Clinical spectrum of STX1B-related epileptic disorders

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies

Clinical spectrum of STX1B-related epileptic disorders

Objective The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin- 1B, and establish genotype-phenotype correlations by identifying further disease related variants. Methods We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies

Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies

Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype–phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype–phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations

Chromium toxicity: spectral and electrochemical studies of Cr(VI) reduction by biomimicking molecules

The reductive abilities of a variety of biomimicking molecules, including OH-containing ones such as, saccharides and their derivatives, nucleotides and their components and mixed group ligands have been determined in vitro using absorption spectra and electrochemical characterisations and were explained based on the nature of the reductants. While the reductive coefficients of these molecules showed a linear correlation with respect to oxidation potential of the ligand (EaP) and/or reduction potential (Ecp) of the final Cr(III)-products, in any given set, such as hexoses, pentoses, polyols, glycols, saccharide derivatives, nucleotides and their components and mixed group ligands, the plot of all the reductants reported in this paper exhibited interesting correlations with respect to these electrochemical parameters. These correlations are expected to be important in the identification of species in routine analysis carried out with pollutants. As reduction of Cr(VI) to Cr(III) by saccharides and their derivatives progresses via soluble and reactive intermediates of Cr(V) having long t½ periods, this may be implicated in the transport of toxic chromium salts from soil to plants and their ultimate entry into the biosphere causing ecological hazards. Based on the results obtained on chromate reduction studies, a working model has been proposed for the toxicity of Cr(VI)

Chromate reductase activity: characterization of Cr(VI) to Cr(III) conversion

In order to understand chromate reductase activity (CRA), related to cellular carcinogenecity and metal toxicity in ecological systems, we began studying the reduction of chromium(VI) salts using cysteine, ascorbic acid and several monosaccharides mainly through EPR and absorption spectroscopic methods. The present study indicates Cr(V) as a definite intermediate and also shows the relative trends of reducing capabilities among various reducing agents employed. Considerable progress has been achieved in the isolation of intermediates and final products as well

In vitro reducing abilities towards chromate of various hydroxy-containing compounds, including saccharides and their derivatives

The reduction of potassium chromate has been carried out with a variety of OH-containing compounds as reductants, which include pentoses, polyols, glycols, and sugar derivatives. The corresponding reactions were followed using UV-vis and EPR spectroscopies and electrochemistry. The progress of the chromate reduction reactions has been monitored by measuring UV-vis and EPR spectra as a function of time. The observed pseudo first-order reaction rate constants are derived based on the changes in the intensities of the Cr(VI), Cr(V), and Cr(III) signals. Cyclic voltammograms of the simple reductants and their final Cr(III) products formed from the reactions of chromate have also been measured. The reductive abilities of all these reductants have been derived from the spectral data and are discussed on a comparative basis. Based on the results, the aspects that makes a particular reductant more efficient has been addressed. The results obtained from UV-vis, EPR, and cyclic voltammetry are found to be mutually dependent and exhibit among themselves a linear correlation, suggesting that both the reducing and complexing nature of these molecules play important roles in the chromate reduction

Transition-metal saccharide chemistry and biology: synthesis, characterisation, redox behaviour, biointeraction and data correlations of dinuclear chromium(III) complexes

A series of dinuclear chromium(III) complexes has been synthesised by reduction of chromate by a variety of saccharides and related compounds. The complexes have been characterised by various analytical (elemental and ICP-AES analysis, TLC, HPLC) and spectroscopic (UV/VIS, FTIR, EPR, 1H and 13C NMR) methods. Antiferromagnetic interactions between the two CrIII centres have been established by magnetic susceptibility measurements and the hydrolytic stability and redox behaviour of the complexes have been established by extensive electrochemical studies which gave several correlations. The interaction of some of the complexes with DNA has been studied by gel electrophoresis

Transition metal saccharide chemistry: synthesis, spectroscopy, electrochemistry and magnetic studies of chromium(III)-hexose complexes and their in vitro interaction with DNA

Saccharide complexes of CrIII were synthesized via chromate reduction. Hexose monosaccharides such as D-glucose, D-fructose, D-galactose, D-mannose and L-sorbose and some acid derivatives, such as D-galacturonic acid and D-gluconic acid, were used. The final CrIII products were isolated, purified and characterized by various analytical, spectroscopic, magnetic and electrochemical methods. All the products reported here are shown to be dinuclear in nature. The inherent stability and robust nature of these complexes is demonstrated and they are shown to affect the pSV2 neo plasmid (DNA) structure in gel electrophoretic experiments

The efficiency of root canal disinfection using a diode laser: In vitro study

Aims: The aim of this study is to verify the disinfection of diode laser, following chemo-mechanical procedures against Enterococcus fecalis. Materials and Methods: Crowns of 30 extracted premolar teeth were sectioned at the cemento- enamel junction. The canals were shaped using step-back technique to K-file #40. The teeth were randomly assigned to three groups and placed into nutrient broth containing bacterial suspension of Enterococcus fecalis. Group A received no laser radiation. Specimens of group B and C were treated with diode laser (Sirona) with energy set at 1.5 and 3 W, respectively. After laser irradiation, the teeth were placed in vials, which contained 2 mL of the nutrient broth. The vials were incubated at 37°C for 24 h. Grown colonies were identified by standard methods. Statistical Analysis Used: Statistical analysis used was the nonparametric Kruskal-Wallis test, with comparison using the Bonferroni methods of means. Results: Higher mean CFU/mL is recorded in Group A (without laser disinfection) followed by Group B (with 1.5 W laser disinfection) and Group C (with 3 W laser disinfection), respectively. The difference in CFU/mL between the three groups is found to be statistically significant ( P < 0.001). Conclusions: The results of this research show that the 980 nm diode laser can eliminate bacteria that has immigrated into dentin, thus being able to increase the success rate in endodontic therapy