Nathalie Angeard

Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression

The presence of variable degrees of cognitive impairment, extending from severe mental retardation to specific deficits, in patients with dystrophinopathies is a well-recognized problem. However, molecular basis underlying mental retardation and its severity remain poorly understood and still a matter of debate. Here, we report one of the largest study based on the comparison of clinical, cognitive, molecular and expression data in a large cohort of 81 patients affected with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products, including Dp71 or all dystrophin products, except Dp71. In addition to the consistent data defining molecular basis underlying mental retardation in DMD, we show that BMD patients with MR have mutations that significantly affect Dp71 expression or with mutations located in exons 75 and 76. We also show that mutations upstream to exon 62, with DMD phenotype, predicted to lead to a loss-of-function of all dystrophin products, except Dp71 isoform, are associated, predominantly, with normal or borderline cognitive performances. Altogether, these reliable phenotype-genotype correlations in combination with Dp71 mRNA and protein expression studies, strongly indicate that loss-of-function of all dystrophin products is systematically associated with severe form of MR, and Dp71 deficit is a factor that contributes in the severity of MR and may account for a shift of 2 SD downward of the intelligence quotient.

Executive function and theory of mind in school-aged children after neonatal corrective cardiac surgery for transposition of the great arteries

Aimu2002 Cardiac malformations resulting in cyanosis, such as transposition of the great arteries (TGA), have been associated with neurodevelopmental dysfunction. The purpose of this study was to assess, for the first time, theory of mind (ToM), which is a key component of social cognition and executive functions in school‐aged children with TGA.

Impact of prenatal diagnosis on neurocognitive outcomes in children with transposition of the great arteries.

OBJECTIVESnTo assess the effect of prenatal diagnosis of congenital heart disease on neurocognitive outcomes in children with d-transposition of the great arteries (TGA) after surgical correction.nnnSTUDY DESIGNnA prospective study of children born with a TGA between 2003 and 2005 and aged 4 to 6 years was conducted. General intelligence, language, executive functions, and social cognition scores and preoperative, intraoperative, and postoperative factors were evaluated according to time of TGA diagnosis. Neurocognitive data were also compared with a control group.nnnRESULTSnForty-five eligible patients (67% male) were examined; 29 had a prenatal diagnosis of TGA and 16 did not. All children were comparable in age, sex, and demographic variables. Diagnostic groups did not differ in preoperative, intraoperative, and postoperative variables. Preoperative acidosis was more frequent in the postnatal group (18% versus 3%). All patients had normal IQ scores, language, and verbal working memory. However, neurocognitive deficits were more prevalent and more severe in children with a postnatal-TGA. Prenatal diagnosis was associated with better outcomes in executive functions.nnnCONCLUSIONSnPrenatal diagnosis of TGA is associated with better neurocognitive outcomes. Time of diagnosis may influence the development of early complex cognitive skills such as executive functions.

Theory of mind: is training contagious?

In this study, preschool children were successfully trained in theory of mind tasks, namely false belief inference and appearance–reality distinction. Results show that both types of training had a direct effect, as measured by the improvement of performance on the FB and AR delayed post-tests. Both types of training also had an indirect effect, as measured by transfer of the benefits of the training to the task that was not in the training. Finally, both types of training were effective even when the children were trained in a task they had already mastered.

Deductive reasoning and matching-bias inhibition training: Evidence from a debiasing paradigm

Using the matching bias example, the aim of the present studies was to show that adults reasoning biases are due to faulty executive inhibition programming. In the first study, the subjects were trained on Wasons classical card selection task; half were given training in how to inhibit the perceptual matching bias (experimental group) and half in logic without the inhibition component (control group). On the pre- and post-tests, their performance was assessed on the Evans conditional rule falsification task (with a negation in the antecedent of the rule), a task that also involves matching bias. In addition, subjects were tested for perceptual field dependence/independence using the Embedded Figures Test. The results brought out a specific inhibition training effect, as well as a clear-cut relationship in the experimental group between receptiveness to training and perceptual field independence. In the second study, the training paradigm was the same except that on the pre- and post-tests, the negation was in the consequent of the conditional rule (in this case, the perceptual matching response corresponds to the logical response). The subjects succeeded on the pre-test, and the matching-bias inhibition training had a negative effect on post-test performance. This specific negative priming effect confirms the inhibitory impact of our experimental training and outlines the dissociation of inhibition and logical components.

