Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

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.

Improving Reading Skills Using a Computerized Phonological Training Program in Early Readers with Reading Difficulties.

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.

Functional connectivity alterations associated with literacy difficulties in early readers.

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.

Age-related brain structural alterations in children with specific language impairment.

Previous neuroimaging studies have suggested that children with specific language impairment (SLI) may show subtle anatomical alterations in specific brain regions. We aimed to characterize structural abnormalities in children with SLI using a voxel-wise analysis over the whole brain. Subjects covered a wide age range (5-17 years) in order to assess the dynamic nature of the disorder across childhood. Three-dimensional MRIs were collected from 36 children with SLI and from a comparable group of healthy controls. Global gray and white matter measurements were obtained for each subject, and voxel-based morphometry (VBM) was used to evaluate between-group differences in regional brain anatomy. Possible age-related changes were assessed in separate analyses of younger (below 11 years of age) and older children. SLI patients showed larger global gray and white matter volumes, particularly in the younger subgroup. Voxel-wise analyses of the whole sample showed two regions of increased gray matter volume in SLI: the right perisylvian region and the occipital petalia. Age-group analyses suggested a more extended pattern of volume increases in the younger subjects, which included entorhinal, temporopolar, caudate nucleus, motor-precentral and precuneus gray matter, and white matter of the frontal and temporal lobes. Our results suggest that in the SLI brain there are enduring anatomical alterations that exist across a wide age range, as well as a distributed pattern of abnormalities that appear to normalize with development. They also suggest that the neuroanatomical basis of SLI may be better characterized by considering the dynamic course of the disorder throughout childhood.

Memoria episódica verbal en pacientes pediátricos intervenidos de cirugía de la epilepsia del lóbulo temporal: un estudio de seguimiento al año / Verbal episodic memory in children undergoing temporal lobe epilepsy surgery: a one-year follow-up study

Introducción La memoria episódica verbal (MEV) no suele resultar alterada en niños con epilepsia focal sometidos a resecciones del lóbulo temporal izquierdo, a diferencia de lo que cabría esperar si se tratara de un cerebro adulto. Los últimos hallazgos sugieren que la actividad epileptógena en los primeros años de vida disrumpe la lateralización del sistema mnésico, lo que conduce al desarrollo de una representación bilateral de la memoria. El presente estudio pretende analizar si la lateralidad de la epilepsia es un predictor significativo de cara al pronóstico posquirúrgico de la MEV en la cirugía de la epilepsia del lóbulo temporal (ELT) en edad pediátrica. Esta investigación también pretende aportar evidencias sobre la relación de la MEV con otros factores demográficos y clínicos relevantes, como el sexo, la edad de inicio de las crisis, la edad quirúrgica y la duración de la epilepsia, así como estudiar el impacto del rendimiento prequirúrgico en la MEV sobre los resultados posquirúrgicos. Pacientes y métodos Se extrajeron de la base de datos del Hospital Sant Joan de Déu y se analizaron retrospectivamente las puntuaciones prequirúrgicas y al año de seguimiento postoperatorio de una tarea de recuerdo de lista de palabras correspondientes a 25 niños intervenidos de ELT (ELT izquierdo, n = 11; ELT derecho, n = 14). Resultados No se encontraron diferencias intergrupales prequirúrgicas significativas al comparar las puntuaciones en MEV sobre la base de la lateralidad de la epilepsia (p > 0,5). En cuanto al grupo de ELT izquierdo, se encontró una alta correlación negativa entre la edad de inicio y la puntuación prequirúrgica del recuerdo libre a largo plazo (rho = –0,72; p = 0,01). No se encontraron cambios intragrupo significativos entre el pre- y el postoperatorio en relación con el rendimiento en la MEV, independientemente de la lateralidad de la epilepsia (grupo de ELT izquierdo, p > 0,56; grupo de ELT derecho, p > 0,12). Conclusiones ... (AU)

