Search results
Found 12032 matches for
Cerebellar function in developmental dyslexia.
Developmental dyslexia is a genetically based neurobiological syndrome, which is characterized by reading difficulty despite normal or high general intelligence. Even remediated dyslexic readers rarely achieve fast, fluent reading. Some dyslexics also have impairments in attention, short-term memory, sequencing (letters, word sounds, and motor acts), eye movements, poor balance, and general clumsiness. The presence of "cerebellar" motor and fluency symptoms led to the proposal that cerebellar dysfunction contributes to the etiology of dyslexia. Supporting this, functional imaging studies suggest that the cerebellum is part of the neural network supporting reading in typically developing readers, and reading difficulties have been reported in patients with cerebellar damage. Differences in both cerebellar asymmetry and gray matter volume are some of the most consistent structural brain findings in dyslexics compared with good readers. Furthermore, cerebellar functional activation patterns during reading and motor learning can differ in dyslexic readers. Behaviorally, some children and adults with dyslexia show poorer performance on cerebellar motor tasks, including eye movement control, postural stability, and implicit motor learning. However, many dyslexics do not have cerebellar signs, many cerebellar patients do not have reading problems, and differences in dyslexic brains are found throughout the whole reading network, and not isolated to the cerebellum. Therefore, impaired cerebellar function is probably not the primary cause of dyslexia, but rather a more fundamental neurodevelopmental abnormality leads to differences throughout the reading network.
Use of multivariate linkage analysis for dissection of a complex cognitive trait.
Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits.
A genomewide linkage screen for relative hand skill in sibling pairs.
Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between minus sign0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.
Investigation of quantitative measures related to reading disability in a large sample of sib-pairs from the UK.
We describe a family-based sample of individuals with reading disability collected as part of a quantitative trait loci (QTL) mapping study. Eighty-nine nuclear families (135 independent sib-pairs) were identified through a single proband using a traditional discrepancy score of predicted/actual reading ability and a known family history. Eight correlated psychometric measures were administered to each sibling, including single word reading, spelling, similarities, matrices, spoonerisms, nonword and irregular word reading, and a pseudohomophone test. Summary statistics for each measure showed a reduced mean for the probands compared to the co-sibs, which in turn was lower than that of the population. This partial co-sib regression back to the mean indicates that the measures are influenced by familial factors and therefore, may be suitable for a mapping study. The variance of each of the measures remained largely unaffected, which is reassuring for the application of a QTL approach. Multivariate genetic analysis carried out to explore the relationship between the measures identified a common factor between the reading measures that accounted for 54% of the variance. Finally the familiality estimates (range 0.32-0.73) obtained for the reading measures including the common factor (0.68) supported their heritability. These findings demonstrate the viability of this sample for QTL mapping, and will assist in the interpretation of any subsequent linkage findings in an ongoing genome scan.
Probing the neurocognitive trajectories of children's reading skills.
Emerging evidence of the high variability in the cognitive skills and deficits associated with reading achievement and dysfunction promotes both a more dimensional view of the risk factors involved, and the importance of discriminating between trajectories of impairment. Here we examined reading and component orthographic and phonological skills alongside measures of cognitive ability and auditory and visual sensory processing in a large group of primary school children between the ages of 7 and 12 years. We identified clusters of children with pseudoword or exception word reading scores at the 10th percentile or below relative to their age group, and a group with poor skills on both tasks. Compared to age-matched and reading-level controls, groups of children with more impaired exception word reading were best described by a trajectory of developmental delay, whereas readers with more impaired pseudoword reading or combined deficits corresponded more with a pattern of atypical development. Sensory processing deficits clustered within both of the groups with putative atypical development: auditory discrimination deficits with poor phonological awareness skills; impairments of visual motion processing in readers with broader and more severe patterns of reading and cognitive impairments. Sensory deficits have been variably associated with developmental impairments of literacy and language; these results suggest that such deficits are also likely to cluster in children with particular patterns of reading difficulty.
Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects.
Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3, ROBO1, DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case-control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families.
Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia.
Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.
Parent-of-origin effects on handedness and schizophrenia susceptibility on chromosome 2p12-q11.
