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In the last years, there has been a big effort to identify risk factors for reading difficulties and to develop new methodologies to help struggling readers. It has been shown that early intervention is more successful than late intervention, and that intensive training programs can benefit children with reading difficulties. The aim of our study is to investigate the effectiveness of an intensive computerized phonological training program designed to improve reading performance in a sample of children with reading difficulties at the early stages of their reading learning process. Thirty-two children with reading difficulties were randomly assigned to one of the two intervention groups: RDIR (children with reading difficulties following a computerized intensive remediation strategy) (n = 20) (7.01 ± 0.69 years), focused on training phonemic awareness, decoding and reading fluency through the computational training; and RDOR (children with reading difficulties following an ordinary remediation strategy) (n = 12) (6.92 ± 0.82 years), which consisted of a reinforcement of reading with a traditional training approach at school. Normal readers (NR) were assigned to the control group (n = 24) (7.32 ± 0.66 years). Our results indicate that both the RDIR and RDOR groups showed an increased reading performance after the intervention. However, children in the RDIR group showed a stronger benefit than the children in the RDOR group, whose improvement was weaker. The control group did not show significant changes in reading performance during the same period. In conclusion, results suggest that intensive early intervention based on phonics training is an effective strategy to remediate reading difficulties, and that it can be used at school as the first approach to tackle such difficulties.

The link between literacy difficulties and brain alterations has been described in depth. Resting-state fMRI (rs-fMRI) has been successfully applied to the study of intrinsic functional connectivity (iFc) both in dyslexia and typically developing children. Most related studies have focused on the stages from late childhood into adulthood using a seed to voxel approach. Our study analyzes iFc in an early childhood sample using the multivariate pattern analysis. This facilitates a hypothesis-free analysis and the possible identification of abnormal functional connectivity patterns at a whole brain level. Thirty-four children with literacy difficulties (LD) (7.1 ± 0.69 yr.) and 30 typically developing children (TD) (7.43 ± 0.52 yr.) were selected. Functional brain connectivity was measured using an rs-fMRI acquisition. The LD group showed a higher iFc between the right middle frontal gyrus (rMFG) and the default mode network (DMN) regions, and a lower iFc between the rMFG and both the bilateral insular cortex and the supramarginal gyrus. These results are interpreted as a DMN on/off routine malfunction in the LD group, which suggests an alteration of the task control network regulating DMN activity. In the LD group, the posterior cingulate cortex also showed a lower iFc with both the middle temporal poles and the fusiform gyrus. This could be interpreted as a failure in the integration of information between brain regions that facilitate reading. Our results show that children with literacy difficulties have an altered functional connectivity in their reading and attentional networks at the beginning of the literacy acquisition. Future studies should evaluate whether or not these alterations could indicate a risk of developing dyslexia.

The link between literacy difficulties and brain alterations has been described in depth. Resting-state fMRI (rs-fMRI) has been successfully applied to the study of intrinsic functional connectivity (iFc) both in dyslexia and typically developing children. Most related studies have focused on the stages from late childhood into adulthood using a seed to voxel approach. Our study analyzes iFc in an early childhood sample using the multivariate pattern analysis. This facilitates a hypothesis-free analysis and the possible identification of abnormal functional connectivity patterns at a whole brain level. Thirty-four children with literacy difficulties (LD) (7.1 ± 0.69 yr.) and 30 typically developing children (TD) (7.43 ± 0.52 yr.) were selected. Functional brain connectivity was measured using an rs-fMRI acquisition. The LD group showed a higher iFc between the right middle frontal gyrus (rMFG) and the default mode network (DMN) regions, and a lower iFc between the rMFG and both the bilateral insular cortex and the supramarginal gyrus. These results are interpreted as a DMN on/off routine malfunction in the LD group, which suggests an alteration of the task control network regulating DMN activity. In the LD group, the posterior cingulate cortex also showed a lower iFc with both the middle temporal poles and the fusiform gyrus. This could be interpreted as a failure in the integration of information between brain regions that facilitate reading. Our results show that children with literacy difficulties have an altered functional connectivity in their reading and attentional networks at the beginning of the literacy acquisition. Future studies should evaluate whether or not these alterations could indicate a risk of developing dyslexia.

