Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis

Fanos, Joanna H.; Gronka, Susan; Wuu, Joanne; Stanislaw, Christine; Andersen, Peter M.; Benatar, Michael

doi:10.1097/gim.0b013e318204d004

Cited by 36 publications

(103 citation statements)

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“…During the first 3 years of Pre-fALS, participants who elected disclosure were randomized to receive counseling either via telephone or in person. The findings 38 highlight the strengths and weaknesses of each approach and provided proof-of-principle that genetic counseling could adequately be performed remotely, at a significantly reduced logistical burden and cost. Based on these results, Pre-fALS procedures were modified such that counseling is by default provided telephonically, though participants may choose in-person counseling.…”

Section: Methods For Detecting Presymptomatic Diseasementioning

confidence: 99%

“…There are potential risks, but these can be mitigated by ensuring that consent is adequately informed and by probing each individual's psychosocial readiness to undergo presymptomatic testing. 37,38 Other issues to consider are whether the results of presymptomatic testing should be made available to research participants, how to provide adequate pretest and post-test counseling for those who elect to learn their test results (including discussing issues such as inheritance patterns, incomplete penetrance, and discovery of polymorphisms of uncertain pathogenicity), and what follow-up is needed for those found not to harbor a genetic mutation. Equally important is the confidentiality and security of this genetic information, with implementation of the necessary safeguards to ensure that genetic knowledge does not compromise individuals' ability to secure health or life insurance, for example.…”

Section: Environmental Risk Factorsmentioning

confidence: 99%

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Presymptomatic studies in ALS

Benatar

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: Methods For Detecting Presymptomatic Diseasementioning

confidence: 99%

Section: Environmental Risk Factorsmentioning

confidence: 99%

Presymptomatic studies in ALS

Benatar

Wuu

2012

Neurology

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“…2. In addition to providing counseling by phone for those who live far away, 27 there is value in exploring the utility of secure video conferencing to provide counseling. 3.…”

Section: Presymptomatic Genetic Testing In Thementioning

confidence: 99%

“…A semi-structured qualitative assessment of a random sample of 20 of these participants informed the decision to continue Pre-fALS using telephone counseling for both pretest and posttest sessions and to offer those contemplating genetic testing a predecision counseling session to help decide whether to learn the results of genetic testing. 27 Currently in Pre-fALS, we only test for mutations already documented in affected family members. That we do not test for all known genetic variants implicated in ALS is clearly communicated during the informed consent process and counseling sessions.…”

Section: Presymptomatic Genetic Testing In Thementioning

confidence: 99%

“…Additionally, many individuals seeking psGT have expressed the sentiment that they have reached a point in their lives where the anxiety of living with the unknown is worse than knowing whether or not they are at genetic risk. 27 Finally, the opportunity to help advance ALS research can be empowering for individuals who have seen family members succumb to the disease, a sentiment shared by many of our participants.…”

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confidence: 99%

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Presymptomatic ALS genetic counseling and testing

Benatar¹,

Stanislaw

Reyes

et al. 2016

Neurology

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Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS. Published guidelines for presymptomatic genetic testing (psGT) in amyotrophic lateral sclerosis (ALS) [1][2][3] have been based in part on experience in Huntington disease (HD) 4,5 and other lateonset neurodegenerative diseases such as Alzheimer disease, 6,7 and in part on experience in a small number of first-degree relatives of patients with superoxide dismutase-1 (SOD1) familial ALS.8 As the spectrum of identified genetic causes of ALS expands and the landscape of ALS genetics becomes ever more complex, 9,10 there is an increasing need to revisit the proposed guidelines. In this article, we highlight clinically relevant aspects of the genetic complexity of ALS and, drawing on the extensive experience acquired through the ongoing Pre-Symptomatic Familial ALS Study (Pre-fALS), present an approach to psGT that we have developed and refined over the last 8 years. While our experience derives from, and is most relevant to, psGT in the research arena, it may also inform the more controversial endeavor of psGT in a clinical setting.BACKGROUND AND RATIONALE "Familial," "sporadic," and "genetic" ALS. Traditionally, a distinction has been drawn between familial ALS (fALS) and sporadic ALS (sALS) based on the presence or absence of a family history of ALS, with a genetic etiology presupposed for fALS, but not for those without a family history. This distinction, however, is artificial and the inference about genetic etiology incorrect, as all the genes known to cause fALS have also been identified in patients with (seemingly) sALS.9 Some have proposed as an alternative the term hereditary ALS.11 While there are many reasons why ALS with a known genetic cause may not reveal a family history (e.g., recessive inheritance, compound heterozygosity, ...

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Evidence‐based consensus guidelines for ALS genetic testing and counseling

Roggenbuck,

Eubank,

Wright

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAdvances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet “standard of care.” Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.MethodsCore clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA‐P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.ResultsA total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single‐step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.InterpretationThese evidence‐based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.

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Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis

Cited by 36 publications

References 36 publications

Presymptomatic studies in ALS

Presymptomatic studies in ALS

Presymptomatic ALS genetic counseling and testing

Evidence‐based consensus guidelines for ALS genetic testing and counseling

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