INTRODUCTION Verbal episodic memory (VEM) is often unimpaired in children with focal epilepsy undergoing left temporal lobe resections, unlike what we might expect in the adult brain. The latter findings suggest that epileptiform activity in early life disrupts memory system lateralization, leading to the development of bilateral memory representation. The present study aims to analyze whether the laterality of epilepsy is a major predictor for post-operative VEM prognosis in pediatric temporal lobe epilepsy (TLE) surgery. This research also pretends to provide evidence about the relationship of VEM performance with other relevant demographical and clinical factors such as sex, age at onset of seizures, age at surgery and duration of epilepsy, as well as to study the impact of presurgical VEM performance on postsurgical outcomes. PATIENTS AND METHODS Pre-operative and one-year follow-up post-operative word-list recall scores from 25 children who underwent TLE surgery (left-sided, n = 11; right-sided, n = 14) were extracted from the Hospital Sant Joan de Déu database and were retrospectively analyzed. RESULTS No significant presurgical intergroup differences were found when comparing VEM scores by laterality of epilepsy (p > 0.5). Looking at the left TLE group, a high negative correlation was found between the onset age and the pre-operative long-term free recall score (rho = –0.72, p = 0.01). No significant pre- to post-operative intragroup changes were found regarding VEM performance, regardless of epilepsy laterality (left TLE group, p > 0.56; right TLE group, p > 0.12). CONCLUSIONS The laterality of epilepsy does not show to be a significant factor in and of itself (AU)

L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy.

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 GluN2B 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 GluN2B-containing NMDARs. 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 NMDARs. 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.

Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement.

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.

A Longitudinal Study on Attention Development in Primary School Children with and without Teacher-Reported Symptoms of ADHD.

Background: Prospective longitudinal studies are essential in characterizing cognitive trajectories, yet few of them have been reported on the development of attention processes in children. We aimed to explore attention development in normal children and children with attention deficit and hyperactivity disorder (ADHD) symptoms in a repeated measures design using the attention network test (ANT). Methods: The population sample included 2,835 children (49.6% girls) aged 7-11 years from 39 schools in Barcelona (Catalonia, Spain) who performed the ANT four times from January 2012 to March 2013. According to teacher ratings, 10.5% of the children presented ADHD symptoms. We performed multilevel mixed-effects linear regression models, adjusting for school and individual, to test the effects of age-related growth on the ANT networks: alerting, orienting and executive attention, and three measurements related to attentiveness: median of hit reaction time (HRT), hit reaction time standard error (HRT-SE) and variability. Results: We observed age-related growth in all the outcomes, except orienting. The curves were steeper at the younger groups, although for alertness the improvement was further at the oldest ages. Gender and ADHD symptoms interacted with age in executive attention, HRT and variability. Girls performed better in executive attention at young ages although boys reached females at around 10 years of age. For HRT, males showed faster HRT. However, girls had a more pronounced improvement and reached the levels of boys at age 11. Children with ADHD symptoms had significant differences in executive attention, HRT and variability compared to children without ADHD symptoms. Conclusions: We detected an ongoing development of some aspects of attention in primary school children, differentiating patterns by gender and ADHD symptoms. Our findings support the ANT for assessing attention processes in children in large epidemiological studies.

School performance in early and continuously treated phenylketonuria.

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.

Perfil y factores pronósticos en el traumatismo craneoencefálico en la edad pediátrica / Prognostic factors and profi le in traumatic brain injury in the paediatric age

INTRODUCCIÓN: El traumatismo craneoencefálico (TCE) es una causa común de muerte y discapacidad en la población pediátrica, aunque la bibliografía en población española sea escasa. Desde la perspectiva de la vulnerabilidad temprana, los hallazgos de investigaciones recientes sugieren que la lesión cerebral temprana tiene peores secuelas y un mayor riesgo de impacto. OBJETIVOS: Analizar el perfil de la inteligencia, las funciones ejecutivas y el comportamiento, y examinar la asociación de la edad a la lesión, la gravedad del TCE y los factores ambientales para los resultados cognitivos y conductuales. PACIENTES Y MÉTODOS: Setenta y un participantes con TCE moderado a grave, con edades entre 6 y 16 años, fueron evaluados con medidas de inteligencia (cociente intelectual), funciones ejecutivas y comportamiento. RESULTADOS: Los niños con TCE tienen un mayor riesgo de discapacidad en todos los aspectos de inteligencia, funciones ejecutivas y comportamiento. Los niños que sufrieron una lesión cerebral traumática en la infancia y preescolar registraron más efectos globales en el cociente intelectual y algunos aspectos de las funciones ejecutivas. CONCLUSIONES: Los factores socioeconómicos y culturales son los mejores predictores para el cociente intelectual y el comportamiento. Estos hallazgos contribuyen a una mejor comprensión de las secuelas de TCE en los niños para ayudar en la planificación de rehabilitación y la readaptación a la vida funcional

