A new ultra low-level HPGe activity counting setup in the Felsenkeller shallow-underground laboratory

A new ultra low-level counting setup has been installed in the shallow-underground laboratory Felsenkeller in Dresden, Germany. It includes a high-purity germanium detector (HPGe) of 163\% relative efficiency within passive and active shields. The passive shield consists of 45m rock overburden (140 meters water equivalent), 40 cm of low-activity concrete, and a lead and copper castle enclosed by an anti-radon box. The passive shielding alone is found to reduce the background rate to rates comparable to other shallow-underground laboratories. An additional active veto is given by five large plastic scintillation panels surrounding the setup. It further reduces the background rate by more than one order of magnitude down to 116$\pm$1 kg$^{-1}$ d$^{-1}$ in an energy interval of 40-2700 keV. This low background rate is unprecedented for shallow-underground laboratories and close to deep underground laboratories.Comment: Submitted to Astroparticle Physics; corrected typo in abstrac

Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy

An analysis-ready and quality controlled resource for pediatric brain white-matter research

We created a set of resources to enable research based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N = 2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available. Data quality plays a key role in the analysis of dMRI. To optimize QC and scale it to this large dataset, we trained a neural network through the combination of a small data subset scored by experts and a larger set scored by community scientists. The network performs QC highly concordant with that of experts on a held out set (ROC-AUC = 0.947). A further analysis of the neural network demonstrates that it relies on image features with relevance to QC. Altogether, this work both delivers resources to advance transdiagnostic research in brain connectivity and pediatric mental health, and establishes a novel paradigm for automated QC of large datasets

Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a

Mutations in the voltage-gated sodium channels SCN1A and SCN2A are responsible for several types of human epilepsy. Variable expressivity among family members is a common feature of these inherited epilepsies, suggesting that genetic modifiers may influence the clinical manifestation of epilepsy. The transgenic mouse model Scn2a Q54 has an epilepsy phenotype as a result of a mutation in Scn2a that slows channel inactivation. The mice display progressive epilepsy that begins with short-duration partial seizures that appear to originate in the hippocampus. The partial seizures become more frequent and of longer duration with age and often induce secondary generalized seizures. Clinical severity of the Scn2a Q54 phenotype is influenced by genetic background. Congenic C57BL/6J.Q54 mice exhibit decreased incidence of spontaneous seizures, delayed seizure onset, and longer survival in comparison with [C57BL/6J × SJL/J]F 1 .Q54 mice. This observation indicates that strain SJL/J carries dominant modifier alleles at one or more loci that determine the severity of the epilepsy phenotype. Genome-wide interval mapping in an N 2 backcross revealed two modifier loci on Chromosomes 11 and 19 that influence the clinical severity of of this sodium channel-induced epilepsy. Modifier genes affecting clinical severity in the Scn2a Q54 mouse model may contribute to the variable expressivity seen in epilepsy patients with sodium channel mutations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46986/1/335_2005_Article_49.pd

Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel α(1) subunit (Na(V)1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent, noninactivating channel activity resembling the pattern of channel dysfunction observed for alleles associated with generalized epilepsy with febrile seizures plus. Our data provide evidence for a range of SCN1A functional abnormalities in SMEI, including gain-of-function defects that were not anticipated in this disorder. Our results further indicate that a complex relationship exists between phenotype and aberrant sodium channel function in these inherited epilepsies

Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome

ObjectiveTo describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology.MethodsWe used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav 1.4.ResultsClinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav 1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics.InterpretationWe conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function