Schizophrenia and non-right-handedness are moderately associated, and both traits are often accompanied by abnormalities of asymmetrical brain morphology or function. We have found linkage previously of chromosome 2p12-q11 to a quantitative measure of handedness, and we have also found linkage of schizophrenia/schizoaffective disorder to this same chromosomal region in a separate study. Now, we have found that in one of our samples (191 reading-disabled sibling pairs), the relative hand skill of siblings was correlated more strongly with paternal than maternal relative hand skill. This led us to re-analyse 2p12-q11 under parent-of-origin linkage models. We found linkage of relative hand skill in the RD siblings to 2p12-q11 with P=0.0000037 for paternal identity-by-descent sharing, whereas the maternally inherited locus was not linked to the trait (P>0.2). Similarly, in affected-sib-pair analysis of our schizophrenia dataset (241 sibling pairs), we found linkage to schizophrenia for paternal sharing with LOD=4.72, P=0.0000016, within 3 cM of the peak linkage to relative hand skill. Maternal linkage across the region was weak or non-significant. These similar paternal-specific linkages suggest that the causative genetic effects on 2p12-q11 are related. The linkages may be due to a single maternally imprinted influence on lateralized brain development that contains common functional polymorphisms.
PCSK6 is associated with handedness in individuals with dyslexia.
Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10(-7)), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10(-8)). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left-right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.
Cerebral mechanisms for different second language writing systems.
In this fMRI study, we examined the cerebral processing associated with second language (L2) reading in different writing systems in late L2 learners. To examine the impacts of cross-linguistic differences between the first language (L1) and L2 on learning to read in L2, we employed a bidirectional approach and compared brain activation during single word processing in two groups of late L2 readers: (1) L2 readers of English whose L1 was Japanese (Japanese-L1/English-L2) and (2) L2 readers of Japanese (of syllabic Kana only) whose L1 was English (English-L1/Japanese-L2). During English reading, the L2 readers of English (Japanese-L1/English-L2) exhibited stronger activation in the left superior parietal lobule/supramarginal gyrus, relative to the L1 readers of English (English-L1/Japanese-L2). This is a region considered to be involved in phonological processing. The increased activation in the Japanese-L1/English-L2 group likely reflects the increased cognitive load associated with L2 English reading, possibly because L1 readers of Kana, which has an extremely regular orthography, may need to adjust to the greater phonological demands of the irregular L2 English orthography. In contrast, during Kana reading, the L2 readers of Japanese Kana (English-L1/Japanese-L2) exhibited stronger activation in the lingual gyrus in both the left and right hemispheres compared to the L1 readers of Kana (Japaese-L1/English-L2). This additional activation is likely to reflect the lower level of visual familiarity to the L2 symbols in the English-L1/Japanese-L2 group; Kana symbols are uniquely used only in Japan, whereas Roman alphabetic symbols are seen nearly everywhere. These findings, bolstered by significant relationships between the activation of the identified regions and cognitive competence, suggest that the cerebral mechanisms for L2 reading in late learners depends both on which language is their L1 and which language is to be learnt as their L2. Educational implications of these results are discussed.
Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort.
Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children - the NeuroDys cohort - that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case-control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case-control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects.
A comparison of two-coloured filter systems for treating visual reading difficulties.
PURPOSE: Visual disturbances that make it difficult to read text are often termed "visual stress". Coloured filters in spectacles may help some children overcome reading problems that are often caused by visual stress. It has been suggested that for optimal effect each child requires an individually prescribed colour for each eye, as determined in systems such as the "Harris Foundation" coloured filters. Alternatively, it has been argued that only blue or yellow filters, as used in the "Dyslexia Research Trust" (DRT) filter system, are necessary to affect the underlying physiology. METHOD: A randomised, double blind trial with 73 delayed readers, was undertaken to compare changes in reading and spelling as well as irregular and non-word reading skills after 3 months of wearing either the Harris or the DRT filters. RESULTS: Reading improved significantly after wearing either type of filter (t = -8.4, p < 0.01), with 40% of the children improving their reading age by 6 months or more during the 3 month trial. However, spelling ability (t = 2.1, p = 0.05) and non-word reading (f = 4.7, p < 0.05) improved significantly more with the DRT than with the Harris filters. CONCLUSION: Education and rehabilitation professionals should therefore, consider coloured filters as an effective intervention for delayed readers experiencing visual stress. IMPLICATIONS FOR REHABILITATION: Any disability that impacts on a child's capacity to read has serious implications for academic development as well as the ability to participate independently in activities of daily living. One reading disability, generally termed "visual stress", is related to visual disturbances that make it difficult to read text. This research demonstrates the beneficial use of coloured filters for promoting visual reading capacity for children with visual stress. Professionals who are involved in the needs of children with reading delay, may like to consider the benefits that coloured filters can afford children with visual reading problems.
Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort
Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children-the NeuroDys cohort-that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case-control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case-control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects. © 2014 Macmillan Publishers Limited All rights reserved.