Identification of candidate genes for dyslexia susceptibility on chromosome 18

Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

Modelling ocular monochromatic aberrations using schematic eyes with homogeneous optical media

Previous research has indicated that schematic eyes incorporating aspheric surfaces but lacking gradient index are unable to model ocular spherical aberration and peripheral astigmatism simultaneously. This limits their use as wide-angle schematic eyes. This thesis challenges this assumption by investigating the flexibility of schematic eyes comprising aspheric optical surfaces and homogeneous optical media. The full variation of ocular component dimensions found in human eyes was established from the literature. Schematic eye parameter variants were limited to these dimensions. The levels of spherical aberration and peripheral astigmatism modelled by these schematic eyes were compared to the range of measured levels. These were also established from the literature. To simplify comparison of modelled and measured data, single value parameters were introduced; the spherical aberration function (SAF), and peripheral astigmatism function (PAF). Some ocular components variations produced a wide range of aberrations without exceeding the limits of human ocular components. The effect of ocular component variations on coma was also investigated, but no comparison could be made as no empirical data exists. It was demonstrated that by combined manipulation of a number of parameters in the schematic eyes it was possible to model all levels of ocular spherical aberration and peripheral astigmatism. However, the unique parameters of a human eye could not be obtained in this way, as a number of models could be used to produce the same spherical aberration and peripheral astigmatism, while giving very different coma levels. It was concluded that these schematic eyes are flexible enough to model the monochromatic aberrations tested, the absence of gradient index being compensated for by altering the asphericity of one or more surfaces.

A preliminary investigation into the effects of ocular lubricants on higher order aberrations in normal and dry eye subjects

Purpose: To study the effects of ocular lubricants on higher order aberrations in normal and self-diagnosed dry eyes. Methods: Unpreserved hypromellose drops, Tears Again™ liposome spray and a combination of both were administered to the right eye of 24 normal and 24 dry eye subjects following classification according to a 5 point questionnaire. Total ocular higher order aberrations, coma, spherical aberration and Strehl ratios for higher order aberrations were measured using the Nidek OPD-Scan III (Nidek Technologies, Gamagori, Japan) at baseline, immediately after application and after 60. min. The aberration data were analyzed over a 5. mm natural pupil using Zernike polynomials. Each intervention was assessed on a separate day and comfort levels were recorded before and after application. Corneal staining was assessed and product preference recorded after the final measurement for each intervention. Results: Hypromellose drops caused an increase in total higher order aberrations (p= <0.01 in normal and dry eyes) and a reduction in Strehl ratio (normal eyes: p= <0.01, dry eyes p= 0.01) immediately after instillation. There were no significant differences between normal and self-diagnosed dry eyes for response to intervention and no improvement in visual quality or reduction in higher order aberrations after 60. min. Differences in comfort levels failed to reach statistical significance. Conclusion: Combining treatments does not offer any benefit over individual treatments in self-diagnosed dry eyes and no individual intervention reached statistical significance. Symptomatic subjects with dry eye and no corneal staining reported an improvement in comfort after using lubricants. © 2013 British Contact Lens Association.

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia

Aim: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Method: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). Results: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. Interpretation: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals. © 2013 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

Higher-order aberrations in amblyopia:an analysis of pre- and post-wavefront-guided laser refractive correction

For more than a century it has been known that the eye is not a perfect optical system, but rather a system that suffers from aberrations beyond conventional prescriptive descriptions of defocus and astigmatism. Whereas traditional refraction attempts to describe the error of the eye with only two parameters, namely sphere and cylinder, measurements of wavefront aberrations depict the optical error with many more parameters. What remains questionable is the impact these additional parameters have on visual function. Some authors have argued that higher-order aberrations have a considerable effect on visual function and in certain cases this effect is significant enough to induce amblyopia. This has been referred to as ‘higher-order aberration-associated amblyopia’. In such cases, correction of higher-order aberrations would not restore visual function. Others have reported that patients with binocular asymmetric aberrations display an associated unilateral decrease in visual acuity and, if the decline in acuity results from the aberrations alone, such subjects may have been erroneously diagnosed as amblyopes. In these cases, correction of higher-order aberrations would restore visual function. This refractive entity has been termed ‘aberropia’. In order to investigate these hypotheses, the distribution of higher-order aberrations in strabismic, anisometropic and idiopathic amblyopes, and in a group of visual normals, was analysed both before and after wavefront-guided laser refractive correction. The results show: (i) there is no significant asymmetry in higher-order aberrations between amblyopic and fixing eyes prior to laser refractive treatment; (ii) the mean magnitude of higher-order aberrations is similar within the amblyopic and visually normal populations; (iii) a significant improvement in visual acuity can be realised for adult amblyopic patients utilising wavefront-guided laser refractive surgery and a modest increase in contrast sensitivity was observed for the amblyopic eye of anisometropes following treatment (iv) an overall trend towards increased higher-order aberrations following wavefront-guided laser refractive treatment was observed for both visually normal and amblyopic eyes. In conclusion, while the data do not provide any direct evidence for the concepts of either ‘aberropia’ or ‘higher-order aberration-associated amblyopia’, it is clear that gains in visual acuity and contrast sensitivity may be realised following laser refractive treatment of the amblyopic adult eye. Possible mechanisms by which these gains are realised are discussed.