INTRODUCTION: Traumatic brain injury (TBI) is a common cause of death and disability in the paediatric population, although the literature on the Spanish population is scarce. From the perspective of early vulnerability, recent research fi ndings suggest that early brain injury has worse sequelae and a higher risk of impact. Aims. To analyse the intelligence profi le, executive functions and behaviour, and examine the association between age at the time of the injury, severity of the TBI and environmental factors for cognitive and behavioural outcomes. PATIENTS AND METHODS: Seventy-one participants with moderate to severe TBI, from 6 to 16 years of age, were assessed with measures of intelligence (intelligence quotient), executive functions and behaviour. RESULTS: Children with TBI are at increased risk of disability in all aspects of intelligence, executive functions and behaviour. Children who suff ered a traumatic brain injury in infancy and the preschool period had more overall eff ects on intelligence quotient and some aspects of the executive functions. CONCLUSIONS: Socioeconomic and cultural factors are the best predictors for intelligence quotient and behaviour. These findings contribute to a better understanding of the sequelae of TBI in children, which will help in rehabilitation planning and re-adaptation to functional life

Alexithymia correlates with the size of the right anterior cingulate.

OBJECTIVE: The authors investigated a possible relationship between interindividual variability in anterior cingulate gyrus (ACG) morphology and alexithymia. MATERIALS AND METHODS: Magnetic resonance images were obtained in 100 healthy university graduates (51 female, 49 male; mean age 25.6 y). Surface area measurements of the ACG were performed on reformatted sagittal views in both hemispheres. The Toronto Alexithymia Scale (TAS-20) and the Temperament and Character Inventory (TCI) were administered. RESULTS: Right ACG surface area significantly correlated with TAS-20 total score in men (r = 0.37; p = 0.009) and in women (r = 0.30; p = 0.034). After controlling for three TCI subscales (harm avoidance, self-directedness, and self-transcendency), the correlation between TAS-20 total and right ACG became nonsignificant in women, but was only slightly reduced (r = 0.32; p = 0.032) in men. A linear regression model with right ACG as a dependent variable revealed brain volume, TCI-harm avoidance and TAS 20 total score as significant predictors in the total sample (explained proportion of total variation (EPTV) 37%). In men, beside brain volume, only TAS-20 total score showed a highly significant contribution (EPTV 41%), whereas in women only TCI-harm avoidance was a significant predictor (EPTV 36%). CONCLUSIONS: The authors' findings indicate that there is a significant positive relation between the size of the right ACG and alexithymia as measured with the TAS in healthy subjects. This applies especially for men whereas in women ACG size is more associated with the subscale harm avoidance of the TCI. Our findings also suggest a partial lateralization of human emotion processing, especially negative emotion.

Enlargement of brain cerebrospinal fluid spaces as a predictor of poor clinical outcome in melancholia.