Autosomal dominant mutations in

International audience; Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-D-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GIuN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GIuN2B-containing NMDAR5. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist D-serine restored function to GluN2B(P553T)-containing NMDAR5. L-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of D-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of L-serine dietary supplementation. Our data suggest that L-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

Background CblC deficiency produces a combination of methylmalonic aciduria (MMA) and homocystinuria (HCU), and is the most common error of cobalamin metabolism. Patients present a wide spectrum of symptoms, ranging from early severe multisystemic forms, to milder late-onset phenotypes. Cognitive and visual impairment are nearly constant. Hydroxocobalamin (OHCbl), betaine, folinic acid, levocarnitine and eventually dietary protein restriction are the main therapeutic approaches. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adaptation exist. No reports on long-term outcomes after high doses of this vitamin have been published. Methods In this study five patients with CblC deficiency (early severe forms) were treated with high doses of OHCbl for 18 to 30 months. Clinical examinations, neurological assessment, and biochemical studies (plasma total homocysteine (tHcy), amino acids, hydroxocobalamin, and methylmalonic acid in urine) were periodically performed. Results Variable clinical and biochemical outcomes were observed in patients treated with high doses of OHCbl. The best biochemical response was observed in those children with the worse metabolic control. By contrast, those patients with a concentration of tHcy around 50 μmol/l or less showed only minor changes. Clinically, a considerable improvement was observed in those patients with severe problems in communication, expressive language and behavior. Conclusions According to our study, high OHCbl doses in CblC deficiency could have a greater benefit in those children with a prior history of suboptimal metabolic control, and also in those with severe neurological phenotypes. More specifically, we observed improvements in communication skills and behavior. These results should encourage further prospective trials to determine the optimal OHCbl regimen and to generate protocols and guidelines in this rare disorder.

Background N -Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B (p.P553T) coding for the GluN2B subunit of NMDAR. Methods We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. Results Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. Conclusions Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.

This paper describes in detail the robot platform used in a rehabilitation program for children with Traumatic Brain Injury (TBI) under a project to compare a rehabilitation program through robotics (1) with a conventional rehabilitation program directed to parents (2) and a control group where no specific intervention is done (3). As LEGO ® has been demonstrated as a useful robotic tool able to enhance children motivation, we have used it attached to an iPod which includes several activities defined by neuropsychologists and customized for each patient. In this paper we present the hardware and the software of this robotic platform and also the description of the activities that have already been proposed to patients. We present results about the use of the robot showing that the drop-out rate is lower in the intervention group with robots than in the program directed to parents.

INTRODUCTION. Phenylketonuria (PKU) is an autosomal recessive metabolic disease caused by a deficiency of phenylalanine hydroxylase. The dietary therapy for the effective management of PKU, in particular the restriction of high-protein foods of animal-origin, compromises patients' intake of fat and distorts the n-3:n-6 ratio of essential fatty acids in the diet. This deficiency can contribute to neurological and visual impairment. AIM. To evaluate changes in white matter alterations, visual evoked potential (VEP) latencies and performance in executive and motor functions in a group of early and continuously treated PKU patients after supplementation with docosahexaneoic acid (DHA). PATIENTS AND METHODS. We selected 21 PKU patients with early diagnosis (age range: 9-25 years), on a Phe-restricted diet and supplemented with PKU formula. Inclusion criteria were: low erythrocyte DHA values, prolonged P100 wave latencies in VEP and/or presence of white matter hyperintensities on brain magnetic resonance imaging (MRI), and intellectual quotient80. All patients were treated with DHA (10 mg/kg/day) for 12 months. Assessment was conducted at baseline and after 12 months of treatment, and included biochemical parameters, brain MRI, VEP, ophthalmologic evaluation and neuropsychological tests. RESULTS AND CONCLUSION. All the patients normalized the DHA levels after supplementation. Improvement in the P100 wave latencies, and fine motor skills was significant. No significant improvement in the other explorations was evident after supplementation. Further investigations seem advisable to establish a cause-effect relationship between DHA treatment and the slight improvement observed in some neurological functions.

Creatine transporter (CRTR) deficiency is one of the most frequent causes of X-linked mental retardation. The lack of an effective treatment for this disease, in contrast to creatine (Cr) biosynthesis disorders that respond to Cr monohydrate (CM), led us to analyze the efficacy of a lipophilic molecule derived from Cr, creatine ethyl ester (CEE), in fibroblasts and patients with CRTR deficiency. CM and CEE uptake studies were performed in six controls and four fibroblast cell lines from patients. We found a significant increase in Cr uptake after 72 h of incubation with CEE (500 micromol/L) in patients and control fibroblasts compared to incubation with CM. Subsequently, we assayed the clinical effect of CEE administration in four patients with CRTR deficiency. After 1 year of treatment, a lack of significant improvement in neuropsychological assessment or changes in Cr level in brain (1)H MRS was observed, and CEE was discontinued. In conclusion, this 12-month trial with CEE did not increase the brain concentration of Cr. Our in vitro data lend support to the idea of a certain passive transport of CEE in both pathological and control cells, although more lipophilic molecules or other cell systems that mimic the BBB should be used for a better approach to the in vivo system.

