Improving reading skills in children with dyslexia: efficacy studies on a newly proposed remedial intervention-repeated reading with vocal music masking (RVM).

In this work, two different studies are examined to evaluate the effectiveness of a novel intervention program for the improvement of reading ability in children with dyslexia, known as repeated reading with vocal music masking (RVM). The proposed remedial approach is inspired by Breznitz's original work. The studies assess a 5-week program of intensive RVM training in a pre-post-test clinical paradigm, as well as a longitudinal paradigm where it is compared to 8 months of the standard remediation program (SRP). The results of both studies support the efficacy of the newly proposed RVM method. Notably in the longitudinal study, the reading speed of children, as well as related phonological, visuo-attentional, and cognitive skills, and attitudes toward reading, were measured regularly. Significant improvements in reading efficiency and related skills were observed, as well as greater motivation to read after RVM training. A modeling of the data specifically linked executive and processing speed skills to be involved in RVM training, suggesting that RVM may help rebalance the phonological and orthographic coding procedures necessary for efficient reading. The short, intensive, and focused nature of RVM training makes it a viable and attractive intervention for clinical practice. As preliminary results are promising, RVM training may prove to be a valuable tool that clinicians can call upon to effectively treat reading fluency disorders, especially when standard programs do not provide results.

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia.

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1-/- induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

Nature and Specificity of Gestural Disorder in Children with Developmental Coordination Disorder: A Multiple Case Study.

Aim: Praxis assessment in children with developmental coordination disorder (DCD) is usually based on tests of adult apraxia, by comparing across types of gestures and input modalities. However, the cognitive models of adult praxis processing are rarely used in a comprehensive and critical interpretation. These models generally involve two systems: a conceptual system and a production system. Heterogeneity of deficits is consistently reported in DCD, involving other cognitive skills such as executive or visual-perceptual and visuospatial functions. Surprisingly, few researches examined the impact of these functions in gestural production. Our study aimed at discussing the nature and specificity of the gestural deficit in DCD using a multiple case study approach. Method: Tasks were selected and adapted from protocols proposed in adult apraxia, in order to enable a comprehensive assessment of gestures. This included conceptual tasks (knowledge about tool functions and actions; recognition of gestures), representational (transitive, intransitive), and non-representational gestures (imitation of meaningless postures). We realized an additional assessment of constructional abilities and other cognitive domains (executive functions, visual-perceptual and visuospatial functions). Data from 27 patients diagnosed with DCD were collected. Neuropsychological profiles were classified using an inferential clinical analysis based on the modified t-test, by comparison with 100 typically developing children divided into five age groups (from 7 to 13 years old). Results: Among the 27 DCD patients, we first classified profiles that are characterized by impairment in tasks assessing perceptual visual or visuospatial skills (n = 8). Patients with a weakness in executive functions (n = 6) were then identified, followed by those with an impaired performance in conceptual knowledge tasks (n = 4). Among the nine remaining patients, six could be classified as having a visual spatial/visual constructional dyspraxia. Gestural production deficits were variable between and within profiles. Discussion: This study confirmed the heterogeneity of gestural production deficit among children with a diagnosis of DCD, at both intra- and inter-individual levels. The contribution of other cognitive deficits in most of the profiles allows discussing the specificity of gestural difficulties. This argues in favor of the necessity to distinguish gestural problems with other deficits made apparent through gesture.

Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

Partial Xp11.23-p11.4 duplication with random X inactivation: clinical report and molecular cytogenetic characterization.

Partial duplications of the short arm of the X chromosome are relatively rare and have been described in males and females. We describe a 4 10/12-year-old girl presenting with developmental delay, severe language retardation and minor anomalies with slightly elevated head circumference (+1.8 SD), prominent forehead, wide palpebral fissures and anteverted nares. No pigmentary dysplasia of the skin was present. The external genitalia were normal. The karyotype completed by cytogenetic analysis with the Whole Chromosome Painting probe of chromosome X revealed a de novo partial duplication of the short arm of an X chromosome. In order to further characterize the duplicated segment, we used a series of BAC probes extending from band Xp11.22 to Xp22.1. BACs from Xp11.23 to Xp11.4 were duplicated. The karyotype was finally defined as 46,X,dup(X)(p11p11).ish dup(X)(p11.23p11.4)(WCPX+,RP11-416I6++,RP11-386N14++,RP11-466C12++). The X-inactivation status was studied using the human androgen receptor (HUMARA) and the FRAXA locus methylation assay. Unexpectedly, the two X chromosomes were found to be randomly inactivated, in the proband. Indeed, usually, in women with structurally abnormal X chromosome, the abnormal X chromosome is preferentially inactivated and those patients share an apparent normal phenotype. So, we speculate that in the present case, the phenotype of the patient could be explained by a functional disomy of the genes present in the duplicated region. We will discuss the possible implication of these genes on the observed phenotype.