The effects of entrance pupil centration and coma aberrations on myopic progression following orthokeratology

Background: The aim was to assess the potential association between entrance pupil location relative to the coaxially sighted corneal light reflex (CSCLR) and the progression of myopia in children fitted with orthokeratology (OK) contact lenses. Additionally, whether coma aberration induced by decentration of the entrance pupil centre relative to the CSCLR, as well as following OK treatment, is correlated with the progression of myopia, was also investigated. Methods: Twenty-nine subjects aged six to 12years and with myopia of -0.75 to -4.00 DS and astigmatism up to 1.00DC were fitted with OK contact lenses. Measurements of axial length and corneal topography were taken at six-month intervals over a two-year period. Additionally, baseline and three-month topographic outputs were taken as representative of the pre- and post-orthokeratology treatment status. Pupil centration relative to the CSCLR and magnitude of associated corneal coma were derived from corneal topographic data at baseline and after three months of lens wear. Results: The centre of the entrance pupil was located superio-temporally to the CSCLR both pre- (0.09±0.14 and -0.10±0.15mm, respectively) and post-orthokeratology (0.12±0.18 and -0.09±0.15mm, respectively) (p>0.05). Entrance pupil location pre- and post-orthokeratology lens wear was not significantly associated with the two-year change in axial length (p>0.05). Significantly greater coma was found at the entrance pupil centre compared with CSCLR both pre- and post-orthokeratology lens wear (both p<0.05). A significant increase in vertical coma was found with OK lens wear compared to baseline (p<0.001) but total root mean square (RMS) coma was not associated with the change in axial length (all p>0.05). Conclusion: Entrance pupil location relative to the CSCLR was not significantly affected by either OK lens wear or an increase in axial length. Greater magnitude coma aberrations found at the entrance pupil centre in comparison to the CSCLR might be attributed to centration of orthokeratological treatments at the CSCLR.

Short- and long-term changes in corneal aberrations and axial length induced by orthokeratology in children are not correlated

PURPOSE: To assess the correlation between changes in corneal aberrations and the 2-year change in axial length in children fitted with orthokeratology (OK) contact lenses. METHODS: Thirty-one subjects 6 to 12 years of age and with myopia −0.75 to −4.00DS and astigmatism ≤1.00DC were fitted with OK. Measurements of axial length and corneal topography were taken at regular intervals over a 2-year period. Corneal topography at baseline and after 3 and 24 months of OK lens wear was used to derive higher-order corneal aberrations (HOA) that were correlated with OK-induced axial length changes at 2 years. RESULTS: Significant changes in C3, C4, C4, root mean square (RMS) secondary astigmatism and fourth and total HOA were found with both 3 and 24 months of OK lens wear in comparison with baseline (all P0.05). Coma angle of orientation changed significantly pre-OK in comparison with 3 and 24 months post-OK as well as secondary astigmatism angle of orientation pre-OK in comparison with 24 months post-OK (all P0.05). DISCUSSION: Short-term and long-term OK lens wear induces significant changes in corneal aberrations that are not significantly correlated with changes in axial elongation after 2-years.

Dynamic image precompensation for improving visual performance of computer users with ocular aberrations

With the progress of computer technology, computers are expected to be more intelligent in the interaction with humans, presenting information according to the user's psychological and physiological characteristics. However, computer users with visual problems may encounter difficulties on the perception of icons, menus, and other graphical information displayed on the screen, limiting the efficiency of their interaction with computers. In this dissertation, a personalized and dynamic image precompensation method was developed to improve the visual performance of the computer users with ocular aberrations. The precompensation was applied on the graphical targets before presenting them on the screen, aiming to counteract the visual blurring caused by the ocular aberration of the user's eye. A complete and systematic modeling approach to describe the retinal image formation of the computer user was presented, taking advantage of modeling tools, such as Zernike polynomials, wavefront aberration, Point Spread Function and Modulation Transfer Function. The ocular aberration of the computer user was originally measured by a wavefront aberrometer, as a reference for the precompensation model. The dynamic precompensation was generated based on the resized aberration, with the real-time pupil diameter monitored. The potential visual benefit of the dynamic precompensation method was explored through software simulation, with the aberration data from a real human subject. An "artificial eye'' experiment was conducted by simulating the human eye with a high-definition camera, providing objective evaluation to the image quality after precompensation. In addition, an empirical evaluation with 20 human participants was also designed and implemented, involving image recognition tests performed under a more realistic viewing environment of computer use. The statistical analysis results of the empirical experiment confirmed the effectiveness of the dynamic precompensation method, by showing significant improvement on the recognition accuracy. The merit and necessity of the dynamic precompensation were also substantiated by comparing it with the static precompensation. The visual benefit of the dynamic precompensation was further confirmed by the subjective assessments collected from the evaluation participants.

Spatial organisation and behaviour of the parental chromosome sets in the nuclei of Saccharomyces cerevisiae × S. paradoxus hybrids

Peer reviewed

Spatial organisation and behaviour of the parental chromosome sets in the nuclei of Saccharomyces cerevisiae × S. paradoxus hybrids

Peer reviewed

Developmental and molecular aberrations associated with deterioration of oocytes during FSH-receptor deficiency

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Structure génétique des populations : modèle amérindien et les haplotypes du chromosome X

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Analyse d'un locus pour trait quantitatif pour l'hypertension sur le chromosome 10 du rat Dahl

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Interactions gène-environnement dans l'obésité associée à l'hypertension chez le rat : rôle du locus génique du TNF-[alpha] trouvé sur le chromosome-20

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.