Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl-Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human Disease.

Aminoacyl-transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl-transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases.

Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology.

The tauopathies are a heterogeneous group of neurodegenerative disorders characterized by the shared presence of tau aggregates and neurofibrillary tangles within the central nervous system. Here, we present a child with a severe neurodegenerative disorder characterized by intractable seizures and significant tau-immunoreactive neurofibrillary degeneration localized predominantly to the substantia nigra on neuropathology with absence of beta-amyloid plaques and Lewy or Pick bodies. Whole-exome sequencing identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1).

Accelerated longitudinal cortical thinning in adolescence.

It remains unclear if changes of the cerebral cortex occur gradually from childhood to adulthood, or if adolescence marks a differential period of cortical development. In the current study of 90 healthy volunteers aged 5-32years (48 females, 85 right handed) with 180 scans (2 scans for each participant with ~4year gaps), thinning of overall mean thickness and across the four major cortical lobes bilaterally was observed across this full age span. However, the thinning rate, calculated as Δcortical thickness/Δage (mm/year) between scans of each participant, revealed an accelerated cortical thinning during adolescence, which was preceded by less thinning in childhood and followed by decelerated thinning in young adulthood.

Diffusion abnormalities of the corpus callosum in patients with malformations of cortical development and epilepsy.

Purpose: Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that can characterize white matter (WM) architecture and microstructure. DTI has demonstrated extensive WM changes in patients with several epileptic syndromes, but few studies have focused on patients with malformations of cortical development (MCD). Our aim was to investigate the quantitative diffusion properties of the corpus callosum (CC), a major commissural bundle critical in inter-hemispheric connectivity, in a large group of patients with MCD.

Classification of hypervascular liver lesions based on hepatic artery and portal vein blood supply coefficients calculated from triphasic CT scans.

Perfusion CT of the liver typically involves scanning the liver at least 20 times, resulting in a large radiation dose. We developed and validated a simplified model of tumor blood supply that can be applied to standard triphasic scans and evaluated whether this can be used to distinguish benign and malignant liver lesions. Triphasic CTs of 46 malignant and 32 benign liver lesions were analyzed.

Electrophysiological correlates of motor sequence learning.

Background: The Error-related negativity (ERN) is a component of the event-related brain potentials elicited by error commission. The ERN is thought to reflect cognitive control processes aiming to improve performance. As previous studies showed a modulation of the ERN amplitude throughout the execution of a learning task, this study aims to follow the ERN amplitude changes from early to late learning blocks in relation with concomitant motor sequence learning using a serial reaction time (SRT) task.

Correlations between Limbic White Matter and Cognitive Function in Temporal-Lobe Epilepsy, Preliminary Findings.

The limbic system is presumed to have a central role in cognitive performance, in particular memory. The purpose of this study was to investigate the relationship between limbic white matter microstructure and neuropsychological function in temporal-lobe epilepsy (TLE) patients using diffusion tensor imaging (DTI). Twenty-one adult TLE patients, including 7 non-lesional (nlTLE) and 14 with unilateral mesial temporal sclerosis (uTLE), were studied with both DTI and hippocampal T2 relaxometry.

Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study.

Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families with clinical descriptions that included childhood-onset epilepsy or seizures not part of a recognizable syndrome or an early-onset encephalopathy where standard-of-care investigations were unrevealing.

On combining image-based and ontological semantic dissimilarities for medical image retrieval applications.

Computer-assisted image retrieval applications can assist radiologists by identifying similar images in archives as a means to providing decision support. In the classical case, images are described using low-level features extracted from their contents, and an appropriate distance is used to find the best matches in the feature space. However, using low-level image features to fully capture the visual appearance of diseases is challenging and the semantic gap between these features and the high-level visual concepts in radiology may impair the system performance.

Comparative secretome analysis of Streptomyces scabiei during growth in the presence or absence of potato suberin.

Background: Suberin is a recalcitrant plant biopolymer composed of a polyphenolic and a polyaliphatic domain. Although suberin contributes to a significant portion of soil organic matter, the biological process of suberin degradation is poorly characterized. It has been suggested that Streptomyces scabiei, a plant pathogenic bacterium, can produce suberin-degrading enzymes.

Response inhibition deficits in children with Fetal Alcohol Spectrum Disorder: relationship between diffusion tensor imaging of the corpus callosum and eye movement control.

Response inhibition is the ability to suppress irrelevant impulses to enable goal-directed behavior. The underlying neural mechanisms of inhibition deficits are not clearly understood, but may be related to white matter connectivity, which can be assessed using diffusion tensor imaging (DTI). The goal of this study was to investigate the relationship between response inhibition during the performance of saccadic eye movement tasks and DTI measures of the corpus callosum in children with or without Fetal Alcohol Spectrum Disorder (FASD).

FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing.

Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation.

