New SMARCA2 mutation in a patient with Nicolaides–Baraitser syndrome and myoclonic astatic epilepsy

We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides–Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be associated with Nicolaides–Baraitser syndrome and adds to chromatin remodeling as a pathway for epileptogenesis. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc

Mutations in GABRB3

Objective: To examine the role of mutations in GABRB3 encoding the b3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands frommultiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy withmyoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant beta(3), together with alpha(5) and gamma(2s) subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism

Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms

Several studies have identified obesity as a risk factor for asthma in both children and adults. An increased prevalence of asthma in subjects with gastro-oesophageal reflux (GOR) and obstructive sleep apnoea syndrome has also been reported. The aim of this investigation was to study obesity, nocturnal GOR and snoring as independent risk factors for onset of asthma and respiratory symptoms in a Nordic population. In a 5-10 yr follow-up study of the European Community Respiratory Health Survey in Iceland, Norway, Denmark, Sweden and Estonia, a postal questionnaire was sent to previous respondents. A total of 16,191 participants responded to the questionnaire. Reported onset of asthma, wheeze and night-time symptoms as well as nocturnal GOR and habitual snoring increased in prevalence along with the increase in body mass index (BMI). After adjusting for nocturnal GOR, habitual snoring and other confounders, obesity (BMI >30) remained significantly related to the onset of asthma, wheeze and night-time symptoms. Nocturnal GOR was independently related to the onset of asthma and in addition, both nocturnal GOR and habitual snoring were independently related to onset of wheeze and night-time symptoms. This study adds evidence to an independent relationship between obesity, nocturnal gastro-oesophageal reflux and habitual snoring and the onset of asthma and respiratory symptoms in adults

Four simple recommendations to encourage best practices in research software [version 1; referees: awaiting peer review]

Scientific research relies on computer software, yet software is not always developed following practices that ensure its quality and sustainability. This manuscript does not aim to propose new software development best practices, but rather to provide simple recommendations that encourage the adoption of existing best practices. Software development best practices promote better quality software, and better quality software improves the reproducibility and reusability of research. These recommendations are designed around Open Source values, and provide practical suggestions that contribute to making research software and its source code more discoverable, reusable and transparent. This manuscript is aimed at developers, but also at organisations, projects, journals and funders that can increase the quality and sustainability of research software by encouraging the adoption of these recommendations. Keyword

Educational paper: Abusive Head Trauma Part I. Clinical aspects

Abusive Head Trauma (AHT) refers to the combination of findings formerly described as shaken baby syndrome. Although these findings can be caused by shaking, it has become clear that in many cases there may have been impact trauma as well. Therefore a less specific term has been adopted by the American Academy of Pediatrics. AHT is a relatively common cause of childhood neurotrauma with an estimated incidence of 14–40 cases per 100,000 children under the age of 1 year. About 15–23% of these children die within hours or days after the incident. Studies among AHT survivors demonstrate that approximately one-third of the children are severely disabled, one-third of them are moderately disabled and one-third have no or only mild symptoms. Other publications suggest that neurological problems can occur after a symptom-free interval and that half of these children have IQs below the 10th percentile. Clinical findings are depending on the definitions used, but AHT should be considered in all children with neurological signs and symptoms especially if no or only mild trauma is described. Subdural haematomas are the most reported finding. The only feature that has been identified discriminating AHT from accidental injury is apnoea. Conclusion: AHT should be approached with a structured approach, as in any other (potentially lethal) disease. The clinician can only establish this diagnosis if he/she has knowledge of the signs and symptoms of AHT, risk factors, the differential diagnosis and which additional investigations to perform, the more so since parents seldom will describe the true state of affairs spontaneously

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response - a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.peer-reviewe

De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Correction to The American Journal of Human Genetics, Volume 95, Issue 4, 2 October 2014, Pages 360-370. Volume 100, Issue 1, 5 January 2017, Page 179.Peer reviewe

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation

Neurologic phenotypes associated with COL4A1/2 mutations

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population