[De novo heterozygous mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria]. / Mutación de novo en heterocigosis en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria.

INTRODUCTION: The aetiology of autosomal dominant mental retardation type 1, also known as pseudo-Angelman, MBD5-associated neurodevelopmental disorder or MBD5 haploinsufficiency, lies in a microdeletion of chromosome 2q23.1 or in a specific alteration of the MBD5 gene, which constitutes the minimum region affected in the aforementioned microdeletion. AIM: To report the case of a girl with a heterozygous de novo mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria. CASE REPORT: We report the case of an 8-year-old girl who was submitted to a developmental follow-up from the age of 18 months after presenting the association of severe intellectual disability and motor delay, lack of language development, segmental hypotonia, a wide forehead and kyphoscoliosis. Magnetic resonance imaging of the brain revealed the presence of a bilateral band heterotopia and parietooccipital polymicrogiria predominant on the left side. In the exome the de novo heterozygous variant c.397+1G>C was detected in the MBD5 gene. CONCLUSION: This is the first observation of a heterozygous mutation in the MBD5 gene associated with a neuronal migration disorder.

TITLE: Mutación de novo en heterocigosis en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria.Introducción. La etiología del retraso mental autosómico dominante 1, también conocido como pseudo-Angelman, trastorno del neurodesarrollo asociado a MBD5 o haploinsuficiencia MBD5, radica en una microdeleción del cromosoma 2q23.1 o en una alteración específica del gen MBD5, que constituye la mínima región afectada en la citada microdeleción. Objetivo. Comunicar el caso de una niña con una mutación heterocigota y de novo en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria. Caso clínico. Niña de 8 años, seguida evolutivamente desde los 18 meses por presentar la asociación de discapacidad intelectual y retraso motor graves, ausencia de desarrollo del lenguaje, hipotonía segmentaria, frente ancha y cifoescoliosis. En la resonancia magnética cerebral se observó la presencia de una heterotopía en banda bilateral y polimicrogiria parietooccipital de predominio izquierdo. En el exoma se detectó la variante de novo c.397+1G>C en heterocigosis en el gen MBD5. Conclusión. Constituye la primera observación con una mutación heterocigota en el gen MBD5 asociada a un trastorno en la migración neuronal.

[Treatment of choline kinase beta deficiency with citicoline]. / Tratamiento de la deficiencia en colina cinasa beta con citicolina.

TITLE: Tratamiento de la deficiencia en colina cinasa beta con citicolina.

[Retrospective analysis of the effect of a vagus nerve stimulator implanted in paediatric patients with refractory epilepsy]. / Analisis retrospectivo sobre el efecto del estimulador vagal implantado en pacientes pediatricos con epilepsia refractaria.

INTRODUCTION: The vagus nerve stimulator is a therapeutic alternative in patients with epilepsy which is refractory to treatment with antiepileptic drugs that are not candidates for surgical resection. AIM: To analyse the effectiveness of vagus nerve stimulator in the paediatric patients of our centre. PATIENTS AND METHODS: Set of 13 patients implanted between 2008 y 2013. It was registered the frequency of crises prior to implantation, after a year and at the end of the monitoring period. As well, it was recorded the number of antiepileptic drugs used and in a qualitative way the behavioural improvement and the change in the intensity of the crises, besides the apparition of secondary effects and the removal or not of the device. RESULTS: After a year, two years and at the end of the monitoring period it has been a fall in the number of crises about of 61%, 66.7% y 69% respectively, finding one patient free of crises after two years. At the end of the monitoring period, the 23% of those who had reduced their crises had experimented a reduction over 90%. Independently the effect on the number of crises, 77% of the patients presented an improvement in the intensity and the length of the crises, the same average showed a behavioural improvement. The secondary effects appeared in a 30.7% of the patients, being of mild intensity. CONCLUSIONS: Despite the small size of our sample, our results shows that the vagus nerve stimulator has a relevant efficacy over the pediatric drug resistant population, as much in the frequency and intensity of the crises, as over the behaviour.

