Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.

Third nerve palsy: Harbinger of basilar artery thrombosis and locked-in syndrome?

We report the first case, to our knowledge, of third nerve palsy preceding basilar artery thrombosis with the subsequent development of locked-in syndrome.

Risk factors associated with deformational plagiocephaly.

OBJECTIVE: This study was designed to statistically evaluate the independent and interacting effects of biological and environmental risk factors that influence lateralization of deformational plagiocephaly (DP) in an attempt to provide future guidance for clinical treatment. METHODS: A database of >20000 children treated for DP was examined by using 2- and 3-way factor analyses for categorical frequency data, representing the largest statistical analysis of DP to date. Data on parity, zygosity, intrauterine presentation, birth number and weight, sleep position, lateralization, and sex were collected from parents of children with DP who were treated at Cranial Technologies, Inc, from 1990 to 2007. RESULTS: As with most DP studies, male patients were significantly overrepresented. Nonetheless, after statistically accounting for sex in our analyses, DP is significantly correlated with primiparity, fewer vertex but more breech and transverse intrauterine presentations, twinning (specifically, dizygosity), and, finally, right-sided lateralization. Additional analyses revealed that several factors correlated with DP, such as intrauterine presentation, sleep position, and lateralization, are not easily explained by an underlying biological factor. Instead, sleep position was the single greatest predictor of lateralization. CONCLUSION: Although previous studies have argued for both environmental and underlying biological factors associated with DP, we found that lateralization in children with DP could be largely explained by environmental factors such as sleep position.

Does science education need the history of science?

This essay argues that science education can gain from close engagement with the history of science both in the training of prospective vocational scientists and in educating the broader public about the nature of science. First it shows how historicizing science in the classroom can improve the pedagogical experience of science students and might even help them turn into more effective professional practitioners of science. Then it examines how historians of science can support the scientific education of the general public at a time when debates over "intelligent design" are raising major questions over the kind of science that ought to be available to children in their school curricula. It concludes by considering further work that might be undertaken to show how history of science could be of more general educational interest and utility, well beyond the closed academic domains in which historians of science typically operate.

A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

PURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. METHODS: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. RESULTS: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. CONCLUSIONS: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

Diagnostic differences in mandibular P4 shape between Neandertals and anatomically modern humans.

This study uses elliptical Fourier analysis to quantify shape differences observed in the P(4) crown of Neandertals and anatomically modern humans. Previously, P(4) shape was assessed qualitatively, and results suggested marked differences between Neandertals and anatomically modern humans (Bailey [2002] New Anat. 269:148-156). The goal of this study was to investigate the P(4) shape in more detail, quantifying it in order to determine its utility for taxonomic classification and phylogenetic analysis. A comparison of mean shapes confirms that the mesiolingual portion of the P(4) is truncated in Neandertals, and that this produces a distinctively asymmetrical P(4). A randomization test confirms that the shape difference between Neandertals and anatomically modern humans is significant. Principal component and discriminant function analyses indicate that the relative size of the lingual portion of the tooth also affects tooth shape, with the lingual portion of the Neandertal P(4) being narrower than that of anatomically modern humans. Classification of P(4) crown shapes using discriminant functions analysis is far from perfect. While 86.4% of the teeth were correctly classified, classification was much better for anatomically modern humans (98.1%) than it was for Neandertals (65%). Fortunately, crown shape is but one of several diagnostic characters of the P(4) crown. P(4) crown asymmetry can be added to the growing list of dental morphological characters distinguishing Neandertals from anatomically modern humans. Moreover, based on a comparison of mean tooth shapes in fossil and recent humans, symmetry, rather than asymmetry, appears to be the primitive state, and the high frequency of P(4) asymmetry is likely derived in Neandertals.

Quantifying temporal bone morphology of great apes and humans: an approach using geometric morphometrics.

The hominid temporal bone offers a complex array of morphology that is linked to several different functional systems. Its frequent preservation in the fossil record gives the temporal bone added significance in the study of human evolution, but its morphology has proven difficult to quantify. In this study we use techniques of 3D geometric morphometrics to quantify differences among humans and great apes and discuss the results in a phylogenetic context. Twenty-three landmarks on the ectocranial surface of the temporal bone provide a high level of anatomical detail. Generalized Procrustes analysis (GPA) is used to register (adjust for position, orientation and scale) landmark data from 405 adults representing Homo, Pan, Gorilla and Pongo. Principal components analysis of residuals from the GPA shows that the major source of variation is between humans and apes. Human characteristics such as a coronally orientated petrous axis, a deep mandibular fossa, a projecting mastoid process, and reduced lateral extension of the tympanic element strongly impact the analysis. In phenetic cluster analyses, gorillas and orangutans group together with respect to chimpanzees, and all apes group together with respect to humans. Thus, the analysis contradicts depictions of African apes as a single morphotype. Gorillas and orangutans lack the extensive preglenoid surface of chimpanzees, and their mastoid processes are less medially inflected. These and other characters shared by gorillas and orangutans are probably primitive for the African hominid clade.

Morphometrics and hominoid phylogeny: Support for a chimpanzee-human clade and differentiation among great ape subspecies.

Taxonomic and phylogenetic analyses of great apes and humans have identified two potential areas of conflict between molecular and morphological data: phylogenetic relationships among living species and differentiation of great ape subspecies. Here we address these problems by using morphometric data. Three-dimensional landmark data from the hominoid temporal bone effectively quantify the shape of a complex element of the skull. Phylogenetic analysis using distance-based methods corroborates the molecular consensus on African ape and human phylogeny, strongly supporting a Pan-Homo clade. Phenetic differentiation of great ape subspecies is pronounced, as suggested previously by mitochondrial DNA and some morphological studies. These results show that the hominoid temporal bone contains a strong phylogenetic signal and reveal the potential for geometric morphometric analysis to shed light on phylogenetic relationships.