Xq27 FRAXA locus is a strong candidate for dyslexia: evidence from a genome-wide scan in French families.

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 50 UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227–DXS8091) to 4 Mb also disclosing a higher LOD score

Psychocognitive and psychiatric disorders associated with developmental dyslexia: A clinical and scientific issue.

Abstract INTRODUCTION: Dyslexia is a complex neurodevelopemental disorder that affects 5 to 10% of school-age children. This condition consists in a specific learning disability with a neurological origin. These learning difficulties are unexpected in relation to other cognitive abilities and the provision of efficient classroom instruction. A range of neurobiological investigations suggests that disruption of the parieto-temporo-occipital systems underlies a failure of skilled reading to develop. The observation that dyslexia is both a familial and heritable problem was made early on and was confirmed by twin studies. They also suggested that both genetic and environmental factors are involved. Several loci have been implicated in dyslexia, notably on chromosomes 2, 3, 6, 15 and 18 and some candidate genes have been proposed, but no functional mutation has yet been identified. LITERATURE REVIEW: Dyslexia seldom appears isolated and dyslexic people are very likely to present other kinds of learning disabilities or psychiatric disorders. Specific language impairment, often with a mild outcome, is the most frequently associated with dyslexia. Indeed, late language development is often reported by dyslexic patients and also occurs more frequently among their siblings. Genetic linkage studies suggest some common genetic factor underlying this comorbidity. Dyscalculia is associated with dyslexia in 25% of cases, but most people with dyscalculia do not have any sign of dyslexia. The question of whether dyscalculia associated with dyslexia and dyscalculia itself rely on the same cognitive impairment is still controversial. Impaired motor development is also a common feature that affects nearly 50% of dyslexics and dyslexia is frequent among dyspraxic patients. This association raises the discussion on the role of motor impairment in dyslexia's physiopathology and the cerebellar theory of dyslexia. Beyond its link with other learning disorders, the study of dyslexia's comorbidity highlights psychopathological issues. ADHD is the most frequent psychiatric disorder associated with dyslexia. Underpinnings of this link between the two disorders seem to rely on common cognitive and genetic factors. Some authors have proposed a candidate gene ADRA2A to determine the condition including ADHD and dyslexia. In addition, dyslexics are exposed to a higher risk of anxiodepressive and behavioural disorders. Dyslexic children experience three times more behavioural disorders and one third of children with behavioural problems turn out to be affected by dyslexia. The literature study reveals inconsistent findings about depressed mood among dyslexics, but evidence of a persistent increase in the rate of anxiety disorders. The authors put forward the impact of environmental factors to explain these psychiatric comorbidities. CONCLUSION: This review emphasizes dyslexia's comorbidities because they represent an important issue, both from a scientific and clinical point of view. Indeed, for clinicians, children showing multiple learning disabilities have specific reeducation and educational needs and dyslexics have a higher risk of emotional and behavioural disorders. On the other hand, dyslexia's comorbidity study provides a powerful method for researchers to investigate the still unknown physiopathology of dyslexi

Stimulation of lactate production in human granulosa cells by metformin and potential involvement of adenosine 5' monophosphate-activated protein kinase

Context: production of 3-carbon units (as lactate) by granulosa cells (GCs) is important in follicular and oocyte development and may be modulated by metformin.Objective: the aim of the study was to examine the action of metformin on GC lactate production and potential mediation via AMP-activated protein kinase (AMPK).Design: GCs were prepared from follicular aspirates. After exposure to metformin and other potential modulators of AMPK in culture, aspects of cellular function were examined.Setting: the study was conducted in a private fertility clinic/university academic center.Patients: women undergoing routine in vitro fertilization participated in the study.Interventions: all agents were added in culture.Main outcome measures: lactate output of GCs was measured. Cell extracts were prepared after culture, and phosphorylated forms of AMPK and acetyl CoA carboxylase (ACC) were assayed using Western analysis.Results: metformin led to a rapid increase in lactate production by GCs [minimum effective dose, 250 mu M; maximum dose studied, 1 mM (1.22-fold; P &lt; 0.01)]. This dose range of metformin was similar to that required for stimulation of phospho-AMPK in GCs [minimum effective dose, 250 mu M; maximum effect, 500 mu M (2.01-fold; P &lt; 0.001)]. Increasing phospho-ACC, as a representative downstream target regulated by AMPK, was apparent over a lower range (minimum effective dose, 31 mu M; maximum effect, 250 mu M; P &lt; 0.001). A level of metformin (125 mu M) insufficient for the stimulation of lactate output when used alone potentiated the effects of suboptimal doses of insulin on lactate production. Adiponectin (2.5 mu g/ml) had a small but significant effect on lactate output.Conclusions: metformin activates AMPK in GCs, stimulating lactate production and increasing phospho-ACC. Metformin also enhances the action of suboptimal insulin concentrations to stimulate lactate production. (J Clin Endocrinol Metab 94: 670-677, 2009<br/

The Effect of AMP-Activated Kinase Activation on Gonadotrophin-Releasing Hormone Secretion in GT1-7 Cells and its Potential Role in Hypothalamic Regulation of the Oestrous Cyclicity in Rats

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