TITLE: Analisis retrospectivo sobre el efecto del estimulador vagal implantado en pacientes pediatricos con epilepsia refractaria.Introduccion. El estimulador vagal es una alternativa terapeutica en los pacientes con epilepsia refractaria al tratamiento con farmacos antiepilepticos que no son candidatos a cirugia de reseccion. Objetivo. Analizar la eficacia del estimulador vagal en los pacientes pediatricos de nuestro centro. Pacientes y metodos. Conjunto de 13 pacientes implantados entre los años 2008 y 2013. Se registro la frecuencia de crisis previa a la implantacion, al año, a los dos años y al final del seguimiento. Asimismo, se recogio el numero de farmacos antiepilepticos utilizados, de forma cualitativa la mejoria conductual y el cambio en la intensidad de las crisis, asi como la aparicion de efectos secundarios y la retirada o no del dispositivo. Resultados. Al año, a los dos años y al final del seguimiento se habia producido una reduccion en el numero de crisis del 61%, 66,7% y 69%, respectivamente, y uno de los pacientes se encontro libre de crisis a los dos años. Al final del seguimiento, un 23% de los que habian disminuido sus crisis habia experimentado una reduccion superior al 90%. De forma independiente al efecto sobre el numero de crisis, el 77% de los pacientes presento una mejoria en la intensidad y duracion de las crisis, y ese mismo porcentaje mostro una mejoria conductual. Los efectos secundarios aparecieron en un 30,7% de los pacientes y fueron de intensidad leve. Conclusiones. A pesar del pequeño tamaño de la muestra, nuestros resultados indican que el estimulador vagal tiene una eficacia relevante en la poblacion pediatrica farmacorresistente, tanto sobre la frecuencia e intensidad de las crisis como sobre la conducta.

[Molecular characterisation and phenotypic description of two patients with reciprocal chromosomal aberrations in the region of the 3q29 microdeletion/microduplication syndromes]. / Caracterizacion molecular y descripcion fenotipica de dos casos con aberraciones cromosomicas reciprocas en la region de los sindromes de microdelecion/microduplicacion 3q29.

INTRODUCTION: The 3q29 microdeletion and microduplication syndromes are characterised by a marked phenotypic heterogeneity, and delayed development and a mild-moderate degree of intellectual disability are the most frequent clinical manifestations. CASE REPORTS: Two patients with reciprocal chromosomal aberrations in the 3q29 region. The patient with 3q29 microdeletion presented learning disabilities, borderline microcephaly, mild facial dysmorphism, attentional deficit and impulsiveness, and anxious and obsessive traits. The patient with reciprocal 3q29 microduplication presented learning disabilities, mild facial dysmorphism and a disruptive behavioural profile that was not previously associated with this duplication. CONCLUSIONS: The phenotypes of these patients are compared and the literature about paediatric patients with 3q29 microdeletions and microduplications is reviewed.

TITLE: Caracterizacion molecular y descripcion fenotipica de dos casos con aberraciones cromosomicas reciprocas en la region de los sindromes de microdelecion/microduplicacion 3q29.Introduccion. Los sindromes de microdelecion y microduplicacion 3q29 se caracterizan por una marcada heterogeneidad fenotipica, y el retraso del desarrollo y la discapacidad intelectual de grado leve-moderado son las manifestaciones clinicas mas frecuentes. Casos clinicos. Dos pacientes con aberraciones cromosomicas reciprocas en la region 3q29. La paciente con la microdelecion 3q29 presenta dificultades de aprendizaje, microcefalia limite, dismorfismo facial leve, deficit atencional e impulsividad, y rasgos ansiosos y obsesivos. El paciente con la microduplicacion 3q29 reciproca presenta dificultades de aprendizaje, dismorfismo facial leve y un perfil conductual disruptivo no asociado previamente con esta duplicacion. Conclusion. Se comparan los fenotipos de estos pacientes y se revisa la bibliografia de pacientes pediatricos con microdeleciones y microduplicaciones 3q29.