BACKGROUND: A number of recent neuroimaging findings in depression have provided new insight into the biological substratum of depressive illness. The question now is what particular relevance the structural brain alteration described may have within the clinical context of depressive patients. We investigated a possible relationship between brain cerebrospinal fluid (CSF) space changes and patient prognosis in melancholic depression. METHOD: Fifty-five patients who met DSM-IV criteria for major depressive disorder with melancholic features were examined with 3-dimensional magnetic resonance imaging, and CSF volumes were measured for global brain CSF and for lateral ventricles and left and right sylvian fissure regions. Clinical outcome was prospectively assessed during a 6-month standardized antidepressive treatment period (Phase I) and in a 2-year follow-up (Phase II) of recovered patients. The outcome measurements were total days to symptom remission (Phase I) and to eventual symptom relapse or recurrence (Phase II). The study took place from July 1998 to Dec. 2001. RESULTS: Phase I: Enlargement of CSF spaces in the left sylvian fissure region predicted poor treatment response. Volume measurements from this region accounted for 35% of remission time variance. Median time to full clinical remission was 82 days in patients with severe changes, 51 days in the case of mild-to-moderate CSF enlargement, and 35 days in patients with no left sylvian fissure region alterations. Phase II: Severe enlargement of global cortical CSF spaces was associated with increased risk of depression relapse or recurrence. Patients with severe cortical CSF changes showed a 7.8-fold excess risk of depression relapse/recurrence compared with patients with no cortical CSF space alteration. CONCLUSION: Our data suggest that MRI-detected CSF space enlargement may be an important neuroimaging marker for poor prognosis in melancholic depression.

Eficacia de una nueva intervención de apoyo a padres y escuelas después de un traumatismo craneoencefálico moderado o grave / Efficacy of a new parent and school-supported intervention after moderate and severe childhood traumatic brain injury

Introducción. El traumatismo craneoencefálico es una causa habitual de discapacidad adquirida durante la infancia. Las intervenciones tempranas que se centran en la participación de los padres pueden resultar efectivas para reducir las disfunciones del niño. Objetivo. Determinar la eficacia de un nuevo programa de asesoramiento dirigido a padres y escuelas en comparación con un grupo control. Pacientes y métodos. La muestra principal del estudio se obtuvo de un hospital pediátrico. La muestra final consistió en 42 niños de 6 a 16 años. Resultados. Comparando con los datos normativos, las comparaciones pre y post intragrupos mostraron una mejora significativa en el grupo de intervención parental con respecto al grupo control. Conclusiones. La superioridad del grupo de intervención parental sobre el grupo control no sólo fue estadísticamente significativa, sino también clínicamente sustancial y relevante. Los resultados del estudio sugieren que los niños con traumatismo craneoencefálico moderado o grave pueden beneficiarse de un tratamiento familiar intensivo de apoyo

Introduction. Traumatic brain injury is a common cause of acquired disability during childhood. Early interventions focusing on parenting practices may prove effective at reducing negative child outcomes. Aim. To determine the efficacy of a new counselling program aimed at parents and schools compared to a control group. Patients and methods. The main study sample was obtained from a paediatric hospital. The final sample consisted of 42 children aged between 6 and 16 years old. Results. Comparing with normative data, pre-post comparisons between groups showed a significant improvement in the parent group with respect to the control group. Conclusions. The superiority of the parental intervention group over those of the control group was not only statistically significant, but also clinically substantial and meaningful. The results of this study suggest that children with moderate to severe traumatic brain injury can benefit from an intensive supported family treatment

[Neurological, neuropsychological, and ophthalmological evolution after one year of docosahexaenoic acid supplementation in phenylketonuric patients]. / Evolucion neurologica, neuropsicologica y oftalmologica tras un ano de suplementacion con acido docosahexaenoico en pacientes fenilcetonuricos.

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 quotient > 80. 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.

[Developmental amnesia as a focal cognitive sequela of a neonatal pathology]. / Amnesia del desarrollo como secuela cognitiva focal de patologia neonatal.

INTRODUCTION: The developmental amnesia is a recently known entity that occurs as a consequence of hypoxic-ischemic events in the perinatal period. This is a specific deficit of episodic memory with greater preservation of semantic memory and other memory components such as the immediate and working memory. It occurs in patients without apparent neurological sequelae, with normal psychomotor development and general intelligence. The developmental amnesia has been associated with bilateral involvement of the hippocampus, which is evident in some cases on magnetic resonance imaging (MRI) as signal disturbance and signs of atrophy, or reduced size of the hippocampus in brain volumetric studies. PATIENTS AND METHODS: We present six observations of developmental amnesia, their clinical, neuropsychological and neuroimaging findings. RESULTS: All of them show impaired episodic memory with preservation of semantic memory, have a normal general intelligence and follow a regular school with special educational needs. CONCLUSIONS: It is necessary to keep in mind this entity in monitoring risk newborns by their perinatal history and include the exploration of memory in neuropsychological study of these subjects. On the other hand, we highlight the specificity of the clinical and neuropsychological profile for the diagnosis of developmental amnesia even in the absence of hippocampal lesions on conventional MRI.

