Mapping the gene for autosomal dominant restless legs syndrome in an Irish family

Restless Legs Syndrome (RLS) is a common neurological disorder affecting nearly 15% of the general population. Ironically, RLS can be described as the most common condition one has never heard of. It is usually characterised by uncomfortable, unpleasant sensations in the lower limbs inducing an uncontrollable desire to move the legs. RLS exhibits a circadian pattern with symptoms present predominantly in the evening or at night, thus leading to sleep disruption and daytime somnolence. RLS is generally classified into primary (idiopathic) and secondary (symptomatic) forms. Primary RLS includes sporadic and familial cases of which the age of onset is usually less than 45 years and progresses slowly with a female to male ratio of 2:1. Secondary forms often occur as a complication of another health condition, such as iron deficiency or thyroid dysfunction. The age of onset is usually over 45 years, with an equal male to female ratio and more rapid progression. Ekbom described the familial component of the disorder in 1945 and since then many studies have been published on the familial forms of the disorder. Molecular genetic studies have so far identified ten loci (5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p). No specific gene within these loci has been identified thus far. Association mapping has highlighted a further five areas of interest. RLS6 has been found to be associated with SNPs in the BTBD9 gene. Four other variants were found within intronic and intergenic regions of MEIS1, MAP2K5/LBXCOR1, PTPRD and NOS1. The pathophysiology of RLS is complex and remains to be fully elucidated. Conditions associated with secondary RLS, such as pregnancy or end-stage renal disease, are characterised by iron deficiency, which suggests that disturbed iron homeostasis plays a role. Dopaminergic dysfunction in subcortical systems also appears to play a central role. An ongoing study within the Department of Pathology (University College Cork) is investigating the genetic characteristics of RLS in Irish families. A three generation RLS pedigree RLS3002 consisting of 11 affected and 7 unaffected living family members was recruited. The family had been examined for four of the known loci (5q, 12q, 14p and 9p) (Abdulrahim 2008). The aim of this study was to continue examining this Irish RLS pedigree for possible linkage to the previously described loci and associated regions. Using informative microsatellite markers linkage was excluded to the loci on 5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p and also within the regions reported to be associated with RLS. This suggested the presence of a new unidentified locus. A genome-wide scan was performed using two microsatellite marker screening sets (Research Genetics Inc. Mapping set and the Applied Biosystems Linkage mapping set version 2.5). Linkage analysis was conducted under an autosomal dominant model with a penetrance of 95% and an allele frequency of 0.01. A maximum LOD score of 3.59 at θ=0.00 for marker D19S878 indicated significant linkage on chromosome 19p. Haplotype analysis defined a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to 2.5 Mb. There are approximately 100 genes annotated within the critical region. Sequencing of two candidate genes, KLF16 and GAMT, selected on the assumed pathophysiology of RLS, did not identify any sequence variant. This study provides evidence of a novel RLS locus in an Irish pedigree, thus supporting the picture of RLS as a genetically heterogeneous trait.

From respect for nature to agency as realisation in response to the ecological emergency

'The ecological emergency’ describes both our emergence into, and the way we relate within, a set of globally urgent circumstances, brought about through anthropogenic impact. I identify two phases to this emergency. Firstly, there is the anthropogenic impact itself, interpreted through various conceptual models. Secondly, however, is the increasingly entrenched commitment to divergent conceptual positions, that leads to a growing disparateness in attitudes, and a concurrent difficulty with finding any grounds for convergence in response. I begin by reviewing the environmental ethics literature in order to clarify which components of the implicit narratives and beliefs of different positions create the foundations for such disparateness of views. I identify the conceptual frameworks through which moral agency and human responsibility are viewed, and that justify an ethical response to the ecological emergency. In particular, I focus on Paul Taylor's thesis of 'respect for nature' as a framework for revising both the idea that we are ‘moral’ and the idea that we are ‘agents’ in this unique way, and I open to question the idea that any response to the ecological emergency need be couched in ethical terms. This revision leads me to formulate an alternative conceptual model that makes use of Timothy Morton’s idea of enmeshment. I propose that we dramatically revise our idea of moral agency using the idea of enmeshment as a starting point. I develop an alternative framework that locates our capacity for responsibility within our capacity for realisation, both in the sense of understanding, and of making real, sets of conditions within our enmeshment. I draw parallels between this idea of ‘realisation as agency’ and the work of Dōgen and other non-dualists. I then propose a revised understanding of ‘the good’ of systems from a biophysical perspective, and compare this with certain features of Asian traditions of thought. I consider the practical implications of these revisions, and I conclude that the act of paying close attention, or realising, contains our agency, as does the attitude, or manner, with which we focus. This gives us the basis for a convergent response to the ecological emergency: the way of our engagement that is the key to responding to the ecological emergency