[How valuable are genetic studies in paediatric neurology?]. / Hasta dónde con los estudios genéticos en neurología pediátrica?

INTRODUCTION AND DEVELOPMENT: Paediatric neurology is fully aware of the fact that important advances in genetics are being applied to the clinical and prenatal diagnoses of a wide range of diseases. The discovery of new genes related to a growing number of pathologies with neurological implications opens up new diagnostic approaches and provides information that is very useful in the process of detecting carriers and identifying pre-symptomatic individuals. More selective genetic techniques with higher resolutions are increasingly more commonly available in genetic laboratories, as is the possibility of sequencing and searching for specific mutations in certain genes; for some processes their application to clinical practice has made them the initial diagnostic approach. A precise clinical orientation and knowledge of their applications and limitations is essential, and requires an increasingly close relationship between clinicians and geneticists in order to design a tailored diagnostic protocol that offers a rational balance between technical availability, cost, time and relevance of the findings. CONCLUSIONS: We discuss some of the current aspects and considerations about advances in specific neuropaediatric pathologies, within the group of neuromuscular disorders, mental retardation, autism spectrum disorders and epilepsy.

Therapeutic criteria in communicating childhood hydrocephalus.

AIM: The aim of this study was to evaluate the usefulness of cerebral blood flow velocity in the middle cerebral artery measured by transcranial Doppler as criteria to therapeutic action in communicating hydrocephalic children. METHODS: In eight non-tumoral communicating hydrocephalic infants, ranging from five to 18 months of age, monitored from 18 to 36 months (mean time of follow-up: 24.25 months), cerebrospinal fluid (CSF) oxypurines (hypoxanthine and xanthine) and uric acid levels were compared by means of the Evans' index, the mean weekly increase in cranial circumference, and the transcranial Doppler measurements. RESULTS: Results indicate that clinical (mean weekly increase in head circumference), radiological (Evans' index), biochemical (oxypurines and uric acid in the CSF), and hemodynamic (transcranial Doppler) criteria have the same role in monitoring infantile hydrocephalus. CONCLUSION: In conclusion the transcranial Doppler measurement can be done noninvasively and examinations can be repeated when needed, obtaining immediate RESULTS: Hence, it is the most adequate monitoring technique in clinical practice.

[The neuroprotective effect of pre and perinatal nutritional factors on neurodevelopment]. / Efecto neuroprotector de los factores dietéticos pre y perinatales sobre el neurodesarrollo.

INTRODUCTION: The development of the nervous central system is a dynamical process determined genetically and modulated by neurochemical, nutritional and environmental factors. DEVELOPMENT: It refers to the neuroprotector effect of the pre and perinatal nutritional factors, specially proteic-energetic intake, long-chain polyinsatured fatty acid, vitamins, minerals, choline, maternal metabolic disorders and the maternal pseudo-nutritive agent intake. CONCLUSION: For a better neurodevelopment, it is necessary that pregnant receives, even before conception, a suitable intake of macro and micronutrients.

[Reversible posterior leukoencephalopathy syndrome: an infrequent complication in the course of haemolytic-uremic syndrome]. / Leucoencefalopatía posterior reversible: una complicación infrecuente en el curso del síndrome hemolítico urémico.

INTRODUCTION: Posterior reversible leukoencephalopathy syndrome (PRLS) is characterised by the sudden and usually transient onset of headaches, visual disorders, decreased awareness and convulsions associated with cerebral oedema in the posterior areas of the brain. Different reports have associated it with numerous processes and possibly with haemolytic-uremic syndrome (HUS). We describe a new case of PRLS within the context of HUS. CASE REPORT: We describe the case of a 4-year-old child with HUS who developed arterial hypertension that did not respond well to treatment and kidney failure that required renal replacement therapy. During the course of the disease the patient presented several transient episodes of headache, a lowered level of consciousness and seizures. Magnetic resonance imaging revealed multiple lesions in the white matter and the cortex that were hyperintense in T2 and hypointense in T1 situated in the bilateral occipital and right frontotemporoparietal regions. The patient made a full clinical recovery in a few days, although an magnetic resonance imaging scan performed at six weeks after the last episode showed partial remission of the lesions and a small cerebral infarction. CONCLUSIONS: The pathogenesis of PRLS is still not fully understood. Its multifactorial origin suggests that several different mechanisms may be involved. In the case reported here, it is possible that the arterial hypertension, retention of fluids and even the sessions of dialysis played a role in its development.

