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Objective: Responsive neurostimulation (RNS) is a US FDA-approved form of neuromodulation to treat patients with focal-onset drug-resistant epilepsy (DRE) who are ineligible for or whose condition is refractory to resection. However, the FDA approval only extends to use in patients with one or two epileptogenic foci. Recent literature has shown possible efficacy of thalamic RNS in patients with Lennox-Gastaut syndrome and multifocal epilepsy. The authors hypothesized that RNS of thalamic nuclei may be effective in seizure reduction for patients with multifocal or regionalized-onset DRE., Methods: The authors performed a retrospective chart review of all patients who had an RNS device managed at Texas Children's Hospital between July 2016 and September 2023, with at least one active electrode in the thalamic nuclei and ≥ 12 months of postimplantation follow-up. Information conveyed by the patient or their caregiver provided data on the change in the clinical seizure frequency, quality of life (QOL), and seizure severity between the preimplantation baseline visit and the last office visit (LOV)., Results: Thirteen patients (ages 8-24 years) were identified with active RNS leads in thalamic nuclei (11 centromedian and 2 anterior nucleus). At LOV, 46% of patients reported 50%-100% clinical seizure reduction (classified as responders), 15% reported 25%-49% reduction, and 38% reported < 25% reduction or no change. Additionally, 42% of patients reported subjective improvement in QOL and 58% reported improved seizure severity. Patients with focal cortical dysplasia (FCD) responded strongly: 3 of 5 (60%) reported ≥ 80% reduction in seizure burden and improvement in seizure severity and QOL. Patients with multifocal epilepsy and bilateral thalamocortical leads also did well, with all 3 reporting ≥ 50% reduction in seizures., Conclusions: RNS of thalamic nuclei shows promising results in reducing seizure burden for patients with multifocal or regional-onset DRE, particularly in a bilateral thalamocortical configuration or when addressing an underlying FCD.

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder., (© 2023 Wiley Periodicals LLC.)

Purpose: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD., Methods: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review., Results: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation., Conclusion: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises., Competing Interests: Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Genetics. S.A.M. serves as Scientific Advisor and consultant for Aytu BioPharma, Inc for the AR101 Enzastaurin Clinical Trial. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking., Objective: The purpose of this study was to describe TDD-related cardiac crises., Methods: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises., Results: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504-600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events., Conclusion: TDD-related cardiac crises are associated with a high risk of arrhythmias, cardiomyopathy, cardiac arrest, and death. Although further studies are needed, early recognition and appropriate treatment are critical. Acutely, intravenous magnesium, isoproterenol, atrial pacing, and ECMO as a last resort seem to be the best current treatment options, and early initiation of feeds may prevent VT events., (Copyright © 2022. Published by Elsevier Inc.)

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals., (© 2020 SSIEM.)

Objectives: The Galápagos provides an important setting to investigate the health impacts of a new drinking water treatment plant (DWTP) in a limited resource environment. We examine how household perceptions and practices affect the relationship between water quality and infections before and after DWTP., Methods: Ethnographic data and self-reported infections were collected from 121 mothers and 168 children ages 2 to 10 from Isla San Cristóbal. Household tap water samples were tested for levels of fecal contamination. Community level infection rates were estimated using discharge records from the Ministry of Public Health. The effects of the new DWTP and fecal contamination levels on infections were tested using logistic and Poisson models., Results: Perceptions of water quality and household practices influenced exposures to contaminated tap water. We found minimal change in drinking water sources with 85% of mothers sampled before the DWTP and 83% sampled after using bottled water, while >85% from the pooled sample used tap water for cooking and hygiene practices. The DWTP opening was associated with lower odds of fecal contamination in tap water, reported urinary infections, and community level rates of urinary and gastrointestinal infections. The household practice of recently washing the cistern contributed to higher contamination levels after the DWTP opened., Conclusions: To ensure access to clean water, public health works need to consider how household perceptions and practices influence tap water use and quality, in addition to infrastructure improvements. Exposures to contaminated tap water contribute to the burden of infectious disease in environments with inadequate water infrastructure., (© 2019 Wiley Periodicals, Inc.)

Background: Ecuador's cesarean delivery rate far exceeds that recommended by the Pan American Health Organization (PAHO) and the World Health Organization (WHO). Using data from three iterations of Ecuador's nationally representative, population-based survey Encuesta Nacional de Salud y Nutrición (ENSANUT/ENDEMAIN), spanning 23 years, this study examines women's mode of delivery outcomes by sociodemographic characteristics and hospital type (private, public, social security) in light of Ecuador's major health care reform over the past two decades., Methods: Using data from the 1994, 2004, and 2012 iterations of the data set, we analyzed trends in cesarean delivery based on province, year, and institution of care. Logistic regression was used to test the odds of cesarean delivery based on hospital type, sociodemographics, and birth complications for the full sample and primiparous women. Predicted probabilities were derived from this model., Results: Ecuador's cesarean rate increased from 22% in 1989 to 41% in 2012. From 2008 to 2012, the probability of cesarean delivery in private centers was significantly higher than in public centers, and from 2009 to 2012, the probability of cesarean delivery in social security centers was significantly higher than in public centers. Higher maternal age, income, education, and parity, earlier prenatal care initiation, and more prenatal visits were associated with risk for cesarean delivery., Conclusions: To decrease the adverse effects of cesarean delivery for women and their babies, cesarean delivery should be reduced. Future research should investigate how incentive structures are used and how medical indication is defined within health institutions in Ecuador., (© 2019 Wiley Periodicals, Inc.)

