symptoms. Whether amyotrophic lateral sclerosis (ALS) is also characterized by a presymptomatic period, and if so how long this period lasts, is unclear. Answers to these questions will not only inform our understanding of disease biology and potential environmental risk factors for ALS, but also the design and implementation of early therapeutic and even preventative clinical trials. Moreover, the potential impact of studying people at genetic risk for ALS, the only population in which it is currently possible to study presymptomatic disease, is underscored by recent progress in our understanding of the shared genetic basis of familial and apparently sporadic ALS. Studying presymptomatic ALS, however, has proven difficult due to the challenge in identifying an at-risk population and various logistical and ethical considerations. In this article we present the rationale for studying presymptomatic ALS, summarize the early evidence supporting the existence of a presymptomatic phase of the disease, and discuss the challenges of studying presymptomatic ALS. We also use Pre-fALS a systematic and longitudinal investigation of a cohort of individuals at genetic risk for ALS, as an example to illustrate how one might approach these challenges. Neurology ® 2012;79:1732-1739 GLOSSARY ALS ϭ amyotrophic lateral sclerosis; DTI ϭ diffusion tensor imaging; fALS ϭ familial amyotrophic lateral sclerosis; FTD ϭ frontotemporal dementia; LMN ϭ lower motor neuron; MN ϭ motor neuron; MRS ϭ magnetic resonance spectroscopy; MUNE ϭ motor unit number estimation; Pre-fALS ϭ Pre-symptomatic Familial ALS study; UMN ϭ upper motor neuron.The last 15 years have witnessed a significant shift in our understanding of neurodegenerative diseases. We increasingly recognize that the degenerative process in disorders such as Alzheimer disease, 1 Huntington disease, 2 and Parkinson disease 3-5 begins years, if not decades, prior to the appearance of typical clinical manifestations. Whether ALS is also characterized by a prolonged presymptomatic period is unclear, but definitively answering this question is likely to have profound implications for understanding disease biology, uncovering environmental risk factors, developing effective therapies, and even disease prevention.To effectively study presymptomatic ALS, one must first identify people who are at risk for developing disease. Although advancing age is a risk factor for ALS, the broad range of age at symptom onset limits its utility in identifying at-risk individuals. Absent any known environmental risk factor, it is currently only possible to study individuals genetically predisposed to developing ALS-namely, presymptomatic gene mutation carriers.We begin this review with the rationale for studying presymptomatic ALS and a review of the relevant literature. We then turn to the ...

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Section: Environmental Risk Factorsmentioning

confidence: 99%

Presymptomatic studies in ALS

Benatar

Wuu

2012

Neurology

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“…1,2 While 5-10% of ALS patients have a positive family history (fALS), the majority of patients are sporadic cases (sALS). 3 The distinction between fALS and sALS, however, is currently being questioned by the awareness that apparently sALS can be inherited. 4 Since 1993, when the superoxide dismutase 1 (SOD1) gene was found to be mutated in fALS patients, an increasing number of disease genes, designated ALS 1-22, have been reported.…”

Section: Introductionmentioning

confidence: 99%

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

et al. 2017

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We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization to explore genotype-phenotype relationships. WES analysis of the ALS family identified the rare heterozygous frameshift variant FIG4:c.759delG, p.(F254Sfs*8) predicted to delete the catalytic domain and active center from the encoded phosphoinositide 5-phosphatase with a key role in endosomal vesicle trafficking. Additionally, novel or rare heterozygous FIG4 missense variants predicted to be deleterious were detected in five sporadic ALS patients revealing an overall FIG4 variant frequency of 3% in our cohort. Four of six variants identified were previously associated with ALS or the motor and sensory neuropathy Charcot-Marie-Tooth disease type 4J (CMT4J), whereas two variants were novel. In FIG4 variant carriers, disease duration was longer and upper motor neuron predominance was significantly more frequent compared with ALS patients without FIG4 variants. Our study provides evidence for FIG4 as an ALS risk gene in a central European cohort, adds new variants to the mutational spectrum, links ALS to CMT4J on a genetic level, and describes a distinctive ALS phenotype for FIG4 variant carriers.

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“…En los Estados Unidos de Norteamérica aproximadamente 20.000 personas sufren ELA con alrededor de 5.000 casos nuevos al año 52 . La mayoría de los casos de ELA son esporádicos, siendo 5 a 10% casos familiares (ELAf) asociada a herencia mendeliana 53 . La ELA se presenta generalmente entre la 5 ta y 7 ma década de vida, siendo los casos de ELAf más precoces (aproximadamente 10 años).…”

Section: Esclerosis Lateral Amiotróficaunclassified

Manifestaciones neuropsiquiátricas y cognitivas en demencia frontotemporal y esclerosis lateral amiotrófica: dos polos de una entidad común

et al. 2014

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Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis

Abstract: The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.

Cited by 303 publications

References 70 publications

Presymptomatic studies in ALS

Presymptomatic studies in ALS

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

Manifestaciones neuropsiquiátricas y cognitivas en demencia frontotemporal y esclerosis lateral amiotrófica: dos polos de una entidad común

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