No abstract

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.

This study investigated the development of prospective memory using tasks based on the prefrontal-lobe model. Three groups each of 30 children, adolescents, and young adults were compared on prospective-memory performance using ongoing tasks with two levels of cognitive demand (low and high), and two levels of importance (unstressed and stressed) of remembering prospective cues. The Self-Ordered Pointing Task (SOPT), Stroop Color Word Interference Test, and Tower of London were also used to assess relationships between prospective memory and prefrontal-lobe functions. The children remembered fewer prospective cues than either the adolescents or adults, but the adolescents and adults remembered equally well. This trend increased significantly as the cognitive demand of the ongoing tasks increased. However, stressing or not stressing the importance of remembering made no difference to prospective-memory performance. Performance on the SOPT and Stroop Colour Word Interference predicted performance on the high- but not on the low-demand condition. These findings implicate the maturation of the brain's prefrontal region in the development of prospective memory.

Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five genes, each encoding a protein component of the sarcomeric thin filament. Recently, we identified mutations in the muscle alpha-skeletal-actin gene (ACTA1) in a subset of patients with NM. In the present study, we evaluated a new series of 35 patients with NM. We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha-skeletal actin account for the disease in approximately 15% of patients with NM. The mutations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission. The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical phenotype, among patients with different mutations in ACTA1 suggests that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha-actin genotype is not the sole determinant of phenotype.

We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(qll-13), spanning markers from D15S9 to D15S12, about 3*5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11*2 years (range 3 to 34 years). All patients were ataxic, severely retarded, and lacking recognisable speech. In all patients, head circumference (HC) at birth was normal but skewed in distribution, with 62-5% at the 10th centile. At last review HC was around the 50th centile in three patients (12-5%) while 15 had poor postnatal head growth. Short stature was not invariable, 5/26 (19%) were on or above the 50th centile. Hypotonia at birth was recorded in 15/24 (63%) and neonatal feeding difficulties were recorded in 20/26 (77%). Epilepsy was present in 26/27 (96%) with onset by the third year of life in 20 patients (83%). Improvement in epilepsy was reported in 11/16 patients (69%) with age. An abnormal EEG was reported in 25/25 patients. Hypopigmentation was present in 19/26 (73%). One patient had oculocutaneous albinism. Five patients could not walk independently. Of the remaining 22 who could walk, age of onset of walking ranged from 2 to 8 years. Disrupted sleep patterns were present in 18/ 21 patients (86%), with improvement in 9/ 12 patients (75%) over 10 years of age.The clinical features in this group of deletional AS patients were similar to previous reports, but these have not separated patients into subgroups based on DNA studies. In our group of deletional cases, 100% showed severe mental retardation, ataxic movements, absent language, abnormal EEG, happy disposition (noted in infancy in 95%), normal birth weight and head circumference at birth, and a large, wide mouth. These features occurred with a higher frequency than in AS patients as a whole. Our study also provided information on the evolution of the phenotype. The data can act as a benchmark for comparisons of AS resulting from other genetic mechanisms.

Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.

This study investigated the effects of pediatric traumatic brain injury (TBI) on prospective memory. Fourteen children and 14 adolescents with TBI were compared with 25 and 23 noninjured children and adolescents, respectively. Based on a prefrontal model, the cognitive demand on the ongoing component of a prospective-memory task was manipulated. Overall, those with TBI had poorer prospective-memory performance than their noninjured peers. Performance was worse in a high cognitive-demand condition than a low, and younger children performed worse than adolescents. Decreases in performance from the low- to high-demand conditions were not significantly different between the two children's groups but were between the two adolescents' groups. Furthermore, the age and injury effects were reflected in the performances on executive function tests: the Self-ordered Pointing Task (SOPT), and the Stroop Color Word Interference Test. The Tower of London (TOL), which did not produce age or injury effects, was nevertheless found to be an important predictor of performance on the high-demand task in those with TBI. Although previous research has demonstrated impaired prospective memory performance in children with TBI, this study attempted to explain why this might occur, specifically that the prefrontal regions might be implicated.

SummaryHeterozygous de novo variants in the autophagy gene, WDR45, are found in betapropeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences. K E Y W O R D Sde novo variant, genetics, magnetic resonance imaging, DEE Aijie Liu, Simone Mandelsta, and Amy Schneider are equal second authors. Yue-Hua Zhang, Heather C. Mefford, and Ingrid E. Scheffer are equal coauthors.