The genetics and pathophysiology of cluster headache and associated disorders

Cluster headache (CH) is described as one of the most painful conditions known to humans. It effects approximately 60,000 individuals in the UK and carries significant morbidity. It exhibits hereditability evident by reports of familial aggregation and is categorised as a trigeminal autonomic cephalalgia (TAC). Despite this, the exact pathophysiological and genetic drivers of this condition remain elusive. The purpose of this thesis is to examine the clinical and genetic determinants of CH, and thus gain insights into the underlying neurobiological mechanisms. This work consists of two components. In the first section, I conduct clinical observational studies to further delineate the CH phenotype. I address the postulated association between pituitary adenomas and CH and question the utility of dedicated pituitary imagining in this patient group. I also describe the largest series of Post-Traumatic Headache of Cluster Headache (PTH-CH) and demonstrate its distinct features and increased intractability to treatment. Finally, through meta-analysis, I estimate the prevalence of familial CH to be 6.27% and demonstrate an overlap with concurrent short-Lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) in familial cases. The second section explores the genetics architecture underlying CH. I perform a Genome-Wide Association Study (GWAS) to identify replicable susceptibility loci and conduct a downstream analysis. Subsequent genetic correlation analysis showed an overlap with migraine, depression, bipolar and sleep disturbance implying the possibility of a common genetic driver for these conditions, which frequently present concurrently. I then carry out linkage analysis in CH families and replicate a linked region suggestive of significance on chromosome 2 that also overlaps a genome wide significant locus. Finally, I execute whole exome sequencing and utilise rare variant association tests and segregation analysis to identify causal variants for familial CH

Ageing, motion sensitivity and eye movement

This thesis aimed to address two separate issues: 1) the effect of fixation and smooth pursuit eye-movement on motion sensitivity and 2) the effect of age on motion sensitivity. Speed, direction and motion coherence thresholds were measured in older and younger observers during fixation and smooth pursuit. Observers of all ages found it more difficult to discriminate direction during smooth pursuit compared to fixation. An age-related decline in direction discrimination was evident during fixation and smooth pursuit at slow speeds only (Experiment 1). An age-related decrease in retinal luminance failed to explain the decline in direction sensitivity in older observers (Experiment 2). The effect of relative motion was assessed and was found not to influence the threshold difference between eye-movement conditions (Experiment 3). Similar effects of speed and eye-movement condition were found in the trajectory-matching task (Experiment 4). Speed discrimination thresholds were also higher during pursuit compared to fixation (Experiment 5). No age effects were found in either eye-movement condition for speed discrimination. Classification analysis demonstrated that in speed and direction discrimination, old and young observers combined retinal and extra-retinal motion cues to make motion judgements regardless of instructed eye-movement. Overall, the discrimination results support the idea that performance in these tasks is limited by internal noise associated with retinal and extra-retinal motion signals that feed into a combination stage responsible for estimating head-centred motion. Motion coherence thresholds were higher for pursued stimuli compared to fixated stimuli (Experiment 6). In addition, observers of all ages found it more difficult to detect collinear signal motion compared to orthogonal signal motion during pursuit. This pattern was significantly worse in older observers. There was no age-related decline in motion coherence for fixated stimuli. Retinal slip due to inaccurate eye-movements could explain the motion coherence findings

The clinical characteristics of familial cluster headache

BACKGROUND: A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup. OBJECTIVES: To assess the rate and mode of inheritance of familial cluster headache in a tertiary referral centre for headache. To describe the clinical features of familial cluster headache. METHODS: A retrospective study conducted between 2007 and 2017. Cluster headache was confirmed in probands and affected relatives. Differences in demographics, clinical characteristics, and response-to-treatment in familial cluster headache were delineated through multivariate analysis using a control cohort of 597 patients with sporadic cluster headache. RESULTS: Familial cluster headache was confirmed in 48 (7.44%) patients and predominantly reflected an autosomal dominant mode of inheritance with reduced penetrance. Familial cases were more likely to report nasal blockage (OR 4.06, 95% CI; 2.600-6.494, p < 0.001) during an attack and a higher rate of concurrent short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (OR 3.76, 95% CI; 1.572-9.953, p = 0.004). CONCLUSION: These findings add to evidence suggesting a genetic component to cluster headache. Here, we demonstrated prominent nasal blockage, and a higher occurrence of concomitant short-lasting unilateral neuralgiform headache with conjunctival injection and tearing in this subgroup, further delineating the phenotype

Children’s voices in the Framework for Early Learning – a portraiture study

The National Council for Curriculum and Assessment (NCCA) is developing a Framework for Early Learning to support adults in working with children from birth to six years. The Framework is premised on an understanding of children as being active in shaping and creating their own lives. This perspective supports the inclusion of children’s voices in decisions which affect them. The NCCA is using a portraiture study to facilitate children as partners in developing the Framework. The portraits will provide a detailed description of individual children’s experiences and reflections on their time in early childhood settings and will provide an important benchmark for the NCCA in developing a national framework for early learning and development which is grounded in an Irish context. This contextualisation will help to ensure that the Framework is relevant and helpful to adults in working with children in Ireland