The lateral asymmetry of the human brain studied by volumetric magnetic resonance imaging.

Improvements in in vivo imaging methods have boosted research on brain asymmetry aimed at further establishing putative anatomical substrates for brain functional lateralization and particularly to explain left-hemisphere specialization for language. We analyzed volume asymmetries for major anatomical divisions of the lateral (perisylvian) brain region and their relative white matter content. A total of 100 healthy right-handed subjects were examined with 3D magnetic resonance imaging (MRI). The insular plane was used to limit the lateral brain, and the sylvian fissure and central sulcus to define frontal, parietal, temporal, and temporo-parieto-occipital regions. Results revealed a frontal region showing similar volumes in both hemispheres, a parietal region and a temporal region both larger in the left hemisphere, and a temporo-parieto-occipital region with predominantly right-sided asymmetry. Volume measurements of the parietal, temporal, and temporo-parieto-occipital regions complemented each other and accounted for 58% of planum temporale area variations. All study regions showed significant asymmetry for relative white matter content (percentage of white matter relative to region volume). White matter asymmetry, however, was particularly relevant for the frontal and temporal regions showing a highly frequent left-sided pattern (frontal region, 90%; temporal region, 91% of subjects). Leftward asymmetry in these two regions occurred in both genders, although hemisphere differences were significantly larger in men. Results from this MRI volume analysis of structural asymmetries in the lateral brain region complement data obtained by other methods and suggest a high occurrence of leftward asymmetry for relative white matter content in language-related regions.

Delayed myelination in children with developmental delay detected by volumetric MRI.

Delayed acquisition of developmental motor and cognitive milestones is a common clinical expression of many etiological processes. Imaging exams of developmentally delayed children often show no structural brain alterations despite suspicion of brain maturation delay. MRI studies increasingly suggest that white matter myelination finely reflects the progression in functional brain maturation. In this volumetric MRI study, we sought to evaluate whether developmental delay in children with normal conventional MRI exams is associated with reduced myelinated white matter. A total of 100 children (mean age, 4.4 years) with developmental delay and 50 normally developing age-matched control children underwent 3-D MRI to measure the volume of myelinated white matter. Patients showed a significant reduction in the relative content of myelinated white matter (accounting for 19.8% of brain volume in patients and 21.4% in control subjects, P = 0.005). The observed difference was equivalent to a 3.2-year myelination delay. Although the whole hemispheres were invariably symmetrical, the volume of myelinated white matter was asymmetrical in 30% of patients and 10% of control subjects (P = 0.006). We conclude that volumetric assessment of white matter may reveal a reduction in brain myelination beyond early childhood in developmentally delayed children showing normal brain appearance. This finding further emphasizes the view of white matter myelination as an indicator of functional brain maturation.

Evolución neurológica, neuropsicológica y oftalmológica tras un año de suplementación con ácido docosahexaenoico en pacientes fenilcetonúricos / Neurological, neuropsychological, and ophtalmological evolution after one year of docosahexaenoic acid supplementation in phenylketonuric patients

