No abstract

Summary Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype–phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.

No abstract

MRI diagnostic criteria are proposed that may be useful in differentiating children experiencing the first attack of multiple sclerosis from those with monophasic acute disseminated encephalomyelitis.

Coffin–Siris and Nicolaides–Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.

The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia.

We propose modifications to the currently established McDonald MRI criteria for lesion dissemination in space that will enhance the diagnostic accuracy of these criteria for multiple sclerosis in children.

Although cerebral sinovenous thrombosis (CSVT) is an uncommon disorder in neonates, the incumbent morbidity, mortality, and adverse neurodevelopmental sequelae highlight the importance of establishing an early diagnosis with an appropriate therapeutic plan. The clinical signs and symptoms of the condition are subtle and invariably masquerade under the umbrella of a broad spectrum of neonatal illnesses. A high index of diagnostic suspicion is essential for investigating and initiating treatment in a timely fashion before major complications ensue. Recent advances in accessible radiographic techniques with reduced radiation exposure have facilitated rapid diagnosis of thrombosis in both the superficial and deep plexuses of the cerebral venous systems. The absence of large-scale randomized trials and solid prospective smaller-sample-sized studies of neonates with CSVT has compromised our ability to develop efficacious treatment decisions. In this review of the scientific literature we offer understanding of the complex etiology of CSVT and inherent problems involved in the diagnosis and treatment of the disorder and focus on the limitations in current follow-up. An approach to neonatal CSVT is proposed on the basis of the available evidence from guidelines, registries, prospective and retrospective infant studies, and case series.