Reply to: "Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions"

n/

A Registered Report Survey of Open Research Practices in Psychology Departments in the UK and Ireland

Open research practices seek to enhance the transparency and reproducibility of research. While there is evidence of increased uptake in these practices, such as study preregistration and open data, facilitated by new infrastructure and policies, little research has assessed general uptake of such practices across psychology university researchers. The current study estimates psychologists' level of engagement in open research practices across universities in the United Kingdom and Ireland, while also assessing possible explanatory factors that may impact their engagement. Data were collected from 602 psychology researchers in the United Kingdom and Ireland on the extent to which they have implemented various practices (e.g., use of preprints, preregistration, open data, open materials). Here we present the summarized descriptive results, as well as considering differences between various categories of researcher (e.g., career stage, subdiscipline, methodology), and examining the relationship between researcher's practices and their self-reported capability, opportunity, and motivation (COM-B) to engage in open research practices. Results show that while there is considerable variability in engagement of open research practices, differences across career stage and subdiscipline of psychology are small by comparison. We observed consistent differences according to respondent's research methodology and based on the presence of institutional support for open research. COM-B dimensions were collectively significant predictors of engagement in open research, with automatic motivation emerging as a consistently strong predictor. We discuss these findings, outline some of the challenges experienced in this study, and offer suggestions and recommendations for future research. Estimating the prevalence of responsible research practices is important to assess sustained behaviour change in research reform, tailor educational training initiatives, and to understand potential factors that might impact engagement

Body composition, inflammation, and 5-year outcomes in colon cancer

Importance: Obesity, particularly visceral obesity and sarcopenia, are poor prognostic indicators in colon cancer. Objectives: To explore the association between body composition profiles and 5-year colon cancer outcomes and delineate the associated underlying inflammatory processes. Design, Setting, and Participants: This multicenter translational cohort study included patients with nonmetastatic colon cancer who did not have underlying chronic inflammatory disorders and were not receiving anti-inflammatory drugs referred to tertiary cancer centers from 2009 to 2015. Preoperative acute phase proteins (white cell count, C-reactive protein, and albumin), cytokines (interleukin [IL]-1b, IL-2, IL-6, IL-10, interferon γ, and tumor necrosis factor α), vascular endothelial growth factor (VEGF), and cell surface receptor expression levels (CD11b and CD14) were measured. All patients underwent follow-up for at least 5 years. Data were analyzed in December 2020. Exposure: Nonmetastatic colon cancer. Main Outcomes and Measures: The associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test and Kaplan-Meier curves. Results: A total of 28 patients were included (median [interquartile range] age, 67 [58-72] years; 22 [78.6%] men). Low skeletal muscle area (SMA) and high visceral to total fat ratio were associated with poor clinical and oncological outcomes, including increased 5-year recurrence (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41-2.89]; P = .04; high visceral to total fat ratio: HR, 5.78 [95% CI, 3.66-7.95]; P = .02). High visceral to total fat ratio was associated with increased 5-year disease-specific mortality (HR, 5.92 [95% CI, 4.04-8.00]; P = .02). Patients with low SMA who developed a cancer recurrence, compared with those who did not, had higher C-reactive protein (mean [SD], 31.24 [6.95] mg/dL vs 8.11 [0.58] mg/dL; P = .003), IL-6 (mean [SD], 1.93 [1.16] ng/mL vs 0.88 [0.14] ng/mL; P = .004), VEGF (mean [SD], 310.03 [122.66] ng/mL vs 176.12 [22.94] ng/mL; P = .007), and CD14 (mean [SD], 521.23 [302.02] ng/mL vs 322.07 [98.35] ng/mL; P = .03) expression and lower albumin (mean [SD], 3.8 [0.6] g/dL vs 43.50 [3.69] g/dL; P = .01), IL-2 (mean [SD], 0.45 [0.25] ng/mL vs 0.94 [0.43] ng/mL; P < .001), IL-10 (mean [SD], 8.15 [1.09] ng/mL vs 16.32 [4.43] ng/mL; P = .004), and interferon γ (mean [SD], 2.61 [1.36] ng/mL vs 14.87 [3.43] ng/mL; P = .02) levels. Patients with high visceral to total fat ratio who developed recurrence had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P = .03) and tumor necrosis factor α (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P = .03). Conclusions and Relevance: These findings suggest that low SMA and high visceral to total fat ratio were associated with worse colon cancer outcomes and with increased expression of proinflammatory cytokines and VEGF and inhibition of anti-inflammatory cytokines

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.Peer reviewe