Objectives: Global increases in caesarean deliveries are exposing more infants to perinatal environments that are evolutionarily novel and potentially increasing their risks for inflammatory conditions. Yet, the pathways linking caesareans to later health outcomes are not well understood, particularly in dual burden contexts. We test two of the hypothesized pathways, altered immune function and gut microbiota, which may link delivery mode to later health outcomes and test whether these associations persist when controlling for postnatal nutritional and pathogenic exposures., Methods: Data come from infants, aged 0 to 2 (n = 41), and young children, aged 2 to 11 (n = 135), from the Galápagos, Ecuador. Differences in morbidity, C-reactive protein (CRP), and gut microbiota by delivery type were tested using linear and logistic regression models adjusted for nutritional and pathogenic exposures and infant age., Results: Over half of infants and over 40% of children were delivered by caesarean. Morbidity and CRP did not differ between infants or children born by caesarean or vaginally. Microbial taxa abundance differed by delivery mode. Infants born by caesarean had a higher abundance of Firmicutes and a lower relative abundance of Bacteroidales. Children born by caesarean had a higher abundance of Proteobacteria and Enterobacteriales. These differences remained after adjustment for environmental exposure., Conclusions: Caesarean delivery is associated with differences in gut microbiota across childhood even in this dual burden context. Our results highlight the importance of examining caesarean delivery across diverse contexts to better understand the impact of perinatal interventions on short- and longer-term health outcomes., (© 2019 Wiley Periodicals, Inc.)

Antibody-mediated encephalopathies associated with serum or cerebrospinal fluid antibodies directed against neuronal structures may present with a multitude of neuropsychiatric syndromes. Although some of the antibody-driven conditions are now well recognized in adults (eg, N-methyl-D-aspartate receptor antibody encephalitis), the spectrum of neuropsychiatric manifestations in the pediatric population is less clear. Psychosis, confusion, catatonia, and additional behavioral changes, along with seizures, encephalopathy, and movement disorders, may be initial manifestations or concurrent features in all age groups. Psychosis, when present, is often part of a broader spectrum of neurological and neuropsychiatric symptoms for which the diagnosis of autoimmune encephalitis is considered. The authors present the case of an adolescent with an acute and isolated psychotic presentation of voltage-gated potassium channel antibody encephalitis, further expanding the phenotypic spectrum of this specific antibody-mediated disease and raising the possibility that specific immune-mediated processes may define a biological subgroup of psychoses.

Piped drinking water is often considered a gold standard for protecting public health but research is needed to explicitly evaluate the effect of centralized treatment systems on water quality in developing world settings. This study examined the effect of a new drinking water treatment plant (DWTP) on microbial drinking water quality at the point-of-use on San Cristobal Island, Galapagos using fecal indicator bacteria total coliforms and Escherichia coli. Samples were collected during six collection periods before and after operation of the DWTP began from the freshwater sources (n=4), the finished water (n=6), and 50 sites throughout the distribution system (n=287). This study found that there was a significant decrease in contamination by total coliforms (two orders of magnitude) and E. coli (one order of magnitude) after DWTP operation began (p<0.001). However, during at least one post-construction collection cycle, total coliforms and E. coli were still found at 66% and 28% of points-of-use (n=50), respectively. During the final collection period, conventional methods were augmented with human-specific Bacteroides assays - validated herein - with the goal of elucidating possible microbial contamination sources. Results show that E. coli contamination was not predictive of contamination by human wastes and suggests that observed indicator bacteria contamination may have environmental origins. Together these findings highlight the necessity of a holistic approach to drinking water infrastructure improvements in order to deliver high quality water through to the point-of-use., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

We examine the associations between overall urbanicity and specific physical and social components of community-level urbanization with C-reactive protein (CRP) in adults participating in the China Health and Nutrition Study. Higher overall urbanicity and environment-related urbanicity component scores, including education, housing quality, and access to markets, were associated with elevated CRP in multilevel models controlling for clustering by community. These associations differed by age and gender and persisted after controlling for individual-level anthropometric, diet, and pathogenic risk factors. These results highlight the importance of place in relation to inflammation across the spectrum of rural and urban environments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Influenced by pathogen exposure and obesity, inflammation provides a critical biological pathway linking changing environments to the development of cardiometabolic disease. This study tests the relative contribution of obesogenic and pathogenic factors to moderate and acute CRP elevations in Chinese children, adolescents and adults., Methods: Data come from 8795 participants in the China Health and Nutrition Study. Age-stratified multinomial logistic models were used to test the association between illness history, pathogenic exposures, adiposity, health behaviors and moderate (1-10 mg/L in children and 3-10 mg/L in adults) and acute (>10mg/L) CRP elevations, controlling for age, sex and clustering by household. Backward model selection was used to assess which pathogenic and obesogenic predictors remained independently associated with moderate and acute CRP levels when accounting for simultaneous exposures., Results: Overweight was the only significant independent risk factor for moderate inflammation in children (RRR 2.10, 95%CI 1.13-3.89). History of infectious (RRR 1.28, 95%CI 1.08-1.52) and non-communicable (RRR 1.37, 95%CI 1.12-1.69) disease, overweight (RRR 1.66, 95%CI 1.45-1.89) and high waist circumference (RRR 1.63, 95%CI 1.42-1.87) were independently associated with a greater likelihood of moderate inflammation in adults while history of infectious disease (RRR 1.87, 95%CI 1.35-2.56) and overweight (RRR 1.40, 95%CI 1.04-1.88) were independently associated with acute inflammation. Environmental pathogenicity was associated with a reduced likelihood of moderate inflammation, but a greater likelihood of acute inflammation in adults., Conclusions: These results highlight the importance of both obesogenic and pathogenic factors in shaping inflammation risk in societies undergoing nutritional and epidemiological transitions., (Copyright © 2013 Wiley Periodicals, Inc.)