Life ‘on high alert’: how do people with a family history of motor neurone disease make sense of genetic risk? insights from an online forum

Genetic exceptionalism. Too much of a good thing?

Genetic counseling is “the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.” Traditionally, this process includes collecting and interpreting the family and medical history, risk assessment, a comprehensive educational process for potential genetic testing, informed consent, and psychosocial assessment and support (National Society of Genetic Counselors' Definition Task Force et al. 2006). While genetic counseling falls within the scope of many health care professionals, clinical geneticists (physicians) and masters level genetic counselors have been working in the United States for more than 40 years, providing genetic counseling primarily for single-gene conditions. Debate about what “genomic counseling” will include and who will practice it has been fueled by the transition from single-gene focused genetic counseling and testing to a full genomic medicine approach. The routine incorporation of genomic medicine will likely induce differences in the scope, approach and process of genetic counseling (Table ​(Table1).1). In this commentary, I will discuss the several areas where practice will likely change as we move toward “genomic” counseling, with a focus on the unique skills and roles that genetic counselors and clinical geneticists provide. Table 1 Changes that will impact the transition to “genomic counseling.”

It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr175 and pThr217, and for amyloid β protein (Aβ) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed ‘significant’ tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer’s disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aβ up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr175 antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer’s disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer’s disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0301-z) contains supplementary material, which is available to authorized users.

Personal genomics: information can be harmful

Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Formal psychological therapies are not routinely part of United Kingdom standard motor neuron disease care due to a lack of evidence-based guidance resulting from a paucity of clinical trials. We aimed to evaluate the clinical and cost-effectiveness of Acceptance and Commitment Therapy plus usual care compared to usual care alone for improving psychological health in people living with motor neuron disease. We conducted qualitative interviews with 15 people living with motor neuron disease, 10 caregivers and 12 healthcare professionals. Findings were used to develop an Acceptance and Commitment Therapy intervention specifically for people living with motor neuron disease. Next, we examined its acceptability and feasibility in an uncontrolled feasibility study with 29 people living with motor neuron disease. Findings from qualitative interviews with 14 people living with motor neuron disease and 11 therapists were used to revise the intervention. Finally, we conducted a multicentre, parallel, two-arm randomised controlled trial in 16 United Kingdom motor neuron disease care centres/clinics. Eligible participants were aged ≥ 18 years with motor neuron disease. Participants were randomly assigned (1 : 1) to receive up to eight sessions of Acceptance and Commitment Therapy plus usual care or usual care alone and followed up at 6 and 9 months post randomisation by blinded outcome assessors. The primary outcome was total score on the McGill Quality of Life Questionnaire-Revised at 6 months. Secondary outcomes included health status using the EuroQol-5 Dimensions, five-level version. Primary analyses were by intention to treat. Acceptance and Commitment Therapy was acceptable to people living with motor neuron disease, and it was feasible to recruit participants, hence trial progression criteria were met. From September 2019 to August 2022, 191 participants were recruited: 97 were allocated to Acceptance and Commitment Therapy plus usual care and 94 to usual care alone. Mean age was 61.9 years (standard deviation 11.4), 58% were male and 95% were White/White British. Acceptance and Commitment Therapy plus usual care was superior to usual care alone on the McGill Quality of Life Questionnaire-Revised at 6 months [adjusted mean difference 0.66 (95% confidence interval 0.22 to 1.10); Cohen's d = 0.46 (95% confidence interval 0.16 to 0.77); p = 0.003] and 9 months [adjusted mean difference 0.76 (95% confidence interval 0.30 to 1.22); Cohen's d = 0.53 (95% confidence interval 0.21 to 0.85); p = 0.001]. Mean differences in total costs and quality-adjusted life-years at 9 months between Acceptance and Commitment Therapy plus usual care versus usual care alone were not statistically significant [costs: £1019 (95% confidence interval -£34 to £2074); quality-adjusted life-years: 0.019 (95% confidence interval -0.07 to 0.05)]. The incremental cost-effectiveness ratio was £88,507/quality-adjusted life-year: this decreased to £13,817/quality-adjusted life-year in those with medium disease-related deterioration in subgroup analyses. Acceptance and Commitment Therapy plus usual care is clinically effective at maintaining or improving psychological health, as measured by the McGill Quality of Life Questionnaire-Revised, in people living with motor neuron disease compared to usual care alone. It was not cost-effective overall when calculated using a standard health status measure (EuroQol-5 Dimensions, five-level version). However, it was cost-effective in a subgroup of people experiencing a medium rate of disease-related deterioration. Participants from ethnic minorities were under-represented, despite recruiting from sites with diverse communities. Between-group differences in outcomes may have been partly attributable to expectancy or non-specific therapeutic effects due to the lack of an active control. Cost-effectiveness analyses may have been underpowered to detect significant between-group differences. Studies should examine the effectiveness of Acceptance and Commitment Therapy in diverse populations, compared to an active control, using a more appropriate measure to assess cost-effectiveness, and in those with different rates of disease-related deterioration. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/81/01.

Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.

ObjectiveTo confirm the symptoms and signs for motor neuron disease (MND) in the Red Flag tool; to quantify the extent to which the key symptoms and signs are associated with...

Background: People with motor neurone disease access healthcare services from disease onset to end-of-life care, but there has been paucity of research on how people with motor neurone disease understand and use healthcare services. Aim: To identify key psycho-social processes that underpin how people with motor neurone disease engage with healthcare services. Design: Grounded theory approach comprising in-depth qualitative interviews was used in this study. Data were collected and analysed using open, axial and selective coding procedures. Setting/participants: A total of 34 people with motor neurone disease were recruited from the Irish motor neurone disease population-based register. Results: We identified that control, reassurance, resignation and trust are key variables that shape how people with motor neurone disease engage with healthcare services. Participants exerted control in care to cope with loss. Most participants were resigned to death and sought reassurances from healthcare professionals about end-of-life care. Participants questioned the benefit of life-sustaining interventions in motor neurone disease and few of them associated life-sustaining interventions with palliative care. Participants trusted healthcare professionals who reassured them about their care and who were attuned to how they were coming to terms with loss. Conclusion: This study identified new and important aspects of control, trust and reassurance which shed light on how people with motor neurone disease engage with healthcare professionals and approach end-of-life care. People with motor neurone disease exert control in care and meaningful relationships with healthcare professionals are important to them. Some people with motor neurone disease prefer to die without life-sustaining interventions.

Predictive genetic testing is increasingly available for individuals with a heightened risk of motor neuron disease (MND). However, little is known about how they decide whether or not to get tested, and how they experience this process. This paper reports findings from a constructivist grounded theory-informed interview study with 24 family members of people with identified or suspected inherited MND (iMND). Fourteen did not know their genetic status, and nine had decided to have predictive testing, of whom six tested positive for the pathogenic gene variant identified in their family and three tested negative. One additional person was identified as negative through a parent's negative result. This paper explores the diverse ways people approached testing, and the many factors and motivations involved, based on personal attitudes and goals, experiences of living with genetic risk, and wider family considerations and circumstances. Results were met with a range of emotions; whatever the outcome, the news disrupted each person's view of the future, and they adapted in their own way and time. Support after results was variable and a perceived lack of support impacted coping and the ability to move forwards. This paper situates findings against literature on other genetic conditions, highlighting experiences as grounded in the unique characteristics of iMND. Thus, it emphasizes the need for disease-specific guidelines and support structures around predictive genetic testing in this context. Understanding people's experiences and responding to these needs is particularly timely given the uptake of testing amongst this group is anticipated to rise with increasing access to genetic testing for people with MND, and gene-specific clinical trials.

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

BackgroundCare provision for Motor Neurone Disease (MND) patients require a Multidisciplinary Team (MDT) approach. Healthcare Professionals (HCPs) and MND patients often find it challenging to communicate effectively. Communication is particularly...

Nitric oxide (NO) mediated oxidative damage may be involved in the pathogenesis of neuronal degeneration in motor neuron disease (MND). The present study was undertaken to evaluate the role of NO and oxidative stress in MND by estimating nitrite and malondialdehyde (MDA) levels in the cerebrospinal fluid (CSF) in 22 patients of MND and 20 control subjects suffering from neurological disorders not known to affect NO metabolism. There was no significant change in the CSF nitrite and MDA levels in MND. The nitrite and MDA levels did not have any significant correlation with age, duration of illness, or severity of disease.­ Univariate analysis of the clinical features in patients with MND and the nitrite levels revealed that two patients with a positive family history had significantly higher CSF nitrite levels as compared to those with a negative family history. There was no correlation between the CSF nitrite and MDA levels. Results of the present study did not indicate significant alterations in the MDA and NO levels in the CSF of MND patients. However, involvement of NO in MND with positive family history is suggested by the results obtained.­