We present a 4-year-old girl with profound global developmental delay and refractory epilepsy characterized by multiple seizure types (partial complex with secondary generalization, tonic, myoclonic, and atypical absence). Her seizure semiology did not fit within a specific epileptic syndrome. Despite a broad metabolic and genetic workup, a diagnosis was not forthcoming.

Clinical characteristics and outcome of patients with Clostridium difficile infection diagnosed by PCR versus a three-step algorithm.

Clinical features of Clostridium difficile infections (CDI) detected by PCR, but not by conventional methods, are poorly understood. We compared the clinical features of CDI cases detected by PCR only and cases detected by both PCR and a three-step algorithm. We performed a retrospective cohort study of patients fulfilling a standardized definition over a 13-month period.

Predicting visual semantic descriptive terms from radiological image data: preliminary results with liver lesions in CT.

We describe a framework to model visual semantics of liver lesions in CT images in order to predict the visual semantic terms (VST) reported by radiologists in describing these lesions. Computational models of VST are learned from image data using linear combinations of high-order steerable Riesz wavelets and support vector machines (SVM). In a first step, these models are used to predict the presence of each semantic term that describes liver lesions.

Structural degree predicts functional network connectivity: a multimodal resting-state fMRI and MEG study.

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales.

Acquisition strategy to reduce cerebrospinal fluid partial volume effects for improved DTI tractography.

Purpose: An acquisition method that does not increase scan time or specific absorption rate is investigated for reducing the deleterious effects of cerebrospinal fluid (CSF) partial volume effects on diffusion tensor imaging (DTI) tractography. It is based on using a shorter repetition time (TR) by means of slice acquisition re-ordering to reduce the signal of long T1 CSF and a non-zero minimum diffusion weighting (b-value) to attenuate rapidly diffusing CSF signal with respect to brain tissue.

Methods: A target reduction of the CSF/brain signal ratio from 3.

Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia.

Background: Sedaghatian-type spondylometaphyseal dysplasia (SSMD) is a neonatal lethal form of spondylometaphyseal dysplasia characterised by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. As part of the FORGE Canada Consortium we studied two unrelated families to identify the genetic aetiology of this rare disease.

Methods And Results: Whole exome sequencing of a child affected with SSMD and her unaffected parents identified two rare variants in GPX4.

Longitudinal MRI reveals impaired cortical thinning in children and adolescents prenatally exposed to alcohol.

Brain imaging studies suggest that cortical thickness decreases during childhood and adolescence, in concert with underlying structural and synaptic changes required for cognitive maturation and regional specialization of function. Abnormalities of this protracted developmental process may provide key insights into the cognitive and behavioral deficits that emerge in individuals with fetal alcohol spectrum disorders (FASD). Several studies have demonstrated cortical thickness differences in children and adolescents who were prenatally exposed to alcohol, though all have been cross sectional, limiting conclusions about cortical development with age.

Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease.

Background: Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy.

Case Presentation: We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia.

Disrupted anatomic white matter network in left mesial temporal lobe epilepsy.

Objective: Brain imaging studies have shown widespread structural abnormalities in patients with temporal lobe epilepsy (TLE) within and beyond the affected temporal lobe, suggesting an altered network. Graph theoretical analysis based on white matter tractography has provided a new perspective to evaluate the connectivity of the brain. The alterations in the topologic properties of a whole brain white matter network in patients with TLE remain unknown.

A hierarchical knowledge-based approach for retrieving similar medical images described with semantic annotations.

Computer-assisted image retrieval applications could assist radiologist interpretations by identifying similar images in large archives as a means to providing decision support. However, the semantic gap between low-level image features and their high level semantics may impair the system performances. Indeed, it can be challenging to comprehensively characterize the images using low-level imaging features to fully capture the visual appearance of diseases on images, and recently the use of semantic terms has been advocated to provide semantic descriptions of the visual contents of images.

In vivo double quantum filtered sodium magnetic resonance imaging of human brain.

Purpose: Sodium signal from ordered environments can be selectively detected using a double-quantum magic angle (DQ-MA) sequence. This study presents the first DQ-MA sodium images of the human brain and evaluates the effect of preparation time (τ) on the signal.

Theory And Methods: Three phantoms of saline, agar gel, and xanthan gum were used to test the correct functioning of the DQ-MA sequence.

The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome.

Background: Despite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as microcephaly, the number of possible genes that would require interrogation by Sanger sequencing is extensive and often prohibitively expensive.

Identification of genes for childhood heritable diseases.

Genes causing rare heritable childhood diseases are being discovered at an accelerating pace driven by the decreasing cost and increasing accessibility of next-generation DNA sequencing combined with the maturation of strategies for successful gene identification. The findings are shedding light on the biological mechanisms of childhood disease and broadening the phenotypic spectrum of many clinical syndromes. Still, thousands of childhood disease genes remain to be identified, and given their increasing rarity, this will require large-scale collaboration that includes mechanisms for sharing phenotypic and genotypic data sets.