Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder.

Enhancing evacuation plans with a situation awareness system based on end-user knowledge provision.

Recent disasters have shown that having clearly defined preventive procedures and decisions is a critical component that minimizes evacuation hazards and ensures a rapid and successful evolution of evacuation plans. In this context, we present our Situation-Aware System for enhancing Evacuation Plans (SASEP) system, which allows creating end-user business rules that technically support the specific events, conditions and actions related to evacuation plans. An experimental validation was carried out where 32 people faced a simulated emergency situation, 16 of them using SASEP and the other 16 using a legacy system based on static signs. From the results obtained, we compare both techniques and discuss in which situations SASEP offers a better evacuation route option, confirming that it is highly valuable when there is a threat in the evacuation route. In addition, a study about user satisfaction using both systems is presented showing in which cases the systems are assessed as satisfactory, relevant and not frustrating.

On the support of scientific workflows over Pub/Sub brokers.

The execution of scientific workflows is gaining importance as more computing resources are available in the form of grid environments. The Publish/Subscribe paradigm offers well-proven solutions for sustaining distributed scenarios while maintaining the high level of task decoupling required by scientific workflows. In this paper, we propose a new model for supporting scientific workflows that improves the dissemination of control events. The proposed solution is based on the mapping of workflow tasks to the underlying Pub/Sub event layer, and the definition of interfaces and procedures for execution on brokers. In this paper we also analyze the strengths and weaknesses of current solutions that are based on existing message exchange models for scientific workflows. Finally, we explain how our model improves the information dissemination, event filtering, task decoupling and the monitoring of scientific workflows.

Enabling flexible and continuous capability invocation in mobile prosumer environments.

Mobile prosumer environments require the communication with heterogeneous devices during the execution of mobile services. These environments integrate sensors, actuators and smart devices, whose availability continuously changes. The aim of this paper is to design a reference architecture for implementing a model for continuous service execution and access to capabilities, i.e., the functionalities provided by these devices. The defined architecture follows a set of software engineering patterns and includes some communication paradigms to cope with the heterogeneity of sensors, actuators, controllers and other devices in the environment. In addition, we stress the importance of the flexibility in capability invocation by allowing the communication middleware to select the access technology and change the communication paradigm when dealing with smart devices, and by describing and evaluating two algorithms for resource access management.

Analysis of EEG patterns and genotypes in patients with Angelman syndrome.

We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006-2010), 115 had complete data (58 boys, median age 3.6 years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in <50% of EEG and interictal epileptiform abnormalities; UPD, UBE3A mutation or imprinting defects in patients with intermittent theta in <50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0 Mb) in patients with >50% theta and normal posterior rhythm; atypical deletions in patients with >50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology.

Vagus nerve stimulation for the management of seizures in children: an 8-year experience.

BACKGROUND: Medication-resistant seizure disorder is a challenging, debilitating, and expensive condition. Although multiple interventions are now available, none is universally effective. In 1997, vagus nerve stimulation (VNS) was approved for treatment of refractory seizures in patients older than 12 years. Vagus nerve stimulation has shown some benefit for these individuals, but less is known about its use in patients younger than 12 years. This review analyzes the safety and efficacy of VNS in young children. METHODS: From March 2000 to February 2008, patients with medication-resistant seizures were implanted with a neurocybernetic prosthesis. Two weeks later, the device was activated. The children were followed for at least 3 months, and adjustments were made. Retrospective chart review was performed to collect data. RESULTS: Of 28 patients, the mean age at implantation was 8 years and 5 months. Twenty-one (75%) children were younger than 12 years. There were no surgical complications. Two children were reimplanted for lead malfunction, and 4 generators were replaced. Two children had transitory adverse effects (hoarseness and stridor). Mean follow-up was 3 years and 5 months. At 1 year, 52% of children had greater than 50% reduction in seizures. CONCLUSIONS: Although the effectiveness of VNS is variable and unpredictable, safety is high even in young children. Because of the potential benefit for these complex patients, the implantation of this nerve stimulation device should be included in the armamentarium of pediatric surgeons.

Microcephaly and congenital grouped pigmentation of the retinal pigment epithelium associated with submicroscopic deletions of 13q33.3-q34 and 11p15.4.

Congenital grouped pigmentation of the retinal pigment epithelium (CGPRPE) is a rare ocular abnormality that has been described as an isolated finding or in conjunction with a few systemic conditions. We present the case of a patient with CGPRPE who also has microcephaly, intrauterine growth retardation, mild developmental delay, and deletions of 13q33.3-q34 and 11p15.4. We believe this represents a distinct syndrome in which CGPRPE and microcephaly are the predominant features and that the responsible gene possibly resides in one of the deleted chromosomal regions.

Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations.

Mutations in the SURF1 gene are the most frequent causes of Leigh disease with cytochrome c oxidase deficiency. We describe four children with novel SURF1 mutations and unusual features: three had prominent renal symptoms and one had ragged red fibers in the muscle biopsy. We identified five pathogenic mutations in SURF1: two mutations were novel, an in-frame nonsense mutation (834G-->A) and an out-of-frame duplication (820-824dupTACAT). Although renal manifestations have not been described in association with SURF1 mutations, they can be part of the clinical presentation. Likewise, mitochondrial proliferation in muscle (with ragged red fibers) is most unusual in Leigh disease but might be part of an emerging phenotype.