[Hepatomioneuropathy secondary to mitochondrial DNA depletion]. / Hepatomioneuropatía secundaria a depleción del ADN mitocondrial.

INTRODUCTION: Mitochondrial DNA depletion (mtDNA) is an highly heterogeneous condition characterized by a decreased number of mtDNA copies. CASE REPORT: The patient is a 22-month-old girl with generalized hypotonia, marked weakness, respiratory failure, arterial hypertension, hyperlactacidemia, hepatosplenomegaly and mild hypertransaminasemia without hepatic failure neither hypoketotic hypoglycemia. Electromyographic findings were consistent with neuromyopathy and muscle biopsy suggested a neurogenic atrophy. Electron microscopy revealed lipid droplets, subsarcolemmal accumulation of mitochondrias and glycogen granules. Respiratory chain enzime activities were normal. Genetic study in muscle showed mtDNA depletion, and the diagnosis of spinal muscular atrophy caused by survival motoneuron gene deletion was excluded. CONCLUSIONS: This case might be a novel phenotype of mtDNA depletion which could be named hepatomioneuropatyc form. A normal result of respiratory chain enzimes in muscle doesn't excluded mtDNA depletion.

[Pontocerebellar hypoplasia type 1: a case report]. / Hipoplasia pontocerebelosa tipo 1: aportación de un caso.

INTRODUCTION: Pontocerebellar hypoplasias constitute a group of hereditary neurodegenerative disorders of uncertain aetiopathogenesis. They have been reported as being associated with deficiencies of complexes in the mitochondrial respiratory chain (MRC) and with congenital disorders of glycosylation. On the basis of clinical and neuropathological criteria, two phenotypes can be distinguished in this condition. Pontocerebellar hypoplasia type 1 is characterised by hypoplasia of the pons and the cerebellum associated with the degeneration of the motor neurons in the anterior horn of the spinal cord. CASE REPORT: A 4-year-old female with symptoms of severe psychomotor retardation associated with microcephaly, important generalised hypotonia, muscle hypotrophy, contractions in the four limbs, absence of stretch reflex and epilepsy with onset in the neonatal period. Magnetic resonance imaging of the brain revealed pontocerebellar hypoplasia. An electroneuromyography showed a trace that was compatible with axonal neuropathy and a biopsy of the deltoid muscle revealed the existence of neurogenic muscular atrophy. In the MRC study conducted in muscle homogenate and in skin fibroblasts, complex IV values were found to be at the lower limits of what could be considered to be normal levels. Results of the genetic study for spinal muscular atrophy were negative. CONCLUSIONS: The case reported here could be included as a case of pontocerebellar hypoplasia type 1. MRC studies can be of interest in cases of pontocerebellar hypoplasia in order to explain the role it plays in this disorder.

[Non-progressive congenital ataxias]. / Ataxias congénitas no progresivas.