This study investigated the relationship between school performance, cognitive functions, and dietary control in a group of 26 early and continuously treated phenylketonuric patients, in comparison with 21 sex- and age-matched control subjects. The cognitive functions study included intelligence measurement, visual and auditory memory and auditory verbal learning abilities, attention, visuospatial, fine motor, language, and executive functions. Participants were asked about school performance. The indexes of dietary control for the first 6 years of life and for the 6 months before the study were calculated. The intelligence score was significantly lower in phenylketonuric patients (P < 0.0001). The percentage of patients with attention problems (P = 0.02), fine motor (P = 0.001) and executive dysfunctions (P = 0.013) was significantly higher than that for control subjects. Patients had more school problems than controls (P = 0.028). Intelligence score was also significantly lower in these patients (P = 0.046). The index of dietary control for the last 6 months was significantly higher than the index for the first 6 years of life, but only in the patients with school problems (P = 0.033). In conclusion, phenylketonuric patients presented more school problems than control subjects, probably related to the disturbed cognitive functions observed. The index of dietary control for the last 6 months yielded a close relationship with school performance.

Introducció: la dislèxia és el trastorn de l’aprenentatge més freqüent en la població infantil amb repercussions importants en el desenvolupament acadèmic, social i emocional dels infants que la pateixen. En els darrers anys s’ha fet un gran esforç per identificar quins són els factors de risc de les dificultats lectores i desenvolupar noves metodologies per ajudar als infants a superar-les. S’ha demostrat que la intervenció primerenca té més èxit que la tardana i que els programes d’entrenament intensiu poden beneficiar els nens i les nenes amb dificultats de lectura. Objectiu: avaluar els canvis cognitius i cerebrals associats a l’aplicació d’un programa intensiu d’entrenament fonològic informatitzat per millorar el rendiment lector en infants de primer cicle d’educació primària amb dificultats lectores. Metodologia: trenta-dos nens i nenes amb dificultats de lectura es van assignar aleatòriament a cadascun dels dos grups d’intervenció amb una durada de 16 setmanes, el grup amb dificultats lectores d’entrenament intensiu informatitzat (sessions diàries individuals de 10-15 minuts, 5 dies a la setmana), DLEI (n=20), centrat en el treball de consciència fonològica, fonèmica, descodificació i velocitat lectora i el grup amb dificultats lectores d’entrenament ordinari a l’aula (1 sessió setmanal de 50 minuts cadascuna, en grup reduït), DLEO (n=12), que va rebre reforç tradicional de lectura a l’escola basat en lectura col·lectiva i modelatge de la mestra. Els nens i les nenes sense dificultats lectores es van assignar al grup de control C (n=24). Tots/es els i les alumnes van ser valorats mitjançant un protocol cognitiu i de neuroimatge en dos moments temporals, abans i després de la intervenció. Resultats: tant els infants del grup DLEI com DLEO van mostrar un major rendiment de lectura després de la intervenció sent superior el del grup DLEI. El grup de C no va mostrar canvis significatius durant el mateix període. Vam observar que presentar rendiments baixos en les variables de precisió i velocitat lectora de pseudoparaules, precisió lectora de paraules i text així com en ortografia natural són predictores d’un baix rendiment en lectura. Tanmateix, la velocitat lectora de lletres, la precisió lectora de pseudoparaules i l’ortografia natural serien les tres variables predictores de l’èxit de la reeducació intensiva. El perfil lector dels alumnes amb dificultats lectores (65,62%) va ser d’afectació mixt. Les anàlisis VBM van objectivar un % de VSB superior en el grup DLEI associat a la intervenció intensiva. Conclusions: els resultats suggereixen que la intervenció primerenca intensiva basada en l’entrenament fonològic, és una estratègia eficaç per solucionar les dificultats de lectura que s’hauria d’utilitzar a l’escola com a primer enfocament per afrontar-les. ntroducción: la dislexia es el trastorno de aprendizaje más frecuente en la población infantil con repercusiones importantes en el desarrollo académico, social y emocional de los niños y las niñas que la padecen. En los últimos años se ha hecho un gran esfuerzo para identificar cuáles son los factores de riesgo de las dificultades lectoras y desarrollar nuevas metodologías para ayudar a los niños y niñas a superarlas. Se ha demostrado que la intervención precoz tiene más éxito que la tardía y que los programes de entrenamiento intensivo pueden beneficiar a los niños y niñas con dificultades lectoras. Objetivo: evaluar los cambios