Psychiatric and cognitive phenotype in children and adolescents with myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is the most frequent inherited neuromuscular disorder. The juvenile form has been associated with cognitive and psychiatric dysfunction, but the phenotype remains unclear. We reviewed the literature to examine the psychiatric phenotype of juvenile DM1 and performed an admixture analysis of the IQ distribution of our own patients, as we hypothesised a bimodal distribution. Two-thirds of the patients had at least one DSM-IV diagnosis, mainly attention deficit/hyperactivity disorder and anxiety disorder. Two-thirds had learning disabilities comorbid with mental retardation on one hand, but also attention deficit, low cognitive speed and visual spatial impairment on the other. IQ showed a bi-modal distribution and was associated with parental transmission. The psychiatric phenotype in juvenile DM1 is complex. We distinguished two different phenotypic subtypes: one group characterised by mental retardation, severe developmental delay and maternal transmission; and another group characterised by borderline full scale IQ, subnormal development and paternal transmission.

Cognitive profile in childhood myotonic dystrophy type 1: Is there a global impairment?

The objective of this study was to assess the cognitive profile in the childhood-onset form of myotonic dystrophy (DM1). We carried out a general cognitive abilities study on 36 patients (6-18 years). Results of Full Scale IQ , VIQ (Verbal IQ) and PIQ (Performance IQ) measures are discussed in terms of global cognitive impairment depending on the (CTG)n repeat size and the transmitting parents sex. The results highlighted a negative correlation between the CTG repeat size and cognitive function: (1) 55% of the subjects (20/34) presented large CTG expansion (mean=761) correlated with significant extensive cognitive deficits (mean Full Scale IQ=56) in both intelligence scales (verbal and non-verbal); most of them exhibited DM1 maternal transmission. (2) In the case of smaller expansion (mean=527), 38% of the subjects exhibited a subnormal intelligence (mean Full Scale IQ=86) but performed poorly on subtests evaluating attention/memory function and presented a severe deficit in visuospatial and/or visuo-constructive skills. Most of these children had paternal transmission but a few had an affected mother.

Psychiatric and cognitive phenotype of childhood myotonic dystrophy type 1

Aimu2002 To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1).

A new window on neurocognitive dysfunction in the childhood form of myotonic dystrophy type 1 (DM1)

Not much is known about the neurocognitive deficits in the childhood phenotypic expression of DM1. Twenty-four children and adolescents with no mental retardation were administered an extensive neuropsychological battery to investigate cognition in terms of memory, executive functions and visuo-spatial abilities. The results showed discrepancies between Wechslers indexes with higher scores in Verbal Comprehension than Perceptive Organization and Speed of Processing. Memory assessment using Signorets Memory Battery revealed a clear difference between verbal and visuospatial memory but no impairment between short and long-term memory. Concerning executive abilities, DM1 subjects showed greater deficits in processing speed than in mental flexibility, inhibition or working memory. This pattern of deficits could implicate a frontoparietal circuit in accordance with the neural networks involved in the adult form of DM1 and reopens the question of a continuum between childhood and adulthood neurocognitive impairments.

Executive Functions Development in 5- to 7-Year-Old Children With Transposition of the Great Arteries: A Longitudinal Study

This longitudinal study investigates executive functions (EF) in children with transposition of the great arteries (TGA) compared to typically developing children at a key age period between 5 and 7 years. We explored the presence and evolution of specific impairments on three core EF components (inhibition, working memory, and cognitive flexibility). Ninety children were evaluated for three consecutive years. Results demonstrated significant delays in inhibition and cognitive flexibility despite normal working memory. Impairments did not systematically worsen with age. EF impairments after TGA are dynamic and may affect selective components. Cyanotic congenital heart disease is associated with altered EF development.