INTRODUCTION: Non-progressive congenital ataxias (NPCA) constitute a heterogeneous group of processes linked to diverse aetiological factors that can be either environmentally or genetically determined. The signs of cerebellar compromise, which are preceded by unspecific signs such as early hypotonia, difficulty in sucking or chewing or retarded motor acquisition, become apparent with development or may remain absent when the disorder is very severe. DEVELOPMENT: NPCA can be accompanied by a number of pathologies and their diagnosis can be made easier by the concurrence of symptoms or signs of extra-cerebellar involvement, such as dysmorphic features or abnormalities affecting the skin, heart, bones, blood, eyes or other areas of the central or peripheral nervous system. Neuroimaging usually reveals vermian hypoplasia and/or hypoplasia of the cerebellar hemispheres, but can be normal in certain situations. The article includes a review of the NPCA following the classification proposed by Steinlin in 1998. CONCLUSIONS: The difficulties inherent in diagnosing these processes makes it necessary to deploy a wide range of complementary examinations, especially metabolic tests, before a generic diagnosis of NPCA can be established. Although the progress made in molecular genetics has made it possible to categorise NPCA better, both their causation and their hereditary or sporadic nature remain unknown in about 50% of cases.

[Pyruvate dehydrogenase deficit associated to the C515T mutation in exon 6 of the E1alpha gene]. / Deficit de piruvato deshidrogenasa asociado a la mutacion C515T en el exon 6 del gen E1alpha.

INTRODUCTION: Pyruvate dehydrogenase (PDH) deficiency constitutes the most frequent metabolic origin of congenital lactic acidosis and is also responsible for a less usual form, found exclusively in females, which leads to a dysmorphic syndrome accompanied by severe cerebral malformations. The most common defect affects fraction E1alpha (gene Xp22.1-22.2). AIM: To report the case of a young female with PDH deficiency, dysmorphic syndrome, cerebral deformations and an unidentified mutation in the corresponding gene. CASE REPORT: An 8-month-old female with microcephaly, a narrow forehead, nasal hypoplasia, anteverted nostrils, thin lips, axial hypotonia, epileptic seizures and an umbilical hernia. Magnetic resonance imaging of the brain revealed intense supra- and infratentorial cortico-subcortical atrophy, ventricular dilatation and agenesis of the corpus callosum. Lactic and pyruvic acid concentrations were high both in blood and in cerebrospinal fluid (CSF), and the level of alanine was high in CSF. Muscular histology results were normal. PDH complex activity in fibroblasts and in muscle tissue, as well as that of the mitochondrial respiratory chain complexes in muscle homogenate, were found to be normal. A molecular genetic study of the gene for PDHE1alpha, both in formed elements in the blood and in fibroblasts, showed a C > T change in nucleotide 515 (C515T) of exon 6, which causes a P172L change in the protein. A study of 108 controls ruled out the possibility of a polymorphism. The parents did not have the mutation. CONCLUSIONS: The C515T mutation of exon 6 of the gene for PDH E1alpha is described. Normal activity of the PDH complex in fibroblasts and in muscle tissue does not exclude this condition.

[Aspects concerning behavioural development and socialisation and how they are linked to attention deficit hyperactivity disorder]. / Aspectos relacionados con el desarrollo de la conductay la socialización con mención a sus nexos con eltrastorno por déficit de atención e hiperactividad.

INTRODUCTION: Despite their importance, little attention has been given to the recognition of early markers of hyperactivity in the scientific literature and in everyday practice it can be difficult to separate some of the physiological behaviours displayed by older babies or preschool infants from pathological processes such as attention deficit hyperactivity disorder (ADHD), specific language impairment, autistic spectrum disorders, conduct disorders or bad habits with regard to discipline within the family context. DEVELOPMENT: Knowledge of some of the key points in behavioural development and sociability in children can help reach a correct interpretation of the manifestations observed in this age group. The development of linguistic competencies, a feeling of what is right and what is wrong, the development of an awareness of oneself and the capacity to infer that is established as progress is made in language are some of the keys to proper behavioural development and socialisation. The gene DRD4 is expressed in the prefrontal cortex and has been implicated in some subtypes of ADHD, as well as being linked to a novelty-seeking personality. Recent genetic evidence supports the notion of an association between certain polymorphisms in the DRD4 gene with resistant or disorganised bonds at early ages. CONCLUSIONS: The detection of several dysfunctional signs related to inadequate self-control that appear during behavioural development and socialisation may provide early keys to the future development of ADHD.