Genetic screening for cancer susceptibility for many cancer sites has become routine for high-risk populations, particularly breast, ovarian, and colon cancer. Such genetic tests hold great promise for informing tailored cancer prevention and risk reduction recommendations. Heightened consumer awareness of "cancer genes" and tests to detect them has escalated interest and demand for cancer risk assessment, generating a pressing need to identify effective, efficient methods of communicating complicated genetic information to patients and their potentially at-risk relatives. As more is learned about cancer genetic susceptibility, population-level demand for genetic screening will necessitate considering new modes and methods for effective genetic risk communication other than traditional in-person genetic counseling. Optimal outcomes of predictive genetic testing for cancer include adherence to preventive or risk-reducing strategies, accurate communication of test results to at-risk relatives, maximization of psychosocial well-being, and ultimately, reduction of morbidity and mortality associated with hereditary or familial cancers. This will require the effective communication of risk information tailored to patients' translation of knowledge into perceptions of cancer risk, and the biopsychosocial factors that mediate and moderate that translation into risk-reduction behaviors.Two very important issues in the effective communication of genetic screening results include (a) the mode of communication and (b) the age of subjects who receive risk information. Thus, the purpose of this session was to review the state of knowledge and to identify the future research necessary to inform policy and practice about testing for, and communication of, cancer risk information to adults and minors.The example used in this session was BRCA1/2 testing, given its widespread use at the population-level in adults.The American Society of Clinical Oncology and other professional societies recommend that predictive genetic testing be paired with pretest and posttest counseling (1) to optimize patients' informed consent, understanding, and processing of the implications of test results (1, 2). Given the complexity of genetic information, the potential for false reassurance, psychosocial sequellae, and limited interventions to modify identified risk for cancer, communication of predictive genetic information has traditionally been conducted in-person by health care professionals trained in clinical genetics. Future demand for cancer risk assessment and predictive genetic testing might surpass the availability of cancer genetic specialists, suggesting a need for alternative, more efficient methods of service delivery (1, 3).Historically, prenatal genetic counselors incorporated telephone communication of teratogenic information into counseling services (4, 5), suggesting one model to extend genetic services. Telephones, computers, and audiovisual equipment could be used to provide genetic services in which geographic or socioeconomic factors or consumer demand have limited access to in-person services (3, 6-11). Interviews with patients and providers suggest that they perceive similarly the potential advantages and disadvantages of telephone disclosure of genetic risk information (12). Genetic counselors and patients most frequently cite patient convenience and lack of nonverbal communication as key potential advantages and disadvantages of telephone communication. Although 98% of genetic counselors had provided some telephone disclosure, their comfort varied widely by test result; 33% reported experiences that made them question telephone disclosure. Only 50% of patients (ages 22-70 years) awaiting BRCA1/2 test results were interested in receiving their results by telephone (12). Of those interviewed after receiving their test results in-person (ages 21-84 years), only 35% reported that they would have been interested in receiving their results by telephone. Like genetic counselors, patient interest varied widely by test result, with those receiving positive results least likely to favor telephone disclosure (12).Systematic evaluation of telephone/internet versus in-person communication of components of genetic services has been limited to small select populations, or women who self-selected their mode of communication (13-15). Other technologies, such as Web-enabled platforms and video conferencing, may overcome some perceived limitations of telephone communication, such as providers' and patients' loss of visual cues (12). However, using novel technologies might limit, rather than improve, access for some, including underserved patients (16). Thus, randomized studies of the mode of pretest counseling and/or disclosure of genetic test results assessing their psychosocial and behavioral outcomes (e.g., screening, risk reduction behaviors, and communication to family members) must be conducted before these procedures become fully incorporated into clinical care models (12, 13). Further, evaluation of biopsychosocial factors that mediate and moderate psychosocial and behavioral outcomes will inform the development of communication interventions tailored to optimize patients' outcomes.Although patients often share genetic information with at-risk adult relatives (17-21), there is an ongoing debate over the value of sharing genetic risk information with, and offering genetic testing to, at-risk minors (22-28). For example in breast/ovarian cancer, risk reduction options for mutation carriers (prophylactic surgeries, heightened surveillance, and/or chemoprevention) are generally not recommended until age 25 years, and thus, genetic testing is not currently recommended until age 25 years (29, 30). There is no known medical benefit to communicating risk to at-risk minors. Virtually all professional societies recommend against offering BRCA1/2 testing to children under age 18 years (1, 31-36). Yet, professional recommendations neither preclude, nor recommend against, the communication of familial risk to children and adolescents. There is evidence that at least 50% of parents share their genetic test results and information about familial risk for cancer with minor at-risk children (37-39). Offspring understanding and biopsychosocial responses to early communication of familial risk remain understudied/unknown (40-42), although a small study of adult offspring who learned of their risk during adolescence or early adulthood suggests that many offspring may understand the parent communicated risk, and may modify their health behaviors (that is, stop smoking, improve diet, increase physical activity; ref. 42).Recent evaluation of semistructured interviews with 163 parents who had BRCA1/2 testing and had an offspring under age 25 years at testing reveals that the majority of parents (66%) share their test results with at least one offspring. Sixty-two percent of offspring (201 of 323) learned of their parent's genetic test result. Communication was associated with older child age (P < 0.001) and parent having a negative test result (P = 0.056). Few parents reported offspring anxiety or distress (19%) following disclosure (38 of 201 offspring), and fewer reported that their child did not understand (11%) or expressed denial, fatalism, or skepticism (3%; ref. 43). Thus, existing and emerging data support further evaluation of the content of parental communication (that is, what parents share), and direct evaluation of offspring understanding and perceptions of risk and performance of health behaviors, to better understand the risks and benefits of early disclosure and nondisclosure of genetic risk throughout child and adolescent development.Many health and risk behaviors that affect the morbidity and mortality of youths and adults begin in (e.g., tobacco and alcohol use, and sexual activity) or become established in (e.g., diet and exercise) adolescence (44-46). Thus, early communication of hereditary risk might create a "teachable moment," an opportunity to facilitate health behaviors and eliminate risk behaviors in adolescence and throughout the life span (42, 46). Additionally, there are ongoing breast cancer awareness education programs in secondary school and college, reaching girls at high risk and population risk for breast cancer (47, 48). What children, adolescents, and young adults understand of cancer as a genetic disease and predictive cancer genetic testing; what they perceive of the relevance of this information for themselves; how they respond to and use this information; and how those processes change into, during, and out of adolescence has not been well described. Further understanding of how genetic susceptibility may interact with environmental determinants even early in life will be crucial in the effective communication of genetic screening results, particularly in minors when healthy life-style choices are typically patterned (18, 49, 50). Thus, this research has the potential to effectively extend the prevention of breast/ovarian cancer and other adult-onset diseases, reducing morbidity and mortality throughout the life course and across the population.Increased availability and heightened consumer awareness of "cancer genes" and testing has increased consumer interest in, and demand for, hereditary cancer risk assessment and thus identified a pressing need for providers and policy makers to ensure effective, efficient, ethical methods of communicating complicated genetic information to patients and their potentially at-risk relatives. Optimizing adherence to risk management strategies, psychosocial well-being, and communication to at-risk family members requires an understanding of the patients' translation of that information into personalized perceptions of disease risk and intervention benefit. Further research evaluating the risks and benefits of novel methods of providing genetic services and early communication of genetic risk to minor offspring is needed to inform guidelines about effective, ethical delivery of genetic services for cancer susceptibility.Given the likelihood of increased use of genetic testing by all ages, increased demand for the service of genetic counselor requires more research into effective, efficient, and ethical communication. In addition, even if guidelines recommend against genetic screening of minors for disease susceptibility for adult-onset cancers such as breast/ovarian cancer, many minors are aware of the role of genes in their cancer risk. Thus, effective, ethical communication of cancer risk, risk reduction, and cancer prevention strategies to minors requires thoughtful multidisciplinary research to inform policy and practice.No potential conflicts of interest were disclosed.Grant Support: Grant no. MRSG-07-014-01-CPPB. This project is funded, in part, under a grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.

Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stageand the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertaintyand the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision. Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website. People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitmentand the developing analysis. Two patient and public involvementcontributors joined a formal advisory panel.

Objective To systematically review the values and preferences of people with lived experience of motor neurone disease (MND), including those living with MND, caregivers and genetic carriers, regarding their health‐related outcomes. Introduction MND is a devastating neurodegenerative disease that significantly impacts those living with the disease, their caregivers, and their families. Understanding the values and preferences of those affected by MND is crucial for providing patient‐centred care and developing trustworthy guidelines. Eligibility Criteria Studies will be included if they report on the values and preferences of adults living with MND; caregivers and families of those diagnosed with MND; clinicians as a proxy for adults living with MND; or asymptomatic genetic carriers of MND. Peer‐reviewed studies utilising either quantitative or qualitative methodologies (or both) will be eligible for inclusion in this review. Methods and Analysis A comprehensive search of electronic databases will be conducted to identify relevant studies. Data extraction, risk of bias assessment (of quantitative studies), and assessment of methodological limitations (of qualitative studies) will be performed independently by two reviewers. Quantitative data will be pooled using meta‐analysis where appropriate, and qualitative data will be synthesised following a modified meta‐aggregative approach. The relevant GRADE approach will be used to assess the certainty of evidence. Systematic Review Registration Number CRD420250653287.