The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

[Completion of the dog toxicity project at the University of Utah: statistical comparison]

Radium (Ra) toxicity in dogs is a cornerstone for the evaluation of plutonium (Pu) toxicity, as it provides a possible link to Pu toxicity in humans. Survival regression models with covariates were used to estimate the risk to survival and the frequency and latency of bone tumor development. It appears for Ra that dose-rate is a more significant contributor to non-survival and bone tumors than is skeletal dose

Evaluation of ion projection using heavy ions suitable for resistless patterning of thin magnetic films

The ion projector at the Fraunhofer Institute ISiT has been used for the development of patterned magnetic media for potential future use in magnetic hard disk drives. By 8.8 times demagnification of an open stencil mask, magnetic contrast is generated by ion intermixing of Co/Pt sandwich layers. In this application a resist process is not necessary and the surface roughness of magnetic media is not altered. Monte Carlo simulations of the intermixing process with the dynamic T-Dyn software for H, He, Ne, Ar and Au ions show that the exposure dose can be reduced by a factor of 100 by irradiation with Ar+ ions instead of He+. This has been confirmed by magnetic force microscopy of 200 nm magnetic dots irradiated at a dose of 6×1013 Ar+/cm2 at 73 keV energy. Sufficient stability of the ion optical system concerning resolution and drift has been demonstrated by exposures in developed and undeveloped (latent image) resist down to 60 nm dots

ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric alpha-beta-gamma protein complex. The alpha 3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum

Nanopatterning of magnetic disks by single-step Ar+ Ion projection

Large-area Ar+ projection has been used to generate planar magnetic nanostructures on a 1¿-format hard disk in a single step (see Figure). The recording pattern was transferred to a Co/Pt multilayer without resist processes or any other contact to the delicate media surface. It is conceivable that magnetic nanostructures can be replicated from a single stencil mask on large quantities of disks for future high-density recording

Ion projection direct structuring for patterning of magnetic media

Ion projection facilitates a direct structuring, which is an attractive potential manufacturing process for patterned storage media. An advantage to this method is that the media roughness remains unchanged. The feasibility of ion projection direct structuring for processing full disk surfaces was investigated using a next generation lithography projector. Co-Pt multilayer films with strong perpendicular anisotropy were deposited on 1-in glass disks as used in the IBM microdrive and on Si substrates. Concentric tracks including data, as well as head positioning servo structures, were patterned in a single exposure step with 45 keV He+ at a 4 × demagnification. In a second experiment, sub-100-nm magnetic islands were produced using projection at 8.7 × demagnification and visualized by magnetic force microscopy