BACKGROUND Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02). CONCLUSIONS Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.)

Purpose: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. Methods: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.Results: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. Conclusions: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling. Genet Med 2006:8(12):784-792.

Background Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke (AIS) and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with AIS. Methods and Results Between 1/2003 and 7/2007, 30 centers within the International Pediatric Stroke Study (IPSS) enrolled 667 children (29 days-19 years of age) with AIS and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or post-varicella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56; 20%). Predictors of arteriopathy include early school age (5-9 years), recent upper respiratory infections (URI), and sickle cell disease, while prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent URI. Conclusions Arteriopathy is prevalent among children with AIS, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent URI predicted cerebral arteriopathy, and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.

Introduction We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings. Methods The “Vascular effects of Infection in Pediatric Stroke” (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (AIS) (2010–2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection, focal cerebral arteriopathy-inflammatory type (FCA-i, which includes transient cerebral arteriopathy, TCA), moyamoya, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype. Results Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya (n=34) occurred mostly in children <8 years old, FCA-i (n=25) in 8–15 year olds, and dissection (n=26) at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected cervical arteries, while moyamoya involved supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of FCA-i, but present in <25% of FCA-i cases; a small lenticulostriate distribution infarct was a more common predictor of FCA-i, present in 76%. It remained difficult to distinguish FCA-i from intracranial dissection of the anterior circulation (FCA-d). We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis. Conclusions Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of FCA.

Background and Purpose Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported five-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era. Methods The Vascular effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009–2014, and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of stroke etiologies, including arteriopathies. Other predictors were measured via parental interview or chart review. Results Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0–3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% CI 4.6–10%) at one month and 12% (8.5–15%) at one year. The sole predictor of recurrence was presence of an arteriopathy, which increased the risk of recurrence 5-fold compared to an idiopathic AIS (hazard ration 5.0, 95% CI 1.8–14). The one-year recurrence rate was 32% (95% CI 18–51%) for moyamoya, 25% (12–48%) for transient cerebral arteriopathy, and 19% (8.5–40%) for arterial dissection. Conclusions Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.

Background and Purpose-Stroke is an important cause of death and disability among children. Clinical trials for childhood stroke require a valid and reliable acute clinical stroke scale. We evaluated interrater reliability (IRR) of a pediatric adaptation of the National Institutes of Health Stroke Scale. Methods-The pediatric adaptation of the National Institutes of Health Stroke Scale was developed by pediatric and adult stroke experts by modifying each item of the adult National Institutes of Health Stroke Scale for children, retaining all examination items and scoring ranges of the National Institutes of Health Stroke Scale. Children 2 to 18 years of age with acute arterial ischemic stroke were enrolled in a prospective cohort study from 15 North American sites from January 2007 to October 2009. Examiners were child neurologists certified in the adult National Institutes of Health Stroke Scale. Each subject was examined daily for 7 days or until discharge. A subset of patients at 3 sites was scored simultaneously and independently by 2 study neurologists. Results-IRR testing was performed in 25 of 113 a median of 3 days (interquartile range, 2 to 4 days) after symptom onset.Patient demographics, total initial pediatric adaptation of the National Institutes of Health Stroke Scale scores, risk factors, and infarct characteristics in the IRR subset were similar to the non-IRR subset. The 2 raters' total scores were identical in 60% and within 1 point in 84%. IRR was excellent as measured by concordance correlation coefficient of 0.97 (95% CI Key Words: childhood Ⅲ ischemic stroke Ⅲ outcome Ⅲ stroke scale Ⅲ validation I schemic stroke affects 1.2 to 7.9 per 100 000 children aged 1 month to 18 years annually in Europe and North America and ranks among the top 10 causes of death. 1,2 Long-term motor and cognitive deficits interfering with activities of daily life and academic attainment affect 40% to 60% of survivors. 3 There are no proven strategies for acute management or prevention of childhood stroke other than blood transfusion for children with sickle cell anemia. Progress in defining factors that determine outcome and designing clinical trials are hindered by the lack of a validated and reliable clinical stroke scale. Previously published cohort studies of acute clinical presentation or long-term outcome in childhood stroke have not used standardized, validated, and reliable measures of clinical stroke severity at stroke onset. The National Institutes of Health Stroke Scale (NIHSS) is a quantitative measure of stroke-related acute neurological deficit, which has proven intra-and interrater reliability (IRR) and predictive validity for outcome among adults. 4 -6 Neurological examination of children requires adjustment according to the maturation of the child's neurological and cognitive function and ability to comprehend instructions. The objective of this study was to evaluate IRR of a pediatric modification of the NIHSS, the Pediatric NIHSS (PedNIHSS), administered by child neurologists in children with ac...

No abstract

Objective Pathogenic variants in KCNB1, encoding the voltage‐gated potassium channel KV2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell‐surface expression. Methods We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high‐throughput functional assays. Specifically, we investigated the biophysical properties and cell‐surface expression of variant KV2.1 channels expressed in heterologous cells using high‐throughput automated electrophysiology and immunocytochemistry–flow cytometry. Results Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild‐type KV2.1. Quantification of protein expression also identified variants with reduced total KV2.1 expression or deficient cell‐surface expression. Interpretation Our study establishes a platform for rapid screening of KV2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899–912