Análisis descriptivo del electroencefalograma en el síndrome de Angelman / Descriptive analysis of the electroencephalogram in Angelman syndrome

INTRODUCCIÓN: El síndrome de Angelman es un trastorno del neurodesarrollo de origen genético, con importantes manifestaciones clínicas motoras, conductuales, comunicativas y electroencefalográficas, con especial relevancia en lo que concierne a la presencia de crisis epilépticas. OBJETIVOS: Describir las características electroencefalográficas (cualitativa y cuantitativamente) de los pacientes con diagnóstico de síndrome de Angelman y determinar el perfil electroencefalográfico según la edad y la alteración genética. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo donde se analizaron las características demográficas, clínicas y electroencefalográficas de 51 pacientes con síndrome de Angelman. RESULTADOS: Se evidenció una mayor potencia delta en todas las regiones cerebrales, con un pico máximo en las regiones frontopolar y temporal, y una menor potencia en el rango de frecuencias alfa y beta en todas las regiones, con mayor preponderancia en los pacientes más jóvenes, con tendencia decreciente con la edad. La coherencia mostró un predominio delta y theta en la región frontopolar, que fue mayor para todas las frecuencias en el grupo de deleción, con predominio delta, especialmente en la región frontopolar. CONCLUSIÓN: El electroencefalograma podría ser un biomarcador útil como herramienta cualitativa y cuantitativa en la investigación del síndrome de Angelman y en la medición de la respuesta a eventuales terapias en investigación

INTRODUCTION: Angelman syndrome is a neurodevelopmental disorder of genetic origin, with important clinical motor, behavioural, communicative and electroencephalographic manifestations, with particular relevance as regards the presence of epileptic seizures. AIMS. To describe the electroencephalographic characteristics (qualitatively and quantitatively) of patients diagnosed with Angelman syndrome and to determine the electroencephalographic profile according to age and genetic alteration. PATIENTS AND METHODS: A retrospective observational study in which the demographic, clinical and electroencephalographic characteristics of 51 patients with Angelman syndrome were analysed. RESULTS: A higher delta power was evident in all brain regions, with a maximum peak in the frontopolar and temporal regions, and a lower power in the alpha and beta frequency range in all regions, with a greater preponderance in younger patients, and a trend that decreases with age. The coherence showed a predominance of delta and theta in the frontopolar region, which was higher for all frequencies in the deletion group, where delta was predominant, especially in the frontopolar region. CONCLUSION. The electroencephalogram could be a useful biomarker as a qualitative and quantitative tool in the investigation of Angelman syndrome and in measuring the response to possible therapies under investigation

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman syndrome (A-MANECE study).

BACKGROUND: Minocycline is an old tetracycline antibiotic that has shown antiinflammatory and antiapoptotic properties in different neurological disease mouse models. Previous single arm study in humans demonstrated benefits in individuals with Angelman Syndrome (AS); however, its efficacy in patients with Angelman Syndrome has not been assessed in a controlled trial. This was a randomized, double-blind, placebo-controlled, crossover trial in individuals with AS, aged 6 years to 30 years (n = 32, mean age 12 [SD 6·29] years). Participants were randomized to minocycline or placebo for 8 weeks and then switched to the other treatment (a subset of 22 patients) or to receive minocycline for up to 16 weeks (10 patients). After week 16, all patients entered a wash-out 8-week follow-up period. RESULTS: Thirty-six subjects were screened and 34 were randomized. Thirty two subjects (94·1%) completed at least the first period and all of them completed the full trial. Intention-to-treat analysis demonstrated the lack of significantly greater improvements in the primary outcome, mean changes in age equivalent of the development index of the Merrill-Palmer Revised Scale after minocycline compared with placebo (1·90 ± 3·16 and 2·00 ± 3·28, respectively, p = 0·937). Longer treatment duration up to 16 weeks did not result in better treatment outcomes (1·86 ± 3·35 for 8 weeks treatment vs 1·20 ± 5·53 for 16 weeks treatment, p = 0·667). Side effects were not significantly different during minocycline and placebo treatments. No serious adverse events occurred on minocycline. CONCLUSIONS: Minocycline treatment for up to 16 weeks in children and young adults with AS resulted in lack of significant improvements in development indexes compared to placebo treatment. Treatment with minocycline appears safe and well tolerated; even if it cannot be completely ruled out that longer trials might be required for a potential minocycline effect to be expressed, available results and lack of knowledge on the actual mechanism of action do not support this hypothesis. TRIAL REGISTRATION: European Clinical Trial database ( EudraCT 2013-002154-67 ), registered 16th September 2013; US Clinical trials database ( NCT02056665 ), registered 6th February 2014.