Novel truncating variants expand the phenotypic spectrum of KAT6B-related disorders.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.

Leucodistrofia hipomielinizante de tipo 6. Claves clínicas y de neuroimagen en la detección de un nuevo caso / Hypomyelinating leukodystrophy type 6. Clinical and neuroimaging key features in the detection of a new case

Introducción. La leucodistrofia hipomielinizante de tipo 6 es una enfermedad neurodegenerativa rara de inicio temprano que cursa clínicamente con un patrón de afectación piramidoextrapiramidal y cerebeloso, y asocia en neuroimagen hipomielinización, hipoplasia cerebelosa y anomalías específicas en los ganglios basales, en concreto atrofia o práctica ausencia del putamen y posible pérdida del volumen del caudado. Se debe a una alteración en la tubulina, está condicionada por mutaciones en heterocigosis en el gen TUBB4A y muestra una penetrancia completa y una expresividad variable. Caso clínico. Niño de 8 años con clínica de retraso de la marcha, temblor, disartria, ataxia, nistagmo, afectación cognitiva y distonía, con un patrón de hipomielinización, hipoplasia vermiana y ausencia del putamen. Estos hallazgos, aunque distintivos, habían sido infraestimados en valoraciones previas y su objetivación conllevó el análisis y la identificación de una variante patógena en el gen TUBB4A. Conclusiones. El deterioro progresivo lleva al paciente a la dependencia total o el fallecimiento en la infancia o la juventud, y no existe tratamiento específico capaz de modificar su curso natural

Introduction. Hypomyelinating leukodystrophy-6 is a rare and early onset neurodegenerative disease which entails a clinical pattern of pyramidal-extrapyramidal and cerebellar involvement and it comes with a neuroimaging consisting of hypomielination, cerebellar hypoplasia and specific abnormalities in basal ganglia, particularly the absence or nearly absence of putamen and the possible loss of caudate’s volume. It is due to an alteration in tubulin and it is determined by mutations in heterocygosis in TUBB4A gene, showing complete penetrance. Case report. An 8-year-old child with history of delayed motor development, tremor, dysathria, ataxia, nystagmus, cognitive deficit and dystonia with pattern of hypomielination, vermis hypoplasia and absence of putamen. These findings, although distinctive, had been underestimated in previous evaluations and their detection determined the analyse and identification of a pathogenic variant in TUBB4A gene. Conclusions. Progressive deterioration leads the patient to total dependence or death in infancy or youth and there is no specific treatment capable of modifying its natural course

Tratamiento de la deficiencia en colina cinasa beta con citicolin / Treatment of choline kinase beta deficiency with citicoline

No disponible

Copy number variation analysis of patients with intellectual disability from North-West Spain.

Intellectual disability (ID) is a complex and phenotypically heterogeneous neurodevelopmental disorder characterized by significant deficits in cognitive and adaptive skills, debuting during the developmental period. In the last decade, microarray-based copy number variation (CNV) analysis has been proved as a strategy particularly useful in the discovery of loci and candidate genes associated with these phenotypes and is widely used in the clinics with a diagnostic purpose. In this study, we evaluated the usefulness of two genome-wide high density SNP microarrays -Cytogenetics Whole-Genome 2.7M SNP array (n=126 patients; Group 1) and CytoScan High-Density SNP array (n=447 patients; Group 2)- in the detection of clinically relevant CNVs in a cohort of ID patients from Galicia (NW Spain). In 159 (27.7%) patients, we detected 186 rare exonic chromosomal imbalances, that were grouped into the following classes: Clinically relevant (67/186; 36.0%), of unknown clinical significance (93/186; 50.0%) and benign (26/186; 14.0%). The 67 pathogenic CNVs were identified in 64 patients, which means an overall diagnostic yield of 11.2%. Overall, we confirmed that ID is a genetically heterogeneous condition and emphasized the importance of using genome-wide high density SNP microarrays in the detection of its genetic causes. Additionally, we provided clinical and molecular data of patients with pathogenic or likely pathogenic CNVs and discussed the potential implication in neurodevelopmental disorders of genes located within these variants.

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

Introducción. El estimulador vagal es una alternativa terapéutica en los pacientes con epilepsia refractaria al tratamiento con fármacos antiepilépticos que no son candidatos a cirugía de resección. Objetivo. Analizar la eficacia del estimulador vagal en los pacientes pediátricos de nuestro centro. Pacientes y métodos. Conjunto de 13 pacientes implantados entre los años 2008 y 2013. Se registró la frecuencia de crisis previa a la implantación, al año, a los dos años y al final del seguimiento. Asimismo, se recogió el número de fármacos antiepilépticos utilizados, de forma cualitativa la mejoría conductual y el cambio en la intensidad de las crisis, así como la aparición de efectos secundarios y la retirada o no del dispositivo. Resultados. Al año, a los dos años y al final del seguimiento se había producido una reducción en el número de crisis del 61%, 66,7% y 69%, respectivamente, y uno de los pacientes se encontró libre de crisis a los dos años. Al final del seguimiento, un 23% de los que habían disminuido sus crisis había experimentado una reducción superior al 90%. De forma independiente al efecto sobre el número de crisis, el 77% de los pacientes presentó una mejoría en la intensidad y duración de las crisis, y ese mismo porcentaje mostró una mejoría 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 población pediátrica farmacorresistente, tanto sobre la frecuencia e intensidad de las crisis como sobre la conducta (AU)

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 (AU)

Caracterización molecular y descripción fenotípica de dos casos con aberraciones cromosómicas recíprocas en la región de los síndromes de microdeleción/microduplicación 3q29 / Molecular characterisation and phenotypic description of two patients with reciprocal chromosomal aberrations in the region of the 3q29 microdeletion/microduplication syndromes

Introducción. Los síndromes de microdeleción y microduplicación 3q29 se caracterizan por una marcada heterogeneidad fenotípica, y el retraso del desarrollo y la discapacidad intelectual de grado leve-moderado son las manifestaciones clínicas más frecuentes. Casos clínicos. Dos pacientes con aberraciones cromosómicas recíprocas en la región 3q29. La paciente con la microdeleción 3q29 presenta dificultades de aprendizaje, microcefalia límite, dismorfismo facial leve, déficit atencional e impulsividad, y rasgos ansiosos y obsesivos. El paciente con la microduplicación 3q29 recíproca presenta dificultades de aprendizaje, dismorfismo facial leve y un perfil conductual disruptivo no asociado previamente con esta duplicación. Conclusión. Se comparan los fenotipos de estos pacientes y se revisa la bibliografía de pacientes pediátricos con microdeleciones y microduplicaciones 3q29 (AU)

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 (AU)

Enfermedad de Alpers juvenil / Juvenile Alpers disease

No disponible

Microdeleción 2q23.1 y hallazgos sindrómicos / Microdeletion 2q23.1 and syndromic findings

No disponible

Microdeleción 16p11.2 asociada a convulsiones benignas de la primera infancia / 16p11.2 microdeletion associated to early onset benign childhood seizures

No disponible