Introducción. La fenilcetonuria (PKU) es una enfermedad metabólica autosómica recesiva causada por la deficiencia defenilalanina hidroxilasa. El tratamiento dietético de la PKU consiste en la restricción de alimentos ricos en proteínas, loque afecta la ingestión de lípidos de los pacientes y distorsiona la relación n-3:n-6 de ácidos grasos esenciales en la dieta. Esta deficiencia puede contribuir al deterioro neurológico y visual de los pacientes. Objetivo. Evaluar los cambios en las alteraciones de la sustancia blanca, potenciales evocados visuales (PEV) y rendimiento en funciones ejecutivas y motrices en pacientes con PKU tratados precozmente tras la suplementación con ácidodocosahexaenoico (DHA).Pacientes y métodos. Se seleccionaron 21 pacientes con PKU (edad: 9-25 años), con dieta restringida en fenilalanina. Loscriterios de inclusión fueron: valores bajos de DHA eritrocitaria, retraso de latencias de la onda P100 en PEV o presencia dehiperintensidad de sustancia blanca en la resonancia magnética (RM) cerebral, y cociente intelectual > 80. Los pacientes se suplementaron con DHA (10 mg/kg/día) durante 12 meses. La evaluación se realizó al inicio del estudio y a los 12 mesesde tratamiento, e incluyó parámetros bioquímicos, RM, PEV, evaluación oftalmológica y pruebas neuropsicológicas. Resultados y conclusión. Los pacientes normalizaron los niveles de DHA tras la suplementación. La mejora en las latencias de la onda P100 y la motricidad fina fue significativa. No se evidenciaron cambios en las otras exploraciones tras el tratamiento. Es necesario proseguir la investigación para establecer una relación causa-efecto entre el tratamiento con DHA y la mejoría observada en algunas funciones neurológicas (AU)

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 foodsof 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) latences 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 quotient > 80. 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 andneuropsychological tests.Results and conclusion. All the patients normalized the DHA levels after supplementation. Improvement in the P100 wavelatencies, and fine motor skills was significant. No significant improvement in the other explorations was evident aftersupplementation. Further investigations seem advisable to establish a cause-effect relationship between DHA treatmentand the slight improvement observed in some neurological functions (AU)

Amnesia del desarrollo como secuela cognitiva focal de patología neonatal / Developmental amnesia as a focal cognitive sequela of a neonatal pathology

Introducción. La amnesia del desarrollo es una entidad de reciente conocimiento que se presenta como secuela de eventos hipóxico-isquémicos en la etapa perinatal. Se trata de un déficit específico de la memoria episódica con mejor preservación e la memoria semántica y otros componentes de la memoria, como son la memoria inmediata y la de trabajo. Se presenta en pacientes sin secuelas neurológicas aparentes, con un desarrollo psicomotor y una inteligencia general normales. La amnesia del desarrollo se ha asociado a la afectación bilateral del hipocampo, evidente en algunos casos en la resonancia magnética en forma de alteración de la señal y signos de atrofia, o bien disminución del tamaño del hipocampo en estudios volumétricos cerebrales.Pacientes y métodos. Se presentan seis observaciones de amnesia del desarrollo, su cuadro clínico, exploración neuropsicológica y hallazgos de neuroimagen. Resultados. Todos ellos muestran una alteración de la memoria episódica con preservación de la memoria semántica. Presentan una inteligencia general normal y siguen una escolarización ordinaria con necesidades educativas especiales. Conclusiones. Es necesario tener presente esta entidad en el seguimiento de los recién nacidos de riesgo por sus antecedentes perinatales e incluir la exploración de la memoria en el estudio neuropsicológico de estos sujetos. Por otra parte, se señala la especificidad del cuadro clínico y del perfil neuropsicológico para el diagnóstico de la amnesia del desarrollo aun en ausencia de lesiones del hipocampo en la resonancia magnética convencional (AU)

Introduction. The developmental amnesia is a recently known entity that occurs as a consequence of hypoxic-ischemic events in the perinatal period. This is a specific deficit of episodic memory with greater preservation of semantic memory and other memory components such as the immediate and working memory. It occurs in patients without apparent neurological sequelae, with normal psychomotor development and general intelligence. The developmental amnesia hasbeen associated with bilateral involvement of the hippocampus, which is evident in some cases on magnetic resonance imaging (MRI) as signal disturbance and signs of atrophy, or reduced size of the hippocampus in brain volumetric studies. Patients and methods. We present six observations of developmental amnesia, their clinical, neuropsychological and neuroimaging findings. Results. All of them show impaired episodic memory with preservation of semantic memory, have a normal general intelligence and follow a regular school with special educational needs. Conclusions. It is necessary to keep in mind this entity in monitoring risk newborns by their perinatal history and include the exploration of memory in neuropsychological study of these subjects. On the other hand, we highlight the specificity of the clinical and neuropsychological profile for the diagnosis of developmental amnesia even in the absence of hippocampal lesions on conventional MR (AU)