Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development

Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme

Releasing latent compassion through an innovative compassion curriculum for Specialist Community Public Health Nurses

Aims: To evaluate the impact of a curriculum based on the Compassionate Mind Model designed to facilitate the expression of compassion in Specialist Community Public Health Nurses. Background: The Compassionate Mind Model identifies that fear of compassion creates a barrier to the flow of compassion. There is some evidence linking self-compassion to compassionate care but no previous research has explored this potential with post registration specialist community public health nursing students. Design: Prospective, longitudinal design using focus group interviews. Methods: 26 students (81% of cohort) agreed to participate in a wider evaluation (2014-2015). For this study, two groups were drawn from those participants (total 13 students) who attended audio-taped group interviews at the course mid- and end-points to explore their perceptions on compassion and compassionate care. Transcripts were analysed thematically. Findings: A number of sub-themes were identified. ‘Cultural change in the NHS’, ‘Workload and meeting targets’ and ‘Lack of time were barriers to compassionate care, as was negative ‘Role modelling’. These were collated under a macro-theme of ‘A culture lacking in compassion’. Secondly, the sub-themes ‘Actualisation of compassion’ and ‘Transformation’ were collated within a macro-theme: ‘Realisation of compassion’. This theme identified realisation of latent compassion from their previous roles that in some transferred into students’ personal lives suggesting a transformation beyond professional attitude. Conclusion: The curriculum facilitated a realisation of compassion in students over the period of the course by enhancing their capacity to be self-compassionate and by actualisation of compassion that had previously been suppressed

Chapter Genetics of Familial Amyotrophic Lateral Sclerosis

Electronics engineerin

Genetics of Familial Amyotrophic Lateral Sclerosis

Electronics engineerin

Long-term physical activity: an exogenous risk factor for sporadic amyotrophic lateral sclerosis?

OBJECTIVES: To conduct a geographically defined, UK-based case-control study, to examine any association between physical activity (PA) and amyotrophic lateral sclerosis (ALS). METHODS: A novel historical PA questionnaire was designed, validated, and subsequently administered in individual face-to-face interviews of 175 newly diagnosed sporadic ALS cases and 317 age- and sex-matched community controls. Historical PA energy expenditure and time spent in vigorous-intensity PA were derived from questionnaire data and compared between cases and controls. RESULTS: Participation in an extra 10kJ/kg/day of PA (equivalent to approximately 45minutes brisk walking) was consistently associated with an increased risk of ALS, with the strongest association observed for adulthood exercise-related PA (OR 1.47, 95% CI 1.10-1.97). An extra 10mins/day of vigorous PA was also associated with the odds of ALS (OR 1.03, 95% CI 1·01-1·05). Results were slightly attenuated following adjustment for smoking and educational attainment. CONCLUSIONS: To our knowledge this is the first study to demonstrate a positive association between ALS and PA participation using a specifically designed and validated historical PA questionnaire. Despite the well-established health benefits of PA, a high activity lifestyle may also be associated with elevated risk of ALS. Large-scale prospective studies in the future may help to confirm this association.This study was funded by a Medical Research Council/Motor Neurone Disease Association Lady Edith Wolfson Fellowship.This is the final version of the article. It first appeared from Taylor and Francis via https://doi.org/10.3109/21678421.2016.115457

Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis

Public health & preventive medicin

Long-term physical activity: an exogenous risk factor for sporadic amyotrophic lateral sclerosis?

Objectives: To conduct a geographically defined, UK-based case-control study, to examine any association between physical activity (PA) and amyotrophic lateral sclerosis (ALS). Methods: A novel historical PA questionnaire was designed, validated, and subsequently administered in individual face-to-face interviews of 175 newly diagnosed sporadic ALS cases and 317 age- and sex-matched community controls. Historical PA energy expenditure and time spent in vigorous-intensity PA were derived from questionnaire data and compared between cases and controls. Results: Participation in an extra 10kJ/kg/day of PA (equivalent to approximately 45minutes brisk walking) was consistently associated with an increased risk of ALS, with the strongest association observed for adulthood exercise-related PA (OR 1.47, 95% CI 1.10-1.97). An extra 10mins/day of vigorous PA was also associated with the odds of ALS (OR 1.03, 95% CI 1·01-1·05). Results were slightly attenuated following adjustment for smoking and educational attainment. Conclusions: To our knowledge this is the first study to demonstrate a positive association between ALS and PA participation using a specifically designed and validated historical PA questionnaire. Despite the well-established health benefits of PA, a high activity lifestyle may also be associated with elevated risk of ALS. Large-scale prospective studies in the future may help to confirm this association.This study was funded by a Medical Research Council/Motor Neurone Disease Association Lady Edith Wolfson Fellowship.This is the final version of the article. It first appeared from Taylor and Francis via https://doi.org/10.3109/21678421.2016.115457