cognitivos y cerebrales asociados a la aplicación de un programa intensivo de entrenamiento fonológico informatizado para mejorar el rendimiento lector en niños y niñas de primer ciclo de educación primaria con dificultades lectoras. Metodología: treinta y dos niños y niñas con dificultades lectoras fueron asignados aleatoriamente a cada uno de los dos grupos de tratamiento con una duración de 16 semanas, el grupo de entrenamiento intensivo informatizado (sesiones diarias individuales de 10-15 minutos, 5 días a la semana), DLEI (n=20), centrado en el trabajo de conciencia fonológica, fonémica, decodificación y velocidad lectora y el grupo de entrenamiento ordinario en el aula (1 sesión semanal de 50 minutos cada una, en grupo reducido), DLEO (n=12), que recibió refuerzo tradicional de lectura en la escuela basado en lectura colectiva y modelado de la maestra. Los niños y niñas sin dificultades lectoras fueron asignados al grupo control, C (n=24). Todos los alumnos y alumnas fueron valorados mediante un protocolo cognitivo y de neuroimagen en dos momentos temporales, antes y después de la intervención. Resultados: los niños y niñas del grupo DLEI y DLEO mostraron un mayor rendimiento de lectura después de la intervención siendo superior el del grupo DLEI. El grupo C no mostró cambios significativos durante el mismo período. Pudimos observar que presentar rendimientos bajos en las variables de precisión y velocidad de pseudopalabras, precisión lectora de palabras y texto así como en ortografía natural son predictoras de dificultades lectoras. A su vez, la velocidad lectora de letras, la precisión lectora de pseudopalabras y la ortografía natural serían las tres variables predictoras del éxito de la reeducación intensiva. El perfil lector de los y las alumnos/as con dificultades lectoras (65,62%) fue de afectación mixto. Los análisis VBM objetivaron un % de VSB superior en el grupo DLEI asociado a la intervención intensiva. Conclusiones: los resultados sugieren que la intervención precoz intensiva basada en entrenamiento fonológico, es una estrategia eficaz para solucionar las dificultades de lectura y que se puede utilizar en la escuela como primer enfoque para afrontar estas dificultades. Introduction: dyslexia is the most common learning disorder in children population and there have a great impact on academic, social and emotional development to the child that suffer from it. Over the last few years there has been a great amount of effort in order to identify what are the risk factors related to reading disabilities and to develop new methodologies to help children to overcome them. It has been proved that an early intervention has a better success than a late one, and that intensive training programs can benefit little boys and girls with reading disabilities. Goal: the evaluation of brain and cognitive changes related to the use of a phonological intensive training software program to improve reading performance on children with reading disabilities in first and second grade. Methodology: thirty-two little boys and girls with reading disabilities were randomly assigned to two intervention groups in 16-week period; one of theses two groups was the intensive training software program group (10-15 minutes individual daily training sessions, 5 days per week) DLEI (n=20), focused on phonological conscience work, phonemics, decoding and reading speed, and the classic "training-at-classroom" group (1 weekly 50 minutes session in small groups), DLEO (n=12), that had received reading reinforcement at school based on collective reading and teacher modelling. Normal readers (C) were assigned to the control group (n=24). All young boys and girls were evaluated through a cognitive and neuroimaging protocol in two temporal stages, before and after the intervention. Results: both DLEI and DLEO kids showed an improved reading capacity after the intervention, with better results on the DLEI group. C group did not show substantial changes on the same period. We found that a low performance on the accuracy and reading speed of pseudowords, words and text reading accuracy and also in natural orthography are predictor variables of a low reading performance. Nevertheless, reading speed of letters, reading accuracy of pseudowords and natural orthography are the three predictor variables that show a favourable outcome of an intensive training. The reading profile of students with reading disabilities (65,62%) was a mixed involvement. VBM analysis put in objective terms a higher percentage of VSB in the DLEI group related to intensive intervention. Conclusions: results suggest that an early intensive intervention based on phonological training is an effective strategy to solve reading disabilities and it can be used at school as a first approach to face up with such disabilities. Universitat Autònoma de Barcelona. Programa de